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Prendergast, Catriona Taguma. "Exploring the pathogenic potential of myelin-reactive Th1 and Th17 cells in central nervous system autoimmune disease". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5285.
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The activation of naïve T cells results in their proliferation and differentiation into a particular T-helper (Th) phenotype, namely Th1, Th2 or Th17 cells. This thesis focuses on the role of pro-inflammatory Th1 and Th17 cells in the induction of autoimmune disease of the central nervous system (CNS), using murine experimental autoimmune encephalomyelitis (EAE) as the model. Classically, EAE has been considered to be a Th1-mediated disease. However, since the emergence of the Th17 cells, there has been a paradigm shift towards Th17 cells being the key pathogenic subset in autoimmune disease. This thesis established robust protocols for the differentiation of naïve T cells into myelin-reactive Th1 or Th17 cells, producing ‘clean’ populations devoid of any contaminating cells. Passive T cell-transfer experiments revealed that myelin-reactive Th1 cells could induce EAE, whereas Th17 cells could not. This lack of disease correlated with the inability of the Th17 cells to accumulate in the non-inflamed CNS. Myelin-reactive Th1 cells did have this capability and only once inflammation was established, could Th17 cells be identified in the CNS, potentially exacerbating the disease. After these differences were observed, the project investigated two main aims: 1) to identify differences in homing molecule expression on Th1 and Th17 cells which could explain the difference in their ability to home to the CNS, and to investigate the functional significance of such differences, by molecular blockade; 2) to investigate the requirements for three key cytokines in EAE pathogenesis in passive T cell transfer models, investigating IFN-γ,IL-17 and TNF-α. P-selectin glycoprotein ligand-1 appeared to be important for the initial entry of inflammatory T cells into the CNS. Th1 cells deficient in IFN-γ were capable of IFNinducing EAE. A proportion of the mice developed “atypical” clinical signs, which correlated with T cell infiltration predominantly of the brain, rather than the spinal cord. This atypical EAE may be IL-17 dependent. In conclusion, this thesis indicates the importance of not focusing all resources and therapeutic approaches on Th17- induced inflammation as Th17 cells may not play such a major role as previously thought.
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Costa, Fernando Augusto Miranda da. "Resposta imune in vitro aos antígenos de Papilomavírus Humano (HPV) em homens na cidade de São Paulo, Brasil". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-04022014-155625/.
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Introdução: O Papilomavírus Humano está muito bem associado com diversos tipos de cânceres humanos, como câncer anogenital e oral. Alguns estudos demonstram que o aparecimento de lesões e a progressão para o câncer estão relacionados ao tipo de resposta imune do hospedeiro. Deste modo, evidências indicam que a resposta imune do hospedeiro tem um papel muito importante para o curso da infecção pelo HPV. Objetivo: Avaliar a resposta imune específica in vitro ao Papilomavírus Humano (HPV) em homens com lesões causadas por HPV e sem lesão por HPV. Material e Métodos: Foram recrutados 31 pacientes e 11 voluntários, que formaram 4 grupos de estudo; sendo 12 pacientes no Grupo A (HIV +/ HPV +); 09 pacientes no Grupo B (HIV-/HPV+); 10 pacientes no Grupo C (HIV+/ HPV-); e 11 indivíduos saudáveis no Grupo D (HIV-/HPV-). Foram realizados ensaios de cultura celular para mensurar a resposta celular específica \"in vitro\" do tipo Th1/Th2/Th17 (INF-y, IL-2, TNFalfa, IL-4, IL-10 e IL-17) sob o estímulo da vacina quadrivalente do HPV (HPV 6, 11, 16 e 18) e à proteína E7 de HPV-16. Resultados: O grupo coinfectado (HIV +/ HPV+) apresentou níveis mais elevados de citocinas, principalmente do perfil Th2, comparando-se com os dados dos demais grupos de estudo. O grupo coinfectado apresentou níveis elevados de IL-6 e IL-10 (Perfil Th2) em relação ao grupo controle (HIV-/HPV-), com significância estatística (p < 0.0001 e p < 0.0001, respectivamente). Conclusão: Foi demonstrada uma elevada produção de citocinas no grupo HPV+/HIV+, sugerindo uma forte imunomodulação pela coinfecção HIV/HPV. Entretanto, novos estudos devem ser realizados para comprovar estes dados. Além de apresentar um perfil essencialmente Th2 do grupo coinfectado, principalmente pelos níveis elevados de IL-6 e IL-10 apresentados, sugerindo que estas duas citocinas possam servir como biomarcadores para persistência viral, uma vez que, os pacientes soropositivos para HIV apresentam maior persistência de HPV, e monitorar a progressão para lesões mais gravesIntroduction: Human Papillomavirus is associated with different types of human cancers, such as anogenital and oral cancer. Some studies show that the appearance of lesions and progression to cancer are related to the type of host immune response. Thus, evidence indicates that the host immune response has a role key in the course of HPV infection. Objective: To evaluate the specific immune response in vitro to HPV in men with lesions caused by HPV and without injury caused by HPV. Methods: We recruited 31 patients and 11 volunteers, who formed four groups, with 12 patients in Group A (HIV+/HPV+); 09 patients in Group B (HIV-/HPV+); 10 patients in Group C (HIV+/HPV-) and 11 healthy subjects in Group D (HIV-/HPV-). Cells culture assay was performed to measure the specific immune response \"in vitro\" Th1/Th2/Th17 (IFN-y, IL-2, TNF-alfa, IL-4, IL-10 and IL-17) under the stimulation of quadrivalent HPV vaccine (HPV 6, 11, 16 and 18) and the E7 protein of HPV-16. Results: The coinfected group (HIV+/HPV+) had higher levels of cytokines, especially Th2 profile, compared with data from the other study groups. The coinfected group showed high levels of IL-6 and IL-10 (Th2 profile) compared to the control Group (HIV- /HPV-), with statistical significance (p < 0.0001 and p < 0.0001, respectively). Conclusion: This study demonstrated a high production of cytokines in the coinfected group, suggesting a strong immunomodulation by coinfection HIV/HPV. However, further studies should be conducted to confirm these data. In addition to presenting essentially a Th2 profile, especially by high levels of IL-6 and IL-10 presented, suggesting that these two cytokines may serve as biomarkers for viral persistence, since HIV seropositive patients have a higher persistence of HPV, and monitor the progression to more serious injuries
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Zhang, W., X. Tian, F. Mumtahana, J. Jiao, T. Zhang, K. D. Croce, D. Ma, B. Kong y B. Cui. "The existence of Th22, pure Th17 and Th1 cells in CIN and Cervical Cancer along with their frequency variation in different stages of cervical cancer". BioMed Central Ltd, 2015. http://hdl.handle.net/10150/610273.
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BACKGROUND: Recently, it is found that T-helper (Th) 22 cells are involved in different types of autoimmune and tumor diseases. But, till now, no study has been carried out to understand the involvement of these cells in cervical cancer (CC). METHODS: Flow cytometry was used to determine the expression of interferon gamma (IFN-gamma), Interleukin-22 (IL-22), IL-17 in the peripheral blood of healthy controls (HC), CIN and cervical cancer patients. From peripheral blood mononuclear cells (PBMCs), mRNA expression levels of Aryl hydrocarbon receptor (AHR), RAR-related orphan receptor C (RORC), TNF-alpha and IL-6 were respectively determined. Using the method of ELISA, plasma concentrations of IL-22, IL-17 and TNF-alpha were examined. RESULTS: Th22 and Th17 cells were elevated in CC and CIN patients. Th1 cells and the plasma concentrations of IL-22 in CC patients were significantly increased compared with HC. In CC patients, an increased prevalence of Th22 cells was associated with lymph node metastases. There was a positive correlation between Th22 and Th17 cells, but an approximately negative correlation between Th22 and Th1 cells in CC patients. The mRNA expression of RORC, TNF-alpha and IL-6 was significantly high in CC patients. CONCLUSIONS: Our results indicate that there is a higher circulatory frequency of Th22, Th17 and Th1 cells in CC which may conjointly participate in the pathogenesis and growth of CC.
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Pereira, Leonardo Biscaro. "Avaliação do perfil de citocinas no tecido subcutâneo de camundongos na presença de cimento endodôntico". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/58/58135/tde-03102013-151254/.
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Avaliou-se a capacidade dos cimentos endodônticos: Sealapex®, Activ-GP® e AH-Plus® de alterarem o perfil das citocinas nas respostas Th1, Th2 e Th17, após a implantação destes em subcutâneo de camundongos. A quantificação das citocinas IL-2, IL-6, TNF-α, IFN-γ, IL-4, IL-10 e IL-17 foi realizada in vivo, no tecido reacional circundante aos implantes, os quais foram confeccionados a partir de sondas nasogástricas estéreis e apirogênicas de cloreto de polivinila preenchidas com os cimentos, tendo um grupo controle com sondas vazias. Utilizou-se camundongos isogênicos da linhagem C57BL/6 machos de 6/8 semanas de vida sendo que cada um recebeu 2 implantes na região dorsal (lado direito e esquerdo). Após os períodos experimentais de 7, 21 e 63 dias, com os camundongos anestesiados, os implantes foram removidos juntamente com o tecido circundante, e os animais sacrificados em seguida por deslocamento cervical. As amostras de cada grupo foram divididas sendo: duas, contendo implante/tecido, processadas histotecnicamente e as demais com apenas tecido (sem implante) foram homogeneizadas e centrifugadas com solução formada por tampão RIPA e inibidor de protease. O sobrenadante, fruto deste processo, foi coletado e a dosagem das citocinas realizada através do kit CBA mouse-Th1/Th2/Th17 Cytokine Kit (BD Cytometric Bead Array, San Jose, CA, USA) em análise por citometria de fluxo. Os parâmetros avaliados foram a concentração da citocina em função do cimento testado em cada período experimental. Submeteu-se os resultados à análise estatística por meio do teste t com a correção de Welch\'s. Para todos os testes o nível de significância foi de 5%. Com relação à IL-2 houve diferenças estatísticas significantes entre os grupos Activ-GP® e AH-Plus® (p=0,0391). No período de 21 dias foram detectadas diferenças entre o grupo controle e AH-Plus® (p=0,0402) e entre o grupo Sealapex® e AH-Plus® (p=0,0244). O AH-Plus® induziou um maior aumento na IL-6, aos 7 dias em relação ao Activ-GP® (p=0,0286) e aos 21 dias entre o grupo controle (p=0.0402) e Activ-GP® (p=0.0244). Os níveis de TNF-α foram estatisticamente superiores após 7 dias quando comparou-se o grupo AH-Plus® com os demais. Observou-se que no grupo controle aos 7 e 21 dias ocorreram diferenças estatísticas em relação ao Sealapex® e AH-Plus® respectivamente quando avaliadas as concentrações de IFN-γ. Houve também diferenças estatísticas entre o grupo controle e Sealapex® (p=0,0158) no período de 7 dias para a citocina IL-4. Os valores de IL-10 foram estatisticamente superiores para o grupo controle em relação ao Activ-GP® no período de 21 dias (p=0,0471). Com relação a IL-17 no período de 21 dias, observou-se os maiores valores para o grupo controle, seguido pelo Sealapex®, Activ-GP® e AH-Plus®. Foram detectadas diferenças entre os grupos controle e AH-Plus® (p=0,0121), controle e Activ-GP® (p=0,0262) e entre Sealapex® e Activ GP® (p=0,0314). Baseado nesses resultados podê-se concluir que: os cimentos endodônticos são capazes de modular as respostas Th1, Th2 e Th17 através da inibição ou estimulação da liberação das citocinas testadas. O cimento AH-Plus® promoveu as maiores diferenças no perfil de resposta Th1.It was evaluated the capacity of the following endodontic sealers: Sealapex, Activ-GP and AH-Plus to modify the cytokine profile in Th1, Th2 and Th17 responses, after their implantation in the subcutaneous tissue of mice. Quantification of IL-2, IL-6, TNF-α, IFN-γ, IL-4, IL-10 and IL-17 was performed in vivo, in the reactional tissue surrounding the implants, which were made from sterile nasogastric probes and apyrogenic of polyvinyl chloride filled with sealer, and a control group of empty probes. It was used isogenic mice of C57BL/6 lineage, 6/8 weeks old males, each of which received two implants in the dorsal region (left and right). After the experimental time of 7, 21 and 63 days, the mice were anesthetized and the implants were removed along with the surrounding tissue, the animals were then sacrificed by cervical dislocation. Samples from each group were divided as follows: two containing implant / tissue processed histologically and with only the remaining tissue (without implant) were mixed and centrifuged with a solution formed by RIPA buffer and protease inhibitors. The supernatant result of this process was collected and cytokine dosage accomplished by mouse-Th1/Th2/Th17 Cytokine CBA Kit Kit (BD cytometric Bead Array, San Jose, CA, USA) for flow cytometry analysis. The evaluated parameters were the cytokine concentration in function of sealer tested in each trial. The results were submitted to statistical analysis using the t test with Welch\'s correction. For all tests the significance level was 5%. With respect to IL-2 there were significant statistical differences between groups-Activ GP and AH-Plus (p=0.0391). In the period of 21 days differences were found between the control group and AH-Plus (p=0.0402) and between the group Sealapex and AH-Plus (p=0.0244). The AH-Plus induced a greater increase in IL-6, at 7 days compared to Activ-GP (p=0.0286) and at 21 days between the control group (p=0.0402) and Activ-GP (p=0.0244). The levels of TNF-α were significantly higher after 7 days when the AH-Plus group was compared with others. It was observed that in the control group at 7 and 21 days there were statistical differences in relation to Sealapex and AH-Plus respectively when evaluated concentrations of IFN-γ. There were also significant differences between the control group and Sealapex (p=0.0158) within 7 days for the cytokine IL-4. The amounts of IL-10 were statistically higher in the control group compared to the Activ GP in a period of 21 days (p=0.0471). With respect to IL-17 in a period of 21 days, it was observed the highest values for the control group, followed by Sealapex, Activ-GP and AH-Plus. Differences were found between the control groups and AH-Plus (p=0.0121), control and Activ-GP (p=0.0262) and between Sealapex and Activ-GP (p=0.0314). Based on the presented results theendodontic sealers are able to promote changes in the response cytokine profile Th1, Th2 and Th17; Sealer AH-Plus produced the greatest changes, in the Th1 response profile.
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Medina, Tiago da Silva. "Participação do eixo Th17/IL-27 no controle da infecção experimental com Trypanosoma cruzi". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-02052014-160055/.
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Produzida por macrófagos e células dendríticas, a IL-27 é uma citocina heterodimérica capaz de induzir células Tr1 produtoras de IL-10 e consequentemente regular linfócitos Th1, Th2 e Th17, dependendo da doença envolvida. Partindo-se do pressuposto de que a infecção causada por Trypanosoma cruzi normalmente induz miocardite refletida pela migração intensa de linfócitos Th1 para o tecido cardíaco, nós analisamos o papel regulador da IL-27 nesta condição inflamatória. Nós inicialmente verificamos que a IL-27 foi prontamente induzida in vitro em células infectadas com T. cruzi. Para gerar miocardite intensa coordenada por linfócitos Th1, nós polarizamos linfócitos T naïves para o padrão Th1 na ausência de moléculas relacionadas ao perfil Th17 (camundongos IL-17R-/-, IL-23-/- e IL-6-/-). Como esperado, a inflamação cardíaca intensa e o dano tecidual foram observados na ausência das moléculas do padrão Th17, o que contribuiu para a morte prematura dos animais IL-17R-/-, IL-23-/- e IL-6-/-, precisa e notoriamente pela indução da migração excessiva de linfócitos Th1 para o tecido cardíaco via CXCL-9 e CXCL-10. Para explorar os mecanismos pelos quais a IL-27 controla a miocardite induzida pelo T. cruzi, nós encontramos um recrutamento substancial de macrófagos produtores de IL-27 para o tecido cardíaco, o qual foi mediado pelas quimiocinas CCL3 e CCL4 na ausência de moléculas do padrão Th17. Para determinar quais os receptores necessários para a produção de IL-27, nós observamos que macrófagos derivados da medula óssea de camundongos deficientes de TLR4-/-, TLR9-/- e NLRP3-/- aboliram completamente a produção desta citocina após a infecção in vitro com T. cruzi, enquanto o receptor TLR2 foi dispensável. Nós também verificamos que macrófagos produtores de IL-27 suprimiram linfócitos Th1 através da indução de células Tr1 produtoras de IL-10 após a infecção com T. cruzi. Em seguida, nós avaliamos se a IL-27 foi correlacionada com a proteção cardíaca durante a doença de Chagas. Nós observamos níveis séricos elevados de IL-27 tanto em pacientes com a forma clínica indeterminada ou cardíaca leve, enquanto pacientes com cardiomiopatia moderada ou grave produziram níveis reduzidos de IL-27. Neste estudo, nós descrevemos um novo mecanismo regulador desempenhado por macrófagos produtores de IL-27 no controle da miocardite induzida por T. cruzi. Macrófagos produtores de IL-27 podem suprimir processos inflamatórios desencadeados por linfócitos Th1, os principais vilões na doença de Chagas.IL-27 is a heterodimeric cytokine produced by macrophages and dendritic cells known to induce IL-10-producing Tr1 cells and to regulate Th1, Th2, and Th17 lymphocytes, depending on the underlying disease. Because the infection caused by Trypanosoma cruzi normally induces myocarditis mirrored by an outstanding migration of Th1 cells to the heart tissue, we analyzed the regulatory role of IL-27 in this inflammatory condition. We firstly verified that IL-27 was promptly induced by in vitro T. cruzi-infected spleen cells. To generate a robust myocarditis coordinated by Th1 lymphocytes, we polarized lymphocytes to a Th1 pattern by infecting mice in the absence of Th17-related molecules (IL-17R-/-, IL-23-/-, and IL-6-/- mice). As expected, an impressive cardiac inflammation and damage was observed in the absence of Th17-related molecules, leading IL-17R-/-, IL-23-/-, and IL-6-/- mice to the premature death, precisely and notably by inducing an exuberant Th1 migration to the heart tissue via CXCL9 and CXCL10 chemokines. To explore the mechanisms by which IL-27 controls T. cruzi-induced myocarditis, we found a striking recruitment of IL-27-producing macrophages to the heart tissue mediated by increased levels of CCL3 and CCL4 chemokines in the absence of Th17-associated molecules. To gain further insights into the receptors required to IL-27 production, we observed that bone marrow-derived macrophages from TLR4-/-, TLR9-/-, and NLRP3-/- mice completely abolished IL-27 production after in vitro T. cruzi infection, while TLR2 was dispensable. We also verified that IL-27-producing macrophages supressed Th1 lymphocytes by inducing IL-10-producing Tr1 cells after T. cruzi infection. We next assessed whether IL-27 was correlated to cardiac protection during Chagas Disease. We observed augmented serum levels of IL-27 in either patients with indeterminate (asymptomatic) form or mild cardiac form, whereas patients with moderate or severe cardiomyopathy were poor producers of IL-27. Here, we described a novel regulatory mechanism developed by IL-27-producing macrophages in the control of T. cruzi-induced myocarditis. IL-27-producing macrophages can suppress inflammatory processes caused by Th1 lymphocytes, the bona fide culprits of Chagas Disease.
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Tigno-Aranjuez, Justine Daphne Tiglao. "Adjuvant Guided T cell Responses". Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244035297.
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Yao, Chengcan. "Prostaglandin E2-EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion". Kyoto University, 2011. http://hdl.handle.net/2433/151930.
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Agorogiannis, Eleftherios. "TH17 cells in transplantation biology". Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540084.
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Hull, Dobrina Nikolaeva. "The dynamics of Th17 and Th1 cells during anti-TNF therapy in patients with inflammatory arthritis and relationship with treatment response". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29116.
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Anti-TNF agents have revolutionised the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA), however a significant proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can increase circulating Th17 and Th1 cells but the relationship of these changes to treatment response remains unclear. The aim of the work in this thesis was to conduct a prospective, longitudinal investigation of patients with inflammatory arthritis during anti-TNF treatment and using clinical, ultrasound and immunological assessments to gain an understanding of the immune correlates of treatment response. Patients with RA (n=25), AS (n=15) and PsA (n=8) were recruited and followed over the first 12 weeks of treatment. Improvement in validated disease activity scores defined treatment responders and non-responders. Power Doppler ultrasound (PDUS) provided a quantitative assessment of changes in synovial thickening and vascularity during treatment, with synovial vascularity showing faster and greater reduction with treatment than synovial thickening. PBMCs testing using IL17 and IFNy ELISpot assays and flow cytometry consistently showed increased frequencies of circulating Th1 and Th17 cells in all three disease groups during anti-TNF therapy. Multiplex cytokine testing demonstrated a decrease in serum levels of proinflammatory cytokines and chemokines. Analyses of relationships between clinical, ultrasonographic and T-cell immunological changes revealed significant negative correlations between the increased frequency of Th1 and Th17 cells and reduction in synovial thickening and vascularity from baseline to 12 weeks on treatment in the RA group. Higher numbers of circulating Th17 cells at baseline in the RA group were associated with poorer anti-TNFa treatment response as defined by DAS28 score and ultrasonographic measures. This is the first study to link changes in T-cell immunopathology evaluated by cellular assays with morphological changes in arthritis assessed by PDUS during anti-TNFa treatment.
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Zager, Adriano. "A ativação imune materna e os efeitos sobre a imunidade, neuroinflamação e desenvolvimento da encefalomielite autoimune experimental na prole de camundongos". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-21112013-113642/.
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Experiências vivenciadas durante o período pré-natal são determinantes para a saúde do feto. A ocorrência de infecções maternas e a consequente ativação do sistema imune da mãe ocasionam uma série de alterações estruturais e funcionais no cérebro da prole, podendo predispor o indivíduo a transtornos psiquiátricos na vida pós-natal, como esquizofrenia e autismo. No entanto, estudos que investigam as alterações imunes na prole ainda são escassos na literatura. Dessa forma, o objetivo do presente estudo foi avaliar, na prole, o impacto da ativação imune materna sobre a atividade imune periférica, a resposta imune-inflamatória no sistema nervoso central (SNC), e sobre o desenvolvimento da encefalomielite autoimune experimental (EAE), o modelo murino de Esclerose Múltipla. Camundongos fêmeas prenhes receberam uma administração de salina ou lipopolissacarídeo (LPS) ao final da gestação (dia gestacional 17) e, quando adulta, a prole foi submetida a 3 experimentos principais, analisando: (1) produção de citocinas, atividade de células da periferia e desenvolvimento da hipersensibilidade do tipo tardia; (2) produção de mediadores inflamatórios por células residentes do SNC e; (3) desenvolvimento dos sintomas clínicos e da resposta imune no decorrer da EAE. Nossos resultados mostraram que a ativação imune materna provocou na prole alterações imunes periféricas, como aumento da produção de Interleucina(IL)- 12 e exacerbação da resposta de hipersensibilidade do tipo tardia; potencialização da produção das citocinas IL-1β e IL-6 em cultura primária de células residentes do SNC e; piora na severidade dos sintomas clínicos causados pela EAE, que coincide com aumento do infiltrado de linfócitos e macrófagos no SNC e ativação imuneinflamatória das células da glia. Tomados em seu conjunto, os dados do presente trabalho sugerem que condições inflamatórias durante a gestação, particularmente durante o final da gestação, podem predispor o feto a distúrbios autoimunes e neurodegenerativos na vida adulta.Prenatal period experiences are crucial for the fetal health. The occurrence of maternal infections and subsequent maternal immune system activation cause a number of structural and functional changes in the brain of the offspring that may predispose individuals to psychiatric disorders in post-natal life, such as schizophrenia and autism. However, studies investigating offspring´s immune alterations are still scarce in the literature. The aim of this study was to evaluate, in mice offspring taken from LPS-treated dams, the impact of maternal immune activation on peripheral immune cell activity, central nervous system (CNS) inflammatory response, and development of experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis. Pregnant female mice received a dose of either saline or lipopolysaccharide (LPS) during late gestation (gestational day 17), and offspring were used in three experiments to analyze: (1) cytokine production and activity by peripheral immune cells and development of delayed type hypersensitivity, (2) production of inflammatory mediators by resident CNS cells and, (3) development of clinical symptoms and immune response during the course of EAE. Our results showed that maternal immune activation resulted in immune alterations in the offspring, such as increased peripheral production of interleukin (IL) -12 and exacerbated response of delayedtype hypersensitivity; enhancement of IL-1β and IL-6 productions in primary CNS resident cells culture and; increased severity of EAE clinical symptoms, which is positively correlated with the increased lymphocytes and macrophages infiltration within the CNS and also with the immune-inflammatory activation of glial cells. Taken together, the data from this study suggest that inflammatory conditions during pregnancy, especially during the late pregnancy, may predispose the fetus to autoimmune and neurodegenerative disorders in adulthood.
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Schumann, Julia. "Intra- und extrazelluläre Signale während der T-Zellaktivierung und -differenzierung". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/17076.
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Im ersten Teil dieser Dissertation wurde der Einfluss des mitochondrialen Proteins TCAIM (T cell activation inhibitor, mitochondrial) auf die T-Zellaktivierung untersucht. Hierzu wurde eine transgene Mauslinie mit einem T-zellspezifischen knock-in (KI) von Tcaim in den Rosa26 Lokus generiert. Die Tcaim-Überexpression beeinflusste die Fission und Umverteilung von Mitochondrien und reduzierte die T-Zellrezeptor (TZR)-induzierte Bildung mitochondrialer, radikaler Sauerstoffspezies. In vitro stimulierte CD4+ Tcaim KI T-Zellen zeigten eine geringere Aktivierung, Proliferation und IL-2 Sekretion als Kontrollzellen. T-Zellen aus Tcaim KI Mäusen, die in Rag-1 knock-out Mäuse transferiert wurden, waren nicht fähig ein allogenes Haut-Transplantat abzustoßen und behielten einen naiven Phänotyp. Diese Ergebnisse zeigen, dass TCAIM als mitochondriales Protein wichtige Schritte in der Zellaktivierung und der Bildung von Gedächtnis-T-Zellen beeinflusst. Der zweite Teil der Dissertation beschäftigte sich mit dem Einfluss der CD44-Oberflächenexpression auf die Differenzierung von T-Helfer (TH)-Zellen. Eine hohe CD44-Expression unterscheidet Effektor- von naiven T-Zellen. Durch die allogene Stimulation von CD4+ T-Zellen bildeten sich drei verschiedene Populationen: CD44+, CD44++ und CD44+++. Sowohl in vitro als auch in vivo generierte alloreaktive TH17-Zellen wurden in der CD44+++ Population, TH1-Zellen hingegen in der CD44++ Population, detektiert. Es wurde beschrieben, dass sowohl eine geringe TZR- als auch eine geringe CD28-Stimulation eher die Bildung von TH17- als TH1-Zellen unterstützen. Unter genau diesen Bedingungen kann CD44 als kostimulatorisches Molekül die Signaltransduktion verstärken. Tatsächlich zeigten allogenreaktive CD44+++ TH-Zellen eine höhere ZAP-70-Phosphorylierung als CD44++ TH-Zellen. Diese Ergebnisse unterstützen die Annahme, dass CD44 durch die Verstärkung der Signaltransduktion die TH17-Differenzierung fördern kann.Within the first part of this thesis, the influence of the mitochondrial Protein TCAIM (T cell activation inhibitor, mitochondrial) on T cell activation was investigated. Tcaim expression correlated negatively with the rejection of allografts and it is down-regulated during T cell activation. To study effects of TCAIM during T cell activation, we generated a T cell-specific mouse strain with a Tcaim knock-in (KI) targeted to the Rosa26 locus. Tcaim overexpression changed the mitochondrial morphology and reduced the T cell receptor (TCR)-induced mitochondrial reactive oxygen species production. In vitro activation of Tcaim KI CD4+ T cells resulted in a decreased activation, proliferation and cytokine release. Importantly, Rag-1 knock-out mice, reconstituted with Tcaim KI T cells, tolerated allogeneic skin grafts. Thus, by regulating TCR-induced mitochondrial distribution and ROS production, TCAIM controls important steps during T cell activation and memory formation. The second part dealt with the influence of CD44 surface expression level for T helper cell (Th cell) differentiation. By association with lymphocyte-specific protein kinase (LCK) it can enhance T cell signaling. Allogeneic stimulation of CD4+ T cells resulted in the formation of three distinguishable populations: CD44+, CD44++ and CD44+++. In vitro and in vivo generated allo-reactive TH17 cells were mainly CD44+++. This is in contrast to TH1 cells which were dominantly CD44++. Titration experiments revealed that low TCR- and co-stimulation supports TH17 rather than TH1 development. Under exactly these conditions it was reported that CD44 can act as co-stimulatory molecule and replace CD28. Indeed, CD44+++CD4+ T cells contained already more phosphorylated ZAP-70 as compared to CD44++ cells. Our results support the notion that CD44 enhances TCR signaling strength by delivering LCK, which is required to support TH17 development.
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Zhao, Xiangli [Verfasser]. "Investigation on the role of CD26 in Th1 and Th17 cell differentiation and allogeneic graft rejection / Xiangli Zhao". Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1158597665/34.
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Ferreira, Maria Carolina 1983. "Avaliação da capacidade de indução de diferenciação de células TH17 por células dendríticas estimuladas com células leveduriformes de Paracoccidioides brasiliensis e mecanismos de sinalização intracelular envolvidos". [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311837.
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Orientadores: Ronei Luciano Mamoni, Maria Heloisa de Souza Lima BlottaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A paracoccidioidomicose (PCM), causada pelo fungo dimórfico Paracoccidioides brasiliensis (Pb), é a micose sistêmica de maior incidência no Brasil. Estudos anteriores demonstraram que a resistência ou suscetibilidade a essa infecção podem ser associadas, respectivamente, a padrões de resposta Th1 ou Th2. Recentemente, foram descritas novas subpopulações de linfócitos T, dentre elas as células Th17, que tem se mostrado importantes na proteção contra infecções fúngicas, mas cujo papel ainda não foi estudado na PCM humana. A diferenciação de células T CD4+ é modulada após o reconhecimento do patógeno por células dendríticas (DCs) por meio de vários receptores de reconhecimento padrão (PRRs), os quais modulam a diferenciação de células Th1, Th2 e Th17. Neste trabalho investigamos o papel dos receptores TLR2, TLR4 e Dectina-1 no reconhecimento de células leveduriformes de P. brasiliensis (Pb) por DCs derivadas de monócitos, assim como, a capacidade dessas DCs em modular a diferenciação de linfócitos T CD4+. Observamos que DCs expostas a células leveduriformes de Pb apresentam um fenótipo maduro (expressão de CCR7, CD83, CD86 e MHC II) e produzem citocinas (IL- ?, IL-6, IL-23, TNF-? e TFG- ?), levando à diferenciação de linfócitos T CD4+ produtores de IL-17, IFN-?, IL-22, IL-17/IL-22 e IL-17/IFN- ?. Também observamos que DCs estimuladas com células leveduriformes de Pb apresentam ativação de moléculas envolvidas na sinalização via TLRs e Dectina-1 (JNK, p38, Akt e ERK para os TLRs e Syk para Dectina-1), e que o bloqueio de Dectina-1 e/ou TLR2 resultou em um número menor de células Th17. Ao analisar a produção de citocinas por células mononucleares do sangue periférico, observamos que pacientes com a FJ da PCM apresentam produção aumentada de IL-4 e que pacientes com a FA apresentam produção elevada de IL-17 e IFN- ?. Em conjunto nossos resultados demonstram que a Dectina-1 e TLR2 são os receptores mais importantes para o reconhecimento de leveduras de Pb por células dendríticas e que esse reconhecimento pode levar à diferenciação de linfócitos T efetores produtores de IL-17 e IFN- ?. Além disso, podemos concluir que a FA da PCM apresenta uma resposta imunológica mista, com participação de linfócitos Th17
Abstract: Paracoccidioidomycosis (PCM), caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb), is the most prevalent systemic mycosis in Brazil. Previous studies showed that resistance or susceptibility to PCM can be associated to a Th1 or Th2 responses respectively. More recently, Th17 response was showed to be protective in fungal infections, but there is no data about Th17 cells in human PCM. T CD4+ differentiation is elicited and shaped after pathogen recognition by dendritic cells (DCs) through several PRRs, which modulate Th1, Th2 and Th17 generation. In this study we evaluated the role of TLR-2, TLR-4 and Dectin-1 in the recognition of Pb yeast cells by monocytes derived DCs, as well as, the capability of these DCs to modulate T CD4+ lymphocytes differentiation. We observed that DCs exposed to Pb presented a mature phenotype (expression of CCR7, CD83, CD80, CD86 and MHC II) and produce cytokines (IL-1, IL-6, IL-23, TNF-? and TGF- ) that promote the differentiation of TCD4+ lymphocytes producing IL- 7, IFN-?, IL-22, IL-17/IL-22 and IL-17/IFN-?. We also observed that DCs stimulated by Pb presented activation of molecules involved in the TLRs and dectin-1 signaling (JNK, p38, AKT, ERK - for TLRs and Syk for dectin- The blockage of dectin-1 and/or TLR2 diminished the differentiation of Th17 cells. We also analyzed PBMCs from patients with the acute/juvenile form (JF) or the chronic/adult form (AF) of PCM. Our results showed that patients with JF present elevated production of IL-4 and AF patients present higher production of IL-17. Altogether our results showed that Dectin-1 and TLR-2 are the most important receptors for human DCs to recognize Pb yeast cells and to produce cytokines such as IL- , IL- ? and TNF-?. After DC activation and cytokine production these cells are able to induce Th1 and Th17 differentiation through these receptors. Also we showed that Th17 cells are a major population in AF patients
Doutorado
Ciencias Biomedicas
Doutora em Ciências Médicas
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Nistala, K. "The role of Th17 cells in juvenile idiopathic arthritis". Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318100/.
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Autoimmune arthritis in childhood, know as juvenile idiopathic arthritis (JIA), has a heterogeneity, ranging from monoarthritis to recalcitrant polyarthritis, making it a model disease in which to study immuno-regulation. Regulatory T cells, key players in peripheral immune homeostasis are enriched in the joints of JIA patients, particularly those with mild arthritis. To test the factors that lead to this enrichment, Treg trafficking was examined in the context of JIA. Synovial Treg showed enhanced chemotaxis to the inflammatory chemokine CCL5, widely detectable within the joint, when compared to Treg from peripheral blood. The trafficking of a related, but highly inflammatory T cell subset, Th17 cells, was also investigated. Th17 cells play a dominant role in murine models of arthritis, yet their contribution to human disease is unknown. The data presented here, showed that IL-17+ CD4 T cells were enriched in the joints of JIA patients, by a CCR6 dependent mechanism and importantly, their frequency correlated with the severity of disease course. The majority of synovial IL-17+ CD4 T cells expressed a cytokine and chemokine receptor phenotype intermediate between Th17 and Th1. Here it was shown that these cells (Th17/1) expressed high levels of both Th17 and Th1 specific transcription factors, RORC2 and T-bet. Modelling the generation of Th17/1 in vitro, Th17 cells ‘converted’ to Th17/1 under conditions which mimicked the disease site, namely low TGFβ and high IL-12 levels. Using CD161, a human Th17 marker, it was shown that synovial Th17/1 cells, and unexpectedly, a large proportion of Th1 cells expressed CD161. This study provided evidence to support a Th17 origin for Th1 cells expressing CD161. In vitro, Th17 cells which converted to a Th1 phenotype maintained CD161 expression, whilst in the joint CD161+ Th1 cells shared features with Th17 cells, with shared T cell receptor clonality and expression of RORC2, although they were IL-17 negative. We propose that Th17 cells may 'convert' to Th17/1 and Th1 cells in human arthritis. Therefore therapies targeting the induction of Th17 cells could also attenuate the Th17/1 and Th1 effector populations within the inflamed joint.
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Abdulaal, Wesam. "The role of Interleukin-1 signaling in the immune defense and in the development of the T helper cell lineage". Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-interleukin-1-signaling-in-the-immune-defense-and-in-the-development-of-the-t-helper-cell-lineage(1432f7f4-7c04-4bc5-9fda-4441b5c14e66).html.
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IL-1 is a pro-inflammatory cytokine which play an important role in the activation and regulation of host defence and immune responses to inflammation or injury. IL-1 is able to bind and activate IL1-RI and IL1-RII, which are found on many cells types. The role of the IL-1 signalling in the deployment of Th cell subsets, especially Th17 cells is well known. However, the specific cells which are responsible for the expression of IL-1 signalling in the immune defense and in the development of the Th cell lineage in response to infection, is still largely unclear. Therefore in this thesis, IL1-RI conditional knockout mice specifically in hematopoietic cells (IL1-RI vaviCre+) were generated. Using IL1-RI vaviCre+ mice in comparison with IL1-RI global knockout mice (IL1-RI-/-) would determine whether the expression IL-1 signalling from hematopoietic cells is responsible for the immune defense and in the development of the Th1, Th2 and Th17 cells against gastrointestinal helminth Trichuris muris (T.muris) infections. The generation of IL1-RI vaviCre+ mice have been investigated at the genomic and proteomic level in order to confirm that the Il1-rI gene is inactivated in hematopoietic cells. The characterisation of IL1-RI vaviCre + mice at the genomic level confirmed that the Il1-rI gene was obliterated successfully. At protein level the characterisation of IL1- RI vaviCre + mice confirmed that IL1-RI was dysfunctional in hematopoietic cells. Additionally, the development of the immune cells was investigated in IL1-RI vaviCre + and IL1-RI-/- mice. Our findings demonstrated that the lymphocyte development was not affected by the deletion of the IL1- RI gene. This data indicated that IL1- RI vaviCre + and IL1-RI-/- mice are vital in vivo models. In high dose infection, both IL1-RI vaviCre + and IL1-RI -/- mice were able to clear the infections due to their ability to generate a Th2 response. Both IL1-RI vaviCre + and IL1-RI -/- mice infected with low dose of T.muris were susceptible to infections and showed high levels of Th1 cytokines. Thus, we hypothesised that IL1-RI signalling in hematopoietic cells was not required for worm expulsion and the generation of Th2 and Th1 response. Interestingly, low dose T.muris infection showed a clear reduction in the Th17 cytokines IL22 and IL17 in both IL1-RI vaviCre + and IL1-RI -/- mice, suggesting that IL-1 signalling expressed from hematopoietic cells is responsible for the development of Th17 cells and secretion of IL17 and IL22. IL1- RI vaviCre + and IL1-RI -/- mice infected with low dose of T.muris also showed an increase in inflammation in the colon and decreased of goblet cell hyperplasia. It is well known that IL22 plays an important role in preventing tissue damage and repair. Thus, in this study IL22 global knockout mice (IL22 -/-) were used to determine if the change in crypt lengths and goblet cell hyperplasia in IL1-RI vaviCre + and IL1-RI -/- was due to an absence of IL22. Our finding showed that IL22 -/- mice infected with low dose of T.muris had increased crypt length and a reduction in goblet cells. The similar phenotype in crypt length and goblet cell hyperplasia between IL22 -/-, IL1-RI vaviCre + and IL1-RI -/- mice suggested that a lack of IL22 in IL1-RI vaviCre + and IL1-RI -/- mice is responsible for the change in mice phenotype. It also provides more evidence for the role of IL-1 signaling in hematopoietic cells in the generation of Th17 cells and in the production of its cytokine IL22.IL1-RII is an inhibitor of IL1-RI, thus, in this study IL1-RII global knockout mice (IL1-RII -/-) mice was used in comparison with IL1-RI -/- mice to verify the role of IL-1 signaling in the development of Th17 cells. Our finding showed an overexpression of IL17 and IL22 in IL1-RII -/- compared with IL1-RI -/- mice and a higher level of IL17 in IL1-RII -/- mice compared with IL1-RII flox/flox mice. This data confirmed that IL-1 signaling is important for the development of Th17 cells and the production of its cytokine IL17 and IL22.
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Ourives, Samantha Soares. "Análise dos parâmetros parasitológicos e hematológicos e das subpopulações de células Th1, Th2, Th17, Treg e T citotóxica em pacientes com malária vivax". Universidade Federal de Mato Grosso, 2014. http://ri.ufmt.br/handle/1/496.
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CNPq
A malária é uma das doenças parasitárias de maior importância global e é responsável pelas principais causas de morbidade e mortalidade nas áreas tropicais e subtropicais do mundo. Apesar dos esforços para o controle da infecção em diferentes áreas endêmicas, a malária continua em expansão, e as medidas tradicionais de controle da transmissão são pouco eficazes. A resposta imune na malária é complexa, e os mecanismos de ativação e regulação de linfócitos T e suas citocinas ainda são pouco compreendidos. O objetivo deste trabalho foi avaliar a correlação da parasitemia com o número de plaquetas e leucócitos, e identificar e quantificar as subpopulações específicas de células Th1, Th2, Th17 e Treg, durante a infecção por P. vivax. Avaliando a parasitemia e o número de plaquetas, foi verificado que existe correlação negativa (p<0,0005) entre esses parâmetros e que, dependendo da quantidade de parasitas, os pacientes com malária vivax apresentavam um maior grau de plaquetopenia (p<0,0001). Avaliando o número de parasitas e de leucócitos totais, foi verificada ausência de correlação entre esses parâmetros em pacientes com malária vivax. Além disso, também não foi detectada alteração no número de leucócitos totais quando comparado aos controles sadios. Posteriormente, foi realizada, por meio de citometria de fluxo, a identificação e quantificação das subpopulações de células T: Th1 (CD3+CD4+IFN-γ+), Th2 (CD3+CD4+IL4+), Th17 (CD3+CD4+IL-17+), Treg (CD4+CD25+CD127-) e citotóxica (CD3+CD8+), em pacientes com malária vivax e em controles sadios após cultura de linfócitos previamente isolados do sangue periférico, para verificar a alteração do número dessas subpopulações de linfócitos pela infecção por P. vivax. O percentual da citocina IL-10 também foi avaliado nas células Treg (CD4+CD25+CD127-IL-10+). Os indivíduos infectados por P. vivax apresentaram percentual de células T citotóxica e Th1 aumentadas. Já o percentual de células Th2, Th17 e Tregs não apresentaram diferenças entre os grupos. Porém, o percentual de células Treg que produziam a citocina IL-10 estava aumentado em pacientes com malária vivax, quando comparado aos controles sadios. Finalmente, a avaliação do número de células T CD4+ e T CD8+, indicou que não houve diferenças entre a proporção desses linfócitos em controles sadios e nem durante o processo infeccioso induzido por P. vivax. Em conclusão, pacientes com malária vivax apresentam um aumento no número de células T citotóxicas, Th1 e de células Treg (CD4+CD25+CD127-) produtoras de interleucina-10, indicando que a infecção por P. vivax ativa células específicas que podem participar na imunorregulação contra esse parasita.
Malaria is a parasitic disease of major global importance and is responsible for leading causes of morbidity and mortality in tropical and subtropical areas of the world. Despite efforts to control the infection in different endemic areas, malaria continues to expand, and the traditional transmission control measures are ineffective. The immune response in malaria is complex, and the mechanisms of activation and regulation of T lymphocytes and their cytokines are still poorly understood. The objective of this study was to evaluate the correlation of parasitemia with the number of platelets and leukocytes, and identify and quantify specific subpopulations of Th1, Th2, Th17 and Treg cells in infection by P. vivax. Evaluating the parasitemia and the number of platelets was verified that there is a negative correlation (p<0,0005) between these parameters and that, dependent of the number of parasites, vivax malaria patients showed higher degree of thrombocytopenia (p<0,0001). Evaluating the number of parasites and total leukocytes was observed no correlation between these parameters in patients with vivax malaria. Moreover, it was also not detected change in the number of total leukocytes when compared to healthy controls. Subsequently, was performed by flow cytometry, identification and quantification of T cell subsets: Th1 (CD3+CD4+IFN-γ+), Th2 (CD3+CD4+IL4+), Th17 (CD3+CD4+IL-17+), Treg (CD4+CD25+CD127-) and cytotoxic (CD3+CD8+) in patients with vivax malaria and healthy controls after lymphocyte culture previously isolated from peripheral blood, to verify the change in the number of these subpopulations lymphocytes by infection with P. vivax. The percentage of IL-10 was also evaluated on Treg cells (CD4+CD25+CD127+IL-10). Individuals infected with P. vivax showed increased percentage of Th1 and cytotoxic T cells. The percentage of Th2, Th17 and Treg cells did not differ between groups. However, the percentage of Treg cells that produce IL-10 cytokine was increased in patients with vivax malaria compared to healthy controls. Finally, the evaluation of the number of CD4+ T and CD8+ T cells indicated that there were no differences between the proportion of these lymphocytes in healthy controls or during the infectious process induced by P. vivax. In conclusion, vivax malaria patients show an increase in the number of cytotoxic T cell, Th1 and Treg cells (CD4+CD25+CD127-) producers of interleukin-10, indicating that infection with P. vivax activate specific cells which can participate in the immunoregulation against this parasite.
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Cheng, Wan-Chien. "The role of IL-17 and Th17 cells in the pathogenesis of periodontitis". Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-il17-and-th17-cells-in-the-pathogenesis-of-periodontitis(624cbe33-5647-4f82-9011-d1b1bb2104a5).html.
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The Th17/IL-17 pathway is increasingly implicated in the pathogenesis of periodontitis. However the mechanisms that drive this pathway in humans and the relationship of this pathway to disease severity are not fully understood. The first aim of this thesis was to investigate whether the periodontal pathogens Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa) promote a Th17/IL-17 response in vitro, and to investigate the underlying mechanisms. The second aim was to determine the frequencies of IL-17+ CD4+ T cells in gingival tissue and peripheral blood from patients with periodontitis versus periodontally healthy control subjects. My results show that Pg and Aa activate monocytes, which can subsequently induce an IL-17/Th17 response in CD4+ T cells in vitro. The underlying mechanism involves the recognition of Pg by TLR2/4 on monocytes leading to an IL-1β/IL-23 dependent induction of IL-17 production by CD4+ T cells, which is further dependent in part on costimulation. The data also show that gingival tissue from patients with periodontitis contains increased frequencies of IL-17+ cells (predominantly CD4+ T cells) as well as IFNγ+ and TNFα+ cells relative to healthy subjects. IL-17+ CD4+ T cells and IL-17 protein are clearly detectable however in both diseased and healthy gingival tissue and GCF. No differences are observed in IL-17+ CD4+ T cell frequencies in peripheral blood from patients or healthy subjects. However, in vitro, Pg induces significantly higher IL- 17 production in anti-CD3 mAb-stimulated monocyte/CD4+ T cell co-cultures from patients with periodontitis compared to healthy controls.
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Silva, Felipe von Glehn 1978. "Esclerose múltipla = produção de citocinas pelos linfócitos Th17 e Th1 de pacientes tratados ou não com interferon beta e quantificação das células dentríficas plasmocitóides no líquido cefalorraquiano". [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310333.
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Orientador: Leonilda Maria Barbosa dos Santos, Benito Pereira DamascenoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A Esclerose Múltipla (EM) é uma doença primária do sistema nervoso central. Geralmente, expressa-se numa fase clínica de surto e remissão, mediada por lesões focais inflamatórias agudas na substância branca cerebral e medula espinhal, podendo evoluir para uma fase progressiva, mediada por perda axonal e neuronal. Paralelamente ao aumento do conhecimento sobre a participação dos linfócitos na execução da resposta imune, cresce a importância das células dendríticas na subseqüente regulação da resposta imune adquirida. O presente estudo teve como objetivo avaliar o efeito do tratamento com o interferon beta na produção de citocinas pelos linfócitos Th17 / Th1 no sangue dos pacientes com EM forma remitente recorrente (EMRR), comparando-os com grupo controle e estudar a concentração de células dendríticas plasmocitóides (pDCs) no líquido cefalorraquiano (LCR) de pacientes com EMRR nas fases aguda e de remissão da doença. Trinta e quatro pacientes, divididos em grupos tratados com interferonß e não tratados, e um grupo controle de 20 voluntários sadios, foram avaliados quanto a resposta de linfoproliferação de células mononucleares extraídas do sangue periférico e colocadas em cultura com estímulo específico e inespecífico, além do grau de produção de citocinas pró- e anti- inflamatória. Posteriormente, a concentração de pDCs foi mensurada no LCR e sangue periférico de pacientes em fase de surto e em fase remissão da EMRR, comparadas com pacientes com doenças não inflamatórias do sistema nervoso central, analisados por citometria de fluxo. Os resultados demonstraram que o tratamento com o IFN-ß diminui a resposta proliferativa fisiológica dos linfócitos T de pacientes em tratamento, e modifica o padrão de citocinas pró- (IFN-? e IL-17) e anti- inflamatória (IL-10) nos pacientes com EMRR. As pDCs estão aumentadas no líquor de pacientes em surto, quando comparada a fase de remissão, sem correspondência no sangue periférico, indicando uma provável migração seletiva
Abstract: Multiple sclerosis (MS) is a primary disease of the central nervous system, clinically characterized by relapses mediated by acute inflammatory lesions in white matter. With time, the disease could evolve to a neurodegenerative phase, characterized by axonal loss. In parallel to the importance of T helpers lymphocytes in the genesis of disease, enhance the knowledge about the participation of dendritic cells in orchestrating the immune response. The objective of this study is to evaluate the effect of interferon beta therapy on the cytokine production of Th1 and Th17 subsets from MS patients, comparing with controls, and to study the plasmacytoid dendritic cells concentration in cerebrospinal fluid of MS patients in different phases, relapse and remitting, of disease. The proliferative response of lymphocytes from PBMC from thirty four patients divided in two groups, interferon beta therapy and no treatment, and a control group with twenty individuals were evaluated in culture with specific and non specific stimulation. After that, the level of pro and anti-inflammatory cytokine production were measure. In a second step, the pDCs concentrations were measured in CSF and PBMC of patients in different phases, comparing with patients with others non inflammatory diseases. The results showed that interferon beta therapy diminished the proliferative response of T lymphocytes compared with the non treated group and modify cytokine production of IFN-y, IL-17 and IL-10 in MS patients. The pDCs were increased in CSF in phase of relapse compared with remittion, with no corresponding increasing in PBMC, indicating a selective migration
Mestrado
Neurologia
Mestre em Ciências Médicas
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Guo, Yawei y 郭雅伟. "Adiponectin limits autoimmune encephalomyelitis by suppressing the differentiation of CD4+ cells into Th17 cells". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45207690.
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Podgaec, Sérgio. "Padrões de resposta imune em pacientes com endometriose". Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-31102006-105026/.
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Objetivo: O objetivo deste estudo foi analisar a relação e a predominância dos padrões de resposta imune Th1 e Th2 em pacientes com endometriose. Pacientes e Métodos: Entre Fevereiro de 2004 e Abril de 2005 foram avaliadas 98 pacientes divididas em dois grupos de acordo com a presença (Grupo A) ou ausência de endometriose (Grupo B), confirmada histologicamente. Foram coletados sangue periférico e fluido peritoneal de todas as pacientes para a dosagem de interleucinas (IL) 2, 4 e 10, fator de necrose tumoral-alfa (TNF-alfa) e interferon-gama (IFN-gama) por citometria de fluxo. Além da presença da endometriose, foram analisadas a fase do ciclo menstrual, o quadro clinico, o estadiamento, o local de acometimento e a classificação histológica da moléstia. Resultados: Observou-se elevação estatisticamente significante nas concentrações de IFN-gama (mediana de 1,5pg/ml no Grupo A e de 0,4pg/ml no Grupo B, p=0,03) e de IL-10 (mediana de 38,6pg/ml no Grupo A e de 15,7pg/ml no Grupo B, p=0,03) do fluido peritoneal das pacientes com endometriose em relação àquelas sem a doença. As pacientes com endometriose apresentaram alteração estatisticamente significativa na relação das concentrações de IL-4/IFN-gama (p<0,001), IL-4/IL-2 (p=0,006), IL-10/IFN-gama (p < 0,001) e IL-10/IL-2 (p<0,001) do fluido peritoneal, com concentrações mais elevadas da IL-4 e da IL-10, o que reflete o predomínio da resposta Th2 sobre a Th1. Conclusão: Os resultados obtidos permitem concluir que, neste estudo, observou-se elevação de citocinas relativas à resposta imune Th2, denotando haver um predomínio deste padrão de resposta em pacientes com endometriose.Objective: The objective of this study was to analyze the relation and the predominance of the immune response patterns Th1 and Th2 in patients with endometriosis. Patients and Methods: Between February 2004 and April 2005, 98 patients were evaluated and divided into two groups, according to the presence (Group A) or absence of endometriosis (Group B), confirmed by histology. Peripheral blood and peritoneal fluid were collected from all patients to obtain the concentrations of interleukines (IL) 2, 4 and 10, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) using flow cytometry. Besides the presence of endometriosis, we analyzed phase of menstrual cycle, clinical complaints, classification, site and histological differentiation of the disease. Results: We observed higher concentrations of IFN-gamma (median of 1.5pg/ml in Group A and 0.4pg/ml in Group B, p = 0.03) and IL-10 (median of 38.6pg/ml in Group A and 15.7pg/ml in Group B, p = 0.03) in peritoneal fluid of patients with endometriosis in relation to those without the disease. Patients with endometriosis presented a significant alteration in IL-4/IFN-gamma (p < 0.001), IL-4/IL-2 (p = 0.006), IL-10/IFN-gamma (p < 0.001) and IL-10/IL-2 (p<0.001) ratio concentrations of peritoneal fluid, with IL-4 and IL-10 predominance, reflecting a Th2 response predominance over the Th1. Conclusion: The results allow concluding that, in this study, it was observed a cytokine elevation related to Th2 immune response, indicating a predominance of this pattern of response in patients with endometriosis.
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Sato, Wakiro. "Human Th17 Cells Are Identified as Bearing CCR2+CCR5- Phenotype". Kyoto University, 2008. http://hdl.handle.net/2433/124335.
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Nguyen, Kim Phung Le. "Cholera Toxin Induces cAMP-dependent Th17 Differentiation by Dendritic Cells". Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1465083.
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Thesis (M.S.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed June 19, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 47-55).
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Patakas, Agapitos. "The role of TH17 cells in a model of rheumatoid arthritis". Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2867/.
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Introduction: While many studies on rheumatoid arthritis have focused on the active phase of the disease, the events that lead to the development of autoimmunity remain poorly defined. We have developed a model of breach of self tolerance, where a Th1 response to irrelevant antigen (OVA) results in arthropathy associated with spontaneous induction of autoreactive T and B cell responses, which allows the investigation of the immnologival events that lead to the development of autoreactivity. Employing this model the role of Th17 cells, a a subset of IL-17 producing CD4+ T important in autoimmunity, was investigated in the development of autoimmunity. In addition, the relative ability of Th1 and Th17 polarised populations in supporting B cell responses was analysed. Finally, in this thesis the role of sterile damage regulation in the development of autoimmunity was assesed, by investigating the role of Siglec-G, a molecule involved in DAMP-signalling regulation, in this process. Results: Transfer of OVA specific Th17 cells induced similar levels of inflammation as Th1 cells, and could induce a breach of self tolerance as demonstrated by CII specific T and B cell responses. While the CII specific T cells in the Th1 recipients produced IFNγ and not IL-17, surprisingly the CII T cell responses in the Th17 recipients were predominantly IFNγ producers. Whereas the transferred OVA specific Th1 population retained its phenotype, the transferred Th17 population displayed significantly reduced IL-17 production. However, cells polarised under Th17 conditions expanded in a higher degree and persisted for longer time in response to immunisation. This resulted in a higher ability of Th17 polarised population in supporting B cell responses. Finally in this thesis, preliminaty data for a role of Siglec-G in the development of autoimmunity were presented, as Siglec-G deficient mice were protected from the development of autoreactive B cell responses. Conclusion: The results of this thesis suggest that the developing autoimmuniy in both Th1 and Th17 models is mediated by Th1 cells. These studies highlight the plasticity of transferred cell populations in vivo, and support the use of blocking and fate-mapping studies to definitively address how auto-reactive responses develop.
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Stilla, Alana. "IL-7 Responses In Th17 Cells Are Dysregulated During HIV Infection". Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/34068.
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In the gut-associated lymphoid tissues, Th17 cells mediate mucosal homeostasis and inflammation. During HIV infection, Th17 cells become depleted and functionally impaired, which is implicated in the pathogenesis of chronic inflammation in patients treated with highly active antiretroviral therapy. IL-7 is a cytokine that mediates homeostatic responses in T lymphocytes, such as proliferation and survival, which are dysregulated during HIV infection. Whether similar dysregulation occurs in Th17 cells has yet to be reported. IL-7 receptor α (CD127) expression and IL-7 responses were therefore measured in blood-derived Th17 cells from uninfected individuals and effectively treated, HIV-infected individuals by flow cytometry. Th17 cells from uninfected individuals expressed CD127 and, in response to IL-7, exhibited phosphorylation of STAT5, upregulation of Bcl-2, and proliferation. During HIV infection, expression of CD127 and pSTAT5 in Th17 cells was comparable to that observed in cells from uninfected individuals. Interestingly, expression of Bcl-2 was upregulated while proliferation was dramatically impaired. These findings may provide further insight into the mechanisms by which Th17 cells fail to become restored during HIV infection.
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Bending, David Alexander. "The behaviour of T helper 17 (Th17) cells in health and disease". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609853.
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Prado, Douglas da Silva. "Participação do Nlrp12 na diferenciação de linfócitos Th17 e no desenvolvimento da artrite experimental". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-20072016-162029/.
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A Artrite reumatoide é uma doença autoimune que acomete cerca de 1% da população mundial adulta, sendo caracterizada pela participação de linfócitos Th17 no seu desenvolvimento. Na busca por novos alvos terapêuticos e pela compreensão da fisiopatologia, se destacam os inflamassomas que são plataformas proteicas, caracterizados pela produção de citocinas pró-inflamatórias por células do sistema imune inato. De forma interessante, foi demonstrado que linfócitos T CD4 também expressam alguns sensores dessas plataformas, como o Nlrp12. Adicionalmente, este sensor é responsável pela modulação negativa do NF-?B, demonstrando outra característica atípica em relação aos outros inflamassomas. Nesse sentido, foi avaliada a participação do Nlrp12 no desenvolvimento da artrite experimental e na diferenciação linfócitos Th17. Foi verificado nesse estudo que o Nlrp12 é regulado positivamente durante o desenvolvimento da artrite experimental, sendo um modulador negativo desse processo. Isso se deve a uma redução na resposta inflamatória inata do modelo e pela modulação negativa na resposta Th17. Nesse sentido, o controle da resposta Th17 e o desenvolvimento da artrite experimental ocorre por um mecanismo dependente da fosforilação do fator de transcrição Stat3, que é crítico na diferenciação de linfócitos Th17. Desta forma, este estudo demonstra uma nova função para o sensor Nlrp12 no desenvolvimento da artrite experimental, por modular a resposta imune adaptativa de forma direta nos linfócitos T CD4Rheumatoid Arthritis is an autoimmune disease that occurs in approximately 1% of the adult population worldwide, with critical role of Th17 cells in your development. In the search for new therapeutic targets and the understanding of the pathophysiology, there are inflammasomes which are protein platforms, characterized through pro-inflammatory cytokines production by innate immune system cells. Interestingly, it was demonstrated that CD4 T cells express some inflammasome sensors, as Nlrp12. Additionally, this sensor is responsible for downregulation of NF-?B, showing another atypical feature in relation to other inflammasomes. Thereby, it was evaluated the role of Nlrp12 on experimental arthritis development and Th17 differentiation. It was found in this study that Nlrp12 is upregulated during experimental arthritis development, working as negative regulator of this process. Thus, Nlrp12 downregulates innate inflammatory response from experimental model and Th17 response. Therefore, experimental arthritis development and Th17 differentiation control occurs in a Stat3 phosphorylation dependente-manne, which is a critical transcription factor on Th17 differentiation. Thus, this study demonstrates a new function for Nlrp12 on experimental arthritis development, by directly to modulate adaptive immune response in CD4 cells
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Pirronello, Fausto [Verfasser] y Alla [Akademischer Betreuer] Skapenko. "Altered T cell plasticity favors Th17 cells in rheumatoid arthritis / Fausto Pirronello ; Betreuer: Alla Skapenko". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1202011888/34.
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Lee, Jinju. "IL-23 generates pathogenic Th17 cells by triggering T cell-intrinsic prostaglandin E2-EP2/4 signaling". Kyoto University, 2018. http://hdl.handle.net/2433/235123.
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Ganakammal, Satishkumar Ranganathan. "CIS REGULATORY MODULE DISCOVERY IN TH1 CELL DEVELOPMENT". Thesis, Proceeding ISB '10 Proceedings of the International Symposium on Biocomputing ACM New York, NY, USA ©2010 table of contents ISBN: 978-1-60558-722-6 doi>10.1145/1722024.1722039, 2010. http://hdl.handle.net/1805/2678.
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Indiana University-Purdue University Indianapolis (IUPUI)Immune response enables the body to resist foreign invasions. The Inflammatory response is an important aspect in the immune response which is articulated by elements such as cytokines, APC, T-cell and B-cell, effector cell or natural killer. Of these elements, T-cells especially T-helper cells; a sub class of T-cells plays a pivotal role in stimulating the immune response by participating in various biological reactions such as, the transcription regulatory network. Transcriptional regulatory mechanisms are mediated by a set of transcription factors (TFs), that bind to a specific region (motifs or transcription factor binding sites, TFBS), on the target gene(s) controlling the expression of genes that are involved in T-helper cell mediated immune response. Eukaryotic regulatory motifs, referred to as cis regulatory modules (CRMs) or cistrome, co-occur with the regulated gene’s transcription start site (TSS) thus, providing all the essential components for building the transcriptional regulatory networks that depends on the relevant TF-TFBS interactions. Here, we study IL-12 stimulated transcriptional regulators in STAT4 mediated T helper 1 (Th1) cell development by focusing on the identification of TFBS and CRMs using a set of Stat4 ChIP-on-chip target genes. A region containing 2000 bases of Mus musculus sequences with the Stat4 binding site, derived from the ChIP-on-chip data, has been characterized for enrichment of other motifs and, thus CRMs. Our experiments identify some potential motifs, (such as NF-κB and PPARγ/RXR) being enriched in the Stat4 binding sequences compared to neighboring background sequences. Furthermore, these predicted CRMs were observed to be associated with biologically relevant target genes in the ChIP-on-chip data set by meaningful gene ontology annotations. These analyses will enable us to comprehend the complicated transcription regulatory network and at the same time categorically analyze the IL-12 stimulated Stat4 mediated Th1 cell differentiation.
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Gabsi, Amira. "CD146/CD146s acteurs et cibles de la sclérodermie systémique". Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0645.
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La sclérodermie systémique (ScS) est une maladie auto-immune systémique caractérisée par des lésions vasculaires, une fibrose excessive et une dérégulation immunitaire. CD146 est une molécule d'adhésion essentiellement exprimée dans le système vasculaire, mais également sur les lymphocytes TH17. Compte tenu du rôle récemment décrit du CD146 dans la ScS, nous avons émis l’hypothèse d’une implication de cellules TH17 CD146 positives dans cette pathologie. Nous avons montré que les taux de CD146 (CD146s) et d’IL17A étaient plus importants chez les patients atteints de ScS par rapport aux témoins sains. Également une augmentation significative des cellules TH17 attestée par une augmentation des facteurs de transcriptions RORγT, de l'ARNm de l'IL17A et des cellules CD4+ l'IL17A+ en plus de cellules TH17 exprimant chez les patients atteints de ScS a été démontré. In vitro, nous avons montré une augmentation du pourcentage de cellules TH17 exprimant CD146 après un traitement cellulaire avec la forme soluble de CD146, ce qui suggère que, chez les patients, l’augmentation de cette sous-population pourrait être la conséquence de l’augmentation de CD146s sérique. D’autre part, nous avons montré que les pourcentages de cellules Treg chez les patients atteints de sclérodermie systémique restent inchangés, mais que ces cellules perdent leur activité suppressive en réprimant l'expression de FOXP3. En conclusion, les cellules TH17 exprimant CD146 pourraient représenter un nouveau composant de la réponse immunitaire adaptative et l’axe TH17 / Treg pourrait être une cible thérapeutique potentielle ouvrant la voie à la mise en place de nouveaux outils de gestion de la ScSSystemic sclerosis (ScS) is an autoimmune disease characterized by vascular damage, excessive fibrosis and immune deregulation. CD146 is an adhesion molecule mainly expressed in the vascular system, but also on TH17 lymphocytes. Given the recently described role of CD146 in ScS, we hypothesized the involvement of TH17 CD146 positive cells in this pathology. We have shown that soluble CD146 (sCD146) and IL17A levels are higher in patients with SSC compared to healthy controls, with a positive correlation between the two factors. Also a significant increase in TH17 cells evidenced by an increase in RORγT transcription factors, IL17A mRNA and IL17A + CD4 + cells in patients with ScS has been demonstrated. Interestingly, the percentage of TH17 cells expressing CD146 was higher in patients with ScS than in controls, and inversely correlated with pulmonary fibrosis. In vitro, we have shown an increase in the percentage of TH17 cells expressing CD146 after cellular treatment with the soluble form of CD146, which suggests that, in patients, the increase in this subpopulation could be the consequence of increase in serum CD146s. On the other hand, we have shown that the percentages of Treg cells in patients with systemic scleroderma remain unchanged, but that these cells lose their suppressive activity by repressing the expression of FOXP3. In conclusion, TH17 cells expressing CD146 could represent a new component of the adaptive immune response and the TH17 / Treg axis could be a potential therapeutic target opening the way for the implementation of new tools for managing ScS
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Morelli, Fernando Christiano Gabriel [UNESP]. "Quantificação de citocinas no conteúdo abomasal de bovinos de corte na presença ou ausência de ulceração gástrica". Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/134249.
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Erosões e úlceras são achados comuns no abomaso e causam preocupação econômica nos mais variados sistemas de produção de gado. Muitos fatores podem predispor ao aparecimento de úlceras e acúmulo de gases no abomaso, incluindo alimentos grosseiros, estresse ambiental, deficiências de vitaminas e minerais e infecções bacterianas. Essas úlceras podem ser subclínicas, sendo descobertas nas necropsias ou após o abate do animal, ou levarem à redução da motilidade do órgão, prejudicando o fluxo do seu conteúdo e causando transtornos digestivos graves e até ao aparecimento de síndromes semelhantes à indigestão vagal. Existem informações a respeito da resposta do sistema imune na maior parte das mucosas do trato gastrintestinal de não-ruminantes e ruminantes, porém são raras a respeito do abomaso. Os objetivos desse estudo foram detectar os níveis de citocinas (IL-17A, IFN-γ, TNF-α, IL-10, IL-6, IL-4, IL-2) no conteúdo abomasal em bovinos de corte, determinar o perfil Th1 ou Th2 dessas citocinas em animais com úlceras de grau 1 e 2 na região cárdica abomasal e comparar esses valores com os níveis de citocinas de animais sem úlceras (controle), em amostras colhidas em abatedouro, para auxiliar na compreensão da fisiopatologia do processo inflamatório local. A avaliação macroscópica e a classificação das úlceras foi realizada por meio de exames visual e histológico em amostras de tecidos da parede da região cárdica abomasal ulcerada. Os níveis de citocinas produzidas do líquido abomasal dos animais com ou sem úlceras foram avaliados por citometria de fluxo (método Cytometric Bead Array). As citocinas citadas foram detectadas no líquido do abomaso dos bovinos. Não houve diferença na liberação das citocinas entre os grupos com úlceras e o grupo sem úlcera, indicando um equilíbrio entre perfis Th1 e Th2 da resposta inflamatória.
Erosions and ulcers are common findings in the abomasum and cause economic concern in several livestock production systems. Many factors may predispose to ulcers and bloat in the abomasum, including roughage, environmental stress, deficiencies of vitamins and minerals and bacterial infections. These ulcers may be subclinical and are found during necropsy or after slaughter, or lead to reduction of abomasal motility, hindering the flow of your content and causing serious digestive disorders and even the appearance of syndromes similar to vagal indigestion. There are some studies evaluating the immune system response in most of the mucous membranes of the gastrointestinal tract of non-ruminants and ruminants, but rarely related to the abomasum. The aims of this study were to investigate the levels of cytokines (IL-17A, IFN-γ, TNF-α, IL-10, IL-6, IL-4, IL-2) in the abomasal fluid of beef cattle, to determine the Th1 or Th2 profile of these cytokines in animals with types 1 or 2 ulcers located in the abomasal cardic region and to compare these levels with those of animals without ulcers (controls), in samples collected in an abbatoir, to help to the understand the pathophysiology of the local inflammatory process. Ulcers from the abomasal cardic region were macroscopicaly evaluated, then classified by histology. Cytokine levels in the abomasal fluid from animals with or without ulcers were evaluated by flow cytometry (Cytometric Bead Array). Cytokines were detected in the abomasum fluid of cattle. There was no difference in the release of cytokines between groups, indicating a balance between Th1 and Th2 profiles of the inflammatory response.
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Morelli, Fernando Christiano Gabriel. "Quantificação de citocinas no conteúdo abomasal de bovinos de corte na presença ou ausência de ulceração gástrica /". Araçatuba, 2016. http://hdl.handle.net/11449/134249.
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Orientador: Juliana Regina PeiróBanca: Lina Maria Wehrle Gomide
Banca:Fernanda Bovino
Banca: José Paes de Oliveira Filho
Banca:Glenda Nicioli da Silva
Resumo: Erosões e úlceras são achados comuns no abomaso e causam preocupação econômica nos mais variados sistemas de produção de gado. Muitos fatores podem predispor ao aparecimento de úlceras e acúmulo de gases no abomaso, incluindo alimentos grosseiros, estresse ambiental, deficiências de vitaminas e minerais e infecções bacterianas. Essas úlceras podem ser subclínicas, sendo descobertas nas necropsias ou após o abate do animal, ou levarem à redução da motilidade do órgão, prejudicando o fluxo do seu conteúdo e causando transtornos digestivos graves e até ao aparecimento de síndromes semelhantes à indigestão vagal. Existem informações a respeito da resposta do sistema imune na maior parte das mucosas do trato gastrintestinal de não-ruminantes e ruminantes, porém são raras a respeito do abomaso. Os objetivos desse estudo foram detectar os níveis de citocinas (IL-17A, IFN-γ, TNF-α, IL-10, IL-6, IL-4, IL-2) no conteúdo abomasal em bovinos de corte, determinar o perfil Th1 ou Th2 dessas citocinas em animais com úlceras de grau 1 e 2 na região cárdica abomasal e comparar esses valores com os níveis de citocinas de animais sem úlceras (controle), em amostras colhidas em abatedouro, para auxiliar na compreensão da fisiopatologia do processo inflamatório local. A avaliação macroscópica e a classificação das úlceras foi realizada por meio de exames visual e histológico em amostras de tecidos da parede da região cárdica abomasal ulcerada. Os níveis de citocinas produzidas do líquido abomasal... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Erosions and ulcers are common findings in the abomasum and cause economic concern in several livestock production systems. Many factors may predispose to ulcers and bloat in the abomasum, including roughage, environmental stress, deficiencies of vitamins and minerals and bacterial infections. These ulcers may be subclinical and are found during necropsy or after slaughter, or lead to reduction of abomasal motility, hindering the flow of your content and causing serious digestive disorders and even the appearance of syndromes similar to vagal indigestion. There are some studies evaluating the immune system response in most of the mucous membranes of the gastrointestinal tract of non-ruminants and ruminants, but rarely related to the abomasum. The aims of this study were to investigate the levels of cytokines (IL-17A, IFN-γ, TNF-α, IL-10, IL-6, IL-4, IL-2) in the abomasal fluid of beef cattle, to determine the Th1 or Th2 profile of these cytokines in animals with types 1 or 2 ulcers located in the abomasal cardic region and to compare these levels with those of animals without ulcers (controls), in samples collected in an abbatoir, to help to the understand the pathophysiology of the local inflammatory process. Ulcers from the abomasal cardic region were macroscopicaly evaluated, then classified by histology. Cytokine levels in the abomasal fluid from animals with or without ulcers were evaluated by flow cytometry (Cytometric Bead Array). Cytokines were detected in the abomasu... (Complete abstract click electronic access below)
Doutor
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Fenton, Thomas. "Integrin αvβ8 on human dendritic cells : a role in intestinal immune homeostasis". Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/integrin-alphav8-on-human-dendritic-cells-a-role-in-intestinal-immune-homeostasis(3820bc76-2c42-4db6-a344-b66e5b77769d).html.
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Intestinal inflammatory disorders such as Crohn’s disease contribute significantly to human mortality and morbidity. Although the cells and molecules involved in suppression of intestinal inflammation have been extensively documented in mouse models, a full understanding of how these work together in the healthy and diseased gut remains elusive. It is known, however, that tight regulation over TH17 cells and regulatory T cells (Treg) is required to maintain immune homeostasis in the intestine. Activation of the cytokine transforming growth factor-β (TGFβ), which is secreted by immune cells as an inactive complex, plays a crucial role in the induction of both Treg and TH17 cells. Recent work has shown that the αvβ8 integrin is required for activation of TGFβ by murine dendritic cells (DC). Murine integrin αvβ8 is thus of fundamental importance for Treg and TH17 induction and, subsequently, for intestinal immune homeostasis. However, little is known about the signals controlling the expression of integrin αvβ8 on intestinal DC. Furthermore, whether this system is also important for regulation of the human system is entirely unknown. Here, expression of integrin αvβ8 is shown on human intestinal CD1c+CD103+SIRPα+ DC and CD1c+CD103-SIRPα+ DC, but not on CD141+CD103+SIRPα- DC. Expression of integrin αvβ8 is increased on DC from Crohn’s disease patients, and on DC from non-IBD donors treated with LPS. Both LPS and a number of probiotic bacteria were also able to induce integrin αvβ8 expression on human monocyte-derived DC (moDC), which suggested that the microbiota may play a role in the regulation of human integrin αvβ8. Importantly, we have also shown that TGFβ is activated by integrin αvβ8 on human moDC, and that integrin αvβ8 promotes expression of forkhead box P3 (FOXP3) in naïve human T cells in vitro. Together, these data suggest that integrin αvβ8-mediated activation of TGFβ by DC may play an important role in the regulation of human T cell responses in the human intestine, and that this pathway may be perturbed during intestinal inflammation.
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Klees, Johanna [Verfasser]. "The Influence of Symbiont Bacteroides vulgatus on Th17 Differentiation via Dendritic Cells / Johanna Klees". Tübingen : Universitätsbibliothek Tübingen, 2021. http://d-nb.info/1240673272/34.
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Rehorova, Hradilkova Kristyna. "Role of Twist1 in metabolism of repeatedly stimulated Th1 cells". Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20584.
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Es stellt sich die Frage, wie diese Zellen im entzündeten Gewebe überleben können und wie sie ihren Stoffwechsel an die dortigen Bedingungen anpassen. Diese Arbeit beschreibt am Beispiel der Juvenilen Idiopathischen Arthritis (JIA) die Analyse des Stoffwechsels von CD4+ T Lymphozyten, die chronische Entzündungen antreiben undim entzündeten Gewebe lange Zeit persistieren. Pathogene CD4+ CD45RO+ PD1+ CXCR5-T Zellen wurden hierfür aus Synovialflüssigkeit von Patienten mit JIA isoliert und gezeigt, dass auch bei diesen Zellen der Stoffwechsel auf Fettsäureoxidation beruht. Wurde die Fettsäureoxidation durch Etomoxir blockiert, starben die Zellen. Die Störung des Stoffwechsels dieser Zellen könnte somit eine Option für einen neuen Therapieansatzdarstellen. Zusätzlich war die Expression des Transkriptionsfaktors Twist 1 in diesen CD4+CD45RO+ PD1+ CXCR5- T Zellen hochreguliert. Twist 1 ist ein Marker für T Lymphozyten, die in entzündetem Gewebe von Patienten mit chronisch-entzündlichen Erkrankungen der Gelenke oder des Darmes persistieren. Untersuchung in vitro ergaben außerdem, dass Twist 1 spezifisch von Th1 Lymphozyten exprimiert wird, die mehrfach restimuliert wurden. Dieser Transkriptionsfaktor wirkt einerseits der Gewebszerstörung, die von T Zellen verursacht wird, entgegen, und unterstützt anderseits die Persistenz der Zellen im Gewebe durch die Induktion der microRNA148a, die die Expression des pro-apoptotischen Proteins Bim reguliert. In dieser Arbeit zeigen wir dessen Einfluss auf die Regulation des Metabolismus von CD4+ T Lymphozyten bei chronischen Entzündungen. Dabei wird die Glycolyse verringert und vermehrt Fettsäuren synthetisiert, um die Zellen vor reaktiven oxidierenden Spezies (ROS) zu schützen. Zusätzlich konnten wir nachweisen, dass mehrfach re-stimulierte, Twist-defizienteTh1 Zellen unfähig sind, durch Fettsäureoxydation zu überleben, sondern den Stoffwechsel auf Lipid- Peroxidierung umstellenHow do CD4+ T cells adapt their metabolism for survival in the inflamed tissue? This thesis describes analysis of the metabolism of CD4 T lymphocytes driving chronic inflammation and persisting at the site of inflammation, exemplified by cells that reside in the inflamed tissue of patients with the rheumatic disease juvenile idiopathic arthritis. To specifically take aim at the CD4+ T lymphocytes persisting at the site of inflammation, it is important to determine how these cells adapt their metabolism. We show that pathogenic CD4+ CD45RO+ PD1+ CXCR5- T cells that were isolated from the synovial fluid of patients with juvenile idiopathic arthritis are dependent on a fatty acid oxidation for survival ex vivo. Their survival can be blocked by blocking FAO with Etomoxir, pointing to the option of targeting such cells by metabolic interference. Furthermore, CD4+ CD45RO+ PD1+ CXCR5- T cells had upregulated expression of Twist1, a hallmark transcription factor of T lymphocytes persisting in the inflamed tissues of patients with chronic-inflammatory diseases of joints or the gut. Expression of Twist1 is specific for Th1 lymphocytes which have repeatedly been re-stimulated in vitro, or isolated from inflamed. This transcription factor dampens immunopathology caused by the T cells and supports their persistence, by inducing microRNA148a, which regulates expression of the proapoptotic protein Bim. This thesis shows, through conditional genetic inactivation of Twist1 in CD4+ T lymphocytes, that Twist1 regulates the metabolism ofCD4 T lymphocytes of chronic inflammation, by downregulating glycolysis, promoting fatty acid synthesis and protecting the cells from ROS. Additionally, we show that Twist1 deficient repeatedly reactivated murine Th1 cells are unable to survive on fatty acid oxidation and have increased levels of lipid peroxidation.
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Ayala-Fontanez, Nilmarie. "Paradoxical onset of psoriasis after IL-6 receptor blockade". Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1436396399.
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Esfandiari, Ehsanollah. "Role of Th1 and Th2 cytokines in the pathogenesis of systemic autoimmune diseases". Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366255.
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Hayes, Mark. "The role of innate and adaptive IL-17 producing cells in chemical allergy". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-innate-and-adaptive-il17-producing-cells-in-chemical-allergy(88fe6cd2-d6ca-4743-8889-cca8ab059815).html.
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The Interleukin (IL)-17 cytokine family, expressed by T helper (Th)17 cells and γδ T cells, plays pivotal roles in adaptive immune responses. They have been implicated in autoimmune and allergic diseases as well having roles in bacterial and fungal clearance. Importantly, IL-17 producing γδ T cells have been shown to be critical for the development of adaptive Th17 responses in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis. Interestingly, natural ligands of the aryl hydrocarbon receptor (AhR) are known to influence the development of Th17 cells. It has been shown previously that prolonged topical exposure of mice to the contact allergen 2-4 dinitrochlorobenzene (DNCB) or to the respiratory sensitiser trimellitic anhydride (TMA) causes the preferential development of a preferential T helper (Th)1 or Th2 response, respectively. The presence of the novel IL-17 family cytokines and their cellular source was investigated following both single and prolonged exposure to allergen. Exposure only to the contact allergen DNCB resulted in up-regulation of the expression of IL-17 by dermal γδ T cells. It was shown also that topical application of a range of contact allergens and of the respiratory allergen TMA resulted in IL-17 expression by γδ T cells in the lymph node draining the site of exposure. However, differential kinetics were observed between the two classes of allergens. Exposure to the contact allergens resulted in rapid expression of IL-17 within 6-16 h, whereas the respiratory allergen displayed considerably delayed kinetics, with maximal levels detected 48 h post exposure. Treatment with DNCB only was shown to be associated with the development of Th17 cells following prolonged exposure to chemical allergen. Thus DNCB provoked a Tc1/Th1/Th17 profile, in contrast prolonged exposure to TMA resulted in a very selective Th2 cytokine pattern. The influence of γδ T cells on polarised responses to chemical allergens was investigated also using γδ T cell knockout mice; here the adaptive Th17 response induced by DNCB was completely abrogated. These data demonstrate that the absence of IL-17 production by γδ T cells during the early innate immune response affects the subsequent adaptive Th17 response stimulated by chemical contact allergens. Finally, the importance of the affinity of the AhR for endogenous ligands during in vitro Th17 polarisation was assessed. Using three strains of mice with differential AhR affinities the contribution of ligation of these receptors in Th17 cell development was investigated. In all three strains AhR ligation was required for optimal polarisation of Th17 cells, even in strains that are reported to express a low affinity receptor. These data suggest that across a range of receptor affinities, including low affinity receptors analogous to that of humans, endogenous AhR ligands may play a major role in driving Th17 cell differentiation, regardless of receptor phenotype.
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Oo, Ye Htun. "Recruitment and positioning of regulatory T cells and Th17/Tc17 in inflamed human liver". Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1128/.
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The liver is a unique tolerogenic organ with dual blood supply. Both regulatory lymphocytes and effector lymphocytes are present in the normal and inflamed liver along with innate immune cells. The balance between these two subsets of lymphocyte is crucial in maintaining immune homeostasis by adjusting either hepatic tolerance or mounting immunity against invading pathogens. Thus, it is important to understand the intrahepatic regulatory T cells phenotype and role played by distinct chemokine receptors expressed on regulatory T cells as they are major player in controlling hepatic tolerance. At the same time, it would be crucial to explore the role of new subset of Th17/Tc17 effector lymphocytes characteristic and their positioning in inflamed liver. This thesis demonstrates the crucial role of chemokine receptors in recruitment and positioning of both intrahepatic regulatory T lymphocytes and IL-17 secreting Th17/Tc17 effector lymphocyte in both normal and inflamed human liver.
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Wanke, Florian [Verfasser]. "The role of EBI2 for encephalitogenic TH17 cells in EAE and in MS / Florian Wanke". Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1148689206/34.
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Hardaway, John C. Zaghouani Habib. "Examination of neonatal immunity in IL-13 receptor alpha 1 deficient mice". Diss., Columbia, Mo. : University of Missouri-Columbia, 2009. http://hdl.handle.net/10355/6977.
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The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on January 5, 2010). Vita. Thesis advisor: Habib Zaghouani. Includes bibliographical references.
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Cantor, Joseph M. "Effector function of pathogenic CD4 TH1 T cells in autoimmune diabetes /". Connect to full text via ProQuest. IP filtered, 2005.
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Thesis (Ph.D. in Immunology) -- University of Colorado, 2005.Typescript. Includes bibliographical references (leaves 180-202). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Mancini, Francesca. "A PROMISING NOVEL FORMULATION OF STAPHYLOCOCCUS AUREUS VACCINE PROTECTS MICE VIA ANTIBODIES AND CD4+ EFFECTOR T CELLS". Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423478.
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Life-threatening Staphylococcus aureus infections and the emergence of antibiotic-resistant strains make vaccination a major medical need. Novartis Vaccines developed a vaccine candidate (Combo) that consists of HlaH35L, a non-toxic mutant of the α-toxin, EsxAB, a fusion of the secreted factors EsxA and EsxB, and of two surface proteins, FhuD2 and Sur2. Combo±alum has shown efficacy in pre-clinical mouse models and has recently been tested in a human phase I clinical trial.
To improve this vaccine further, Combo antigens were formulated with alum/SMIP-7.10 (alum-S-7), a novel adjuvant formulation composed of a Toll-like receptor 7 agonist small molecule adsorbed to alum. We characterized the immune responses elicited by this novel formulation, and compared its efficacy to that induced by Combo±alum in a mouse model of S. aureus-induced peritonitis.
Combo+alum-S-7 showed increased efficacy than Combo+alum, with 75%, respectively 40%, of mice surviving a lethal challenge. Compared to Combo+alum, Combo+alum-S-7 induced higher vaccine-specific antibody titers, and polarized CD4+ T-cell responses towards Th1 and Th17 effectors (IFN-ϒ or IL-17 production, respectively). In vivo depletion of CD4+ effector T cells in mice vaccinated with Combo+alum-S-7 reduced the efficacy of this vaccine by 20%. The residual protection was likely due to Combo-specific antibodies since passive transfer of sera from mice immunized with Combo+alum-S-7 to naïve mice resulted in 30% of survival. The requirement of B cells/antibodies to confer protection against S. aureus in the peritonitis model by Combo vaccination was confirmed by the death of 96% of B-cell ko JH mice vaccinated with Combo+alum/S-7 or Combo+alum. In vivo neutralization of IL-17A, either alone or together with IFN-ϒ, but not of IFN-ϒ alone, increased bacterial loads in kidneys of mice immunized with Combo+alum-S-7 as did the depletion of CD4+ effector T cells.
Overall these data show that adding SMIP-7.10 to Combo+alum increases the efficacy of this candidate vaccine through combined antibody and Th17 responses in an animal model of S. aureus infection.L'emergenza di ceppi di Staphylococcus aureus resistenti agli antibiotici rende il trattamento dei pazienti più difficile e, al tempo stesso, più urgente la necessità di un vaccino. Novartis Vaccines ha sviluppato un candidato vaccino (Combo) che consiste di: HlaH35L, un mutante atossico della tossina-α; EsxAB, fusione delle due proteine secrete EsxA e EsxB; FhuD2 e Sur2, due proteine di superficie. È stato dimostrato che Combo±alum è efficace in modelli animali preclinici ed il vaccino è stato recentemente testato nella fase I di un clinical trial. Al fine di migliorare ulteriormente il vaccino, gli antigeni di Combo sono stati formulati con alum/SMIP-7.10 (alum-S-7), un nuovo adiuvante composto da una small molecule, agonista del Toll-like receptor 7, adsorbita all’alum. Abbiamo caratterizzato le risposte immunitarie indotte da questa nuova formulazione e abbiamo confrontato la sua efficacia con quella di Combo±alum in un modello murino di peritonite indotta da S. aureus. Combo+alum-S-7 ha dimostrato un’efficacia superiore a quella di Combo+alum, con il 75% dei topi, rispetto al 40%, che sopravvivevano all’infezione letale. In confronto a Combo+alum, Combo+alum-S-7 ha indotto titoli anticorpali specifici per il vaccino più elevati e ha polarizzato le riposte T CD4+ verso risposte di tipo Th1 e Th17 effettrici (produzione di IFN-ϒ o IL-17, rispettivamente). La deplezione in vivo delle cellule T CD4+ effettrici nei topi vaccinati con Combo+alum-S-7 ha ridotto l’efficacia del vaccino del 20%. La protezione residua era verosimilmente dovuta agli anticorpi specifici per il vaccino: un passive transfer di sieri di topi immunizzati con Combo+alum-S-7 in topi naïve ha infatti conferito una protezione del 30%. La necessità della presenza di cellule B/anticorpi per proteggere i topi vaccinati con Combo dall’infezione con S. aureus nel modello di peritonite è stata confermata dalla morte del 96% dei topi JH (deficienti delle cellule B) vaccinati con Combo+alum/S-7 o Combo+alum. La neutralizzazione in vivo di IL-17A, sia da sola che in combinazione con IFN-ϒ, ma non del solo IFN-ϒ, ha aumentato la carica batterica nei reni dei topo immunizzati con Combo+alum-S-7, come successo in seguito a deplezione delle cellule T CD4+ effettrici. Nell’insieme, questi dati dimostrano che l’aggiunta dello SMIP-7.10 al vaccino Combo+alum ne aumenta l’efficacia in un modello animale di infezione con S. aureus attraverso l’induzione di anticorpi e risposte Th17.
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Andrade, Mariana Macedo Costa de. "O efeito da tolerância à endotoxina nos linfócitos T regulatórios e Th 17". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5164/tde-20092016-155050/.
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O controle de respostas imunes patológicas (autoimunidade, alergia, rejeição de transplantes) tem sido um dos principais objetivos dos imunologistas. Apesar dos avanços recentes, a maioria dos tratamentos atuais ainda procura diminuir a imunidade e inflamação em vez de restabelecer o estado saudável da tolerância imunológica. Sepse é uma doença desencadeada pela presença de bactérias e/ou produtos bacterianos como lipopolissacarídeos (LPS), componente principal da membrana externa de bactérias gram-negativas, ativando a resposta imune do hospedeiro. A caracterização do perfil de linfócitos na resposta à tolerância ao LPS são de extrema importância para a contribuição do estudo da imunodepressão na sepse. O objetivo deste estudo foi investigar se a comprovada redução de mortalidade previamente vista em modelo de sepse animal através tolerância ao LPS, pode ser associada com o aumento da população de linfócitos T CD4+ regulatórios e Th17. Camundongos machos C57/6, receberam por via subcutânea ( s.c.) injecções de LPS ( 1mg/kg ) durante 5 dias , seguido por perfuração e ligadura cecal (CLP ) . Citocinas e linfócitos marcados foram medidos durante, após a tolerância e o desafio CLP. Ambos os subtipos de células T analisados Treg e Th17 , mostrou aumento destas células no baço durante e após a tolerância. Este estudo demonstrou que a mortalidade reduzida depois de tolerância previamente constatada pode ser associada com o aumento da população de células T regulatórias e Th17 devido a imunorregulação do hiperinflamação e recrutamento de neutrófilosThe control of pathological immune responses (autoimmunity, allergy, transplant rejection) has been a major goal of immunologists. Despite recent advances, most current treatments still seeks to reduce immunity and inflammation rather than restore the healthy state of immune tolerance. Sepsis is a disease triggered by the presence of bacteria and / or bacterial products like lipopolysaccharide (LPS), the main component of the outer membrane of gram-negative bacteria, activating the immune response of the host. The characterization of lymphocyte profile in response to LPS tolerance is extremely important for the study of immunosuppression in sepsis contribution. The aim of this study was to investigate whether the proven reduction in mortality seen previously in animal sepsis model by tolerance to LPS, can be associated with the increase in population of CD4 + regulatory and Th17. Mice C57 / 6 mice received subcutaneous (s.c.) injection of LPS (1mg / kg) for 5 days, followed by cecal ligation and puncture (CLP). Cytokines and marked lymphocytes were measured during after tolerance and CLP challenge. Both subtypes of T cells Treg and Th17 analyzed showed an increase of these cells in the spleen during and after tolerance. This study demonstrated that reduced mortality after previously seen tolerance may be associated with increasing the population of regulatory T cells and Th17 because immunoregulation of the hiperinflamação and neutrophil recruitment
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Monteiro, Barbara Vanessa de Brito. "An?lise da resposta Th17 em l?quen plano oral". Universidade Federal do Rio Grande do Norte, 2012. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17122.
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Th17 cells have been strongly associated with the pathogenesis of several autoimmune and inflammatory diseases. IL-17 and IL-23 are important cytokines associated with this lineage. The aim of this study was to analyze, through immunohistochemical methods, the immunoexpression of IL-17 and IL-23 in the inflammatory infiltrate of oral lichen planus (OLP) lesion compared to that of inflammatory fibrous hyperplasia (IFH) and between clinical forms reticular and erosive of OLP. The sample included 41 cases of OLP, of which 23 were reticular and 18 erosive and 10 cases of IFH. The results were subjected to nonparametric statistical tests with a 5% significance level. In OLP lesions histomorphological analysis, the most common findings were: hyperparakeratinization, specimens with atrophic epithelium in erosive clinical form (p = 0.011), epithelial projections in most of reticular type of lesions, in addition Civatte bodies were identified in most samples of both clinical forms. For immunohistochemistry analysis, five fields with strong immunoreactivity for IL-17 and IL-23 were photomicrographed at 400x magnification, images were transferred to a computer where with ImageJ software?, lymphocytes that exhibited cytoplasmic immunostaining for these cytokines were counted. A mean was established after for each case. There was no statistically significant difference in the number of imunopositive lymphocytes for IL-17 and IL-23 among the group of OLP and IFH group, however a larger amount of lymphocytes imunopositive for IL-17 was found in the LPO group (p = 0.079) and significantly higher amounts of those lymphocytes were found in the erosive OLP when compared to the group of reticular OLP and IFH (p = 0.019). Furthermore, a marker epithelial immunopositivity for IL-17 was observed in OLP group. Although the results of this study do not permit the forceful assertion about the participation of Th17 lineage in OLP lesions, the findings of immunopositive lymphocytes counting for IL-17 and IL-23, which are potent proinflammatory cytokines, together with the the marked epithelial immunopositivity found for IL-17 in this study, suggest a possible role of this lineage in the pathogenesis of this disorder
As c?lulas Th17 t?m sido fortemente associadas com a patogenia de diversas doen?as autoimunes e inflamat?rias. A IL-17 e a IL-23 s?o importantes citocinas associadas com esta linhagem. O objetivo do presente trabalho foi analisar, atrav?s de m?todos imunohistoqu?micos, a imunoexpress?o da IL-17 e da IL-23 no infiltrado inflamat?rio das les?es de l?quen plano oral (LPO) comparando ao da hiperplasia fibrosa inflamat?ria (HFI) e entre as formas cl?nicas reticular e erosiva do LPO com o intuito de esclarecer se a linhagem Th17 participa da patog?nese do LPO. Na amostra foram inclu?dos 41 casos de LPO, dos quais 23 eram reticulares e 18 erosivos, al?m de 10 casos de HFI. Os resultados foram submetidos a testes estat?sticos n?o param?tricos com n?vel de signific?ncia de 5%. Na an?lise histomorfol?gica das les?es de LPO, observou-se predom?nio de: les?es hiperparaceratinizadas, esp?cimes com epit?lio atr?fico na forma cl?nica erosiva (p=0,011), proje??es epiteliais nas les?es do tipo reticular, al?m de corpos de Civatte identificados na maior parte da amostra de ambas as formas cl?nicas. Para o estudo imuno-histoqu?mico, cinco campos com forte imunorreatividade para a IL-17 e para a IL-23 foram fotomicrografados sob o aumento de 400x, as fotos foram transferidas para um computador onde com o aux?lio do software ImageJ?, realizou-se a contagem dos linf?citos que exibiram imunomarca??o citoplasm?tica para estas citocinas. Posteriormente, foi estabelecida uma m?dia para cada caso. N?o foram observadas diferen?as estatisticamente significativas na quantidade de linf?citos imunopositivos para a IL-17 e para a IL-23 entre o grupo do LPO e da HFI, no entanto uma maior quantidade desses linf?citos para a IL-17 foi encontrada no grupo do LPO (p=0,079) e uma quantidade significativamente maior de linf?citos imunopositivos para a IL- 23 foi encontrada entre o grupo do LPO erosivo e da HFI (p=0,019). Al?m disto, foi observada uma marcante imunopositividade epitelial para a IL-17 no grupo do LPO. Ainda que os resultados do presente estudo n?o permitam a afirma??o contundente da participa??o da linhagem Th17 nas les?es de LPO, os achados da contagem dos linf?citos imunopositivos para a IL-17 e para a IL-23, que s?o potentes citocinas pr?-inflamat?rias, somados ? marcante imunopositividade epitelial encontrada para a IL-17 neste estudo, sugerem uma poss?vel participa??o desta linhagem na patog?nese desta desordem
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Santos, Juliana do Outeiro. "Impacto da exposição fetal ao HIV-1 na função das células T e das células dendríticas de neonatos não infectados". Universidade do Estado do Rio de Janeiro, 2010. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=3795.
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Conselho Nacional de Desenvolvimento Científico e TecnológicoA síndrome da imunodeficiência adquirida (AIDS), causada pelo vírus da imunodeficiência humana (HIV), é uma das epidemias mais impactantes do milênio e, desde o início, o número de mulheres jovens infectadas vem aumentando vertiginosamente, principalmente nos países em desenvolvimento onde muitas destas engravidam precocemente. Apesar da grande maioria dos casos de AIDS pediátrico no mundo resultar da transmissão vertical, aproximadamente dois terços dos neonatos expostos ao HIV durante a vida fetal não são contaminados. Neste sentido, seguindo as recomendações do consenso brasileiro (Ministério da Saúde), toda criança cuja transmissão vertical tenha sido descartada laboratorialmente não necessita de acompanhamento ambulatorial particularizado. Entretanto, resultados anteriores obtidos pelo nosso grupo demonstraram que, gestantes infectadas pelo HIV-1 que não controlam a carga viral plasmática (CVP), apresentam níveis elevados de citocinas inflamatórias e, no presente estudo, resultados revelam que neonatos não-infectados nascidos dessas gestantes apresentam anormalidades imunofuncionais no compartimento das células T do cordão umbilical quando expostos in vitro a ativadores policlonais, mas não aos antígenos do HIV-1. Ademais, quando comparada a neonatos não expostos, a ativação in vitro das células T de neonatos expostos ao HIV-1 com anti-CD3/anti-CD28 induziu a produção de níveis elevados de IL-17 e reduzidos de IL-10. Interessantemente, essa tendência das células T em secretar IL-17 parece estar relacionada à liberação de níveis elevados de IL-23 pelas células dendríticas derivadas de monócitos do sangue do cordão umbilical estimuladas com lipopolissacarídeo bacteriano. Uma ausência de sensibilização uterina aos antígenos do HIV-1 sugere que essas alterações possam traduzir um efeito adverso da produção elevada de citocinas inflamatórias maternas sobre o sistema imune do neonato, o que pode desequilibrar os eventos envolvidos na maturação e homeostasia imune fetal e neonatal, favorecendo o predomínio de fenótipos Th anômalos, tal como Th17. Essa hiper-responsividade das células Th17 pode vir a comprometer não apenas a capacidade da criança em responder de forma adequada a diferentes estímulos antigênicos ao longo de sua vida, como também pode torná-la mais suscetível a desordens imunomediadas
The acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), is one of the most impelling epidemic in the world, and the HIV-infection in young women has been increasing fast in the recent times, mainly in developing countries where most of them become pregnant precociously. Although the great majority of the pediatric AIDS cases all over the world results from vertical transmission, approximately, two thirds of the children exposed to HIV during fetal life are not contaminated. In this context, following brazilian consensus recommendations (Health Ministry), every child whom vertical transmission had been laboratorialy discarded does not need a specific ambulatorial follow up. However, our previous results demonstrated that HIV-1-infected pregnant women who did not control their plasma viral load presented elevated levels of inflammatory cytokines, and in the present study our results revealed that non-infected neonates, born from these pregnant women display immune functional abnormalities in umbilical cord T cells compartment when exposed in vitro to policlonal activators, but not to HIV-1 antigens. Furthermore, when compared to non-exposed neonates, T cell in vitro activation with anti-CD3/anti-CD28 from neonates exposed to HIV-1 induced production of high IL-17 levels and decreased of IL-10. Interestingly, this T cell bias in secreting IL-17 seem to be related to liberation of high IL-23 levels by dendritic cells derived from umbilical cord blood monocytes following stimulation with bacterial lipopolysacharide (LPS). The lack of uterine sensitization to HIV-1 antigens suggests that, these alterations, may translate an adverse effect of a high level maternal inflammatory cytokines production on neonates immune system, which may unbalance events related to neonatal and fetal immune maturation and homeostasis, favoring Th anomalous phenotypes predominance, such as Th17. This Th17 hyper-responsiveness may then compromise not only the childs capacity to respond in an adequate way to different antigenic stimuli through life, as well as becoming them more susceptible to immune-mediated disorders
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Santos, Márcio Bezerra. "Resposta imune a antígenos de Mycobacterium leprae e apresentação clínica da hanseníase como perspectiva para o desenvolvimento de ferramentas para prognóstico e imunoprofilaxia". Universidade Federal de Sergipe, 2017. http://ri.ufs.br:8080/xmlui/handle/123456789/3640.
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Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is estimated that less than 1% of the individuals infected with M. leprae develop the disease. Several authors suggest that the genetic pattern and variations in the mechanisms of the patient's immune response influence the susceptibility or resistance to disease. The most recent studies have established the role of Th1, Th2 and Treg cell responses in immunopathogenesis of leprosy. However, several mechanisms of the immune response that act in clinical evolution still lack clarification, such as the role of Th17 cells, and the innate immune response. The objective of this study was to evaluate the role of the immune response in the clinical presentation of leprosy and the use of M. leprae recombinant antigens as a perspective for the development of prognostic and immunoprophylaxis tools. To investigate the involvement of immune response in the pathogenesis of leprosy, we analyzed the cytokine profile in lesions, in serum, and peripheral blood mononuclear cells (PBMC) stimulated with M. leprae antigens in leprosy patients and household contactants (HHC). CD4+IL-17+ T cells expressing IL-17A, IFN-γ and IL-10 were evaluated by confocal microscopy in lesions from patients with tuberculoid (TT, n = 09) and lepromatous leprosy (LL, n = 08). Inflammatory cytokines were measured in serum samples from 23 paucibacillary (PB) patients, 28 multibacillary (MB) and 23 HHC, using the Luminex technique. The phenotype of lymphocytes producing IL-17A and IFN-γ was determined by flow cytometry. In addition, PBMC from leprosy patients and HHC were stimulated with crude M. leprae (MLCS) and M. tuberculosis (PPD) and a recombinant antigen of M. leprae (ML2028), and the cytokine profile and the CD4+ and CD8+ multifunctional T cells (producing IFN-γ, IL-2 or TNF-α) of effector and central memory were analyzed. We observed that TT lesions expressed more CD4+IL-17A+ cells than LL. Higher levels of IFN-γ were detected in PB patients, but also in MB patients who presented leprosy reactions (LR) at the time of evaluation (MB LR+). Significantly, higher concentrations of IL-17A and IL-1β were observed in serum from PB than in from MB patients. Ex vivo cell analysis by flow cytometry revealed higher frequency of Th17 cells in TT than LL patients, and it is not high in LL patients with LR. These results indicate that the Th17 cells are associated with an effective inflammatory response that occurs in PB presentation of leprosy but were not associated with the inflammatory response in LR. Th1 response was also associated with PB presentation. However, high levels of IFN-γ were also associated with LR. Multiparameter analyzes by flow cytometry revealed a higher frequency of multifunctional T cells specific for M. leprae antigens in HHC than in leprosy patients, and it might explain the absence of disease in these individuals. These data indicate that these antigens are capable of inducing a more effective immune response and multifunctional T cell memory against M. leprae infection, and open perspectives for the future development of immunoprophylaxis with M. leprae antigens. Additionally, this study suport the attempt to induce a Th1 and Th17 response in individuals at risk of acquiring the disease, even considering this could induce only a partial protection, because it would protect against the most severe MB forms of leprosy, and reduce the disease transmission. This Thesis includes one paper accepted for publication, about the role of Th1 and Th17 cells in subjects with different clinical forms of leprosy, and another paper submitted about the immune response to M. leprae crude and recombinant antigens.A Hanseníase é uma doença infecciosa crônica e de evolução lenta causada pelo Mycobacterium leprae. A literatura sugere que menos de 1% dos indivíduos infectados pelo bacilo evolui com a doença. O padrão genético dos indivíduos e diferenças nos mecanismos da resposta imune do paciente influenciam na susceptibilidade ou resistência à infecção e apresentação clínica da doença. Os estudos mais recentes estabeleceram o papel das respostas de células Th1, Th2 e Treg na imunopatogênese da hanseníase. No entanto, diversos mecanismos das células Th17 e o papel da resposta imune inata na doença ainda não estão bem estabelecidos. Diante disso, este estudo teve como objetivo avaliar o papel da resposta imune na apresentação clínica da hanseníase e o uso de antígenos brutos e recombinante de M. leprae como perspectiva para o desenvolvimento de ferramentas de prognóstico e imunoprofilaxia. Para investigar o envolvimento das células da resposta imune na patogênese da hanseníase, analisamos o perfil de citocinas em lesões, nos soros, e em células mononucleares do sangue periférico (PBMC) estimuladas com antígenos de M. leprae em pacientes com hanseníase e controles contactantes sadios (CCS). As células T CD4+IL-17+ e que expressam IL-17A, IFN- e IL-10 foram avaliadas por microscopia confocal em biópsias de lesões de pacientes com hanseníase tuberculóide (HT, n = 9) e virchowiana (HV, n = 8). As citocinas inflamatórias foram dosadas em amostras de soro de 23 paucibacilares (PB), 28 multibacilares (MB) e em 23 CCS, pela técnica de Luminex. O fenótipo de linfócitos produtores de IL-17A e IFN-γ foi determinado por citometria de fluxo. Além disso, PBMC de pacientes com hanseníase e de CCS foram estimuladas com os antígenos brutos de M. leprae (MLCS), M. tuberculosis (PPD) e recombinante de M. leprae, (ML2028), e o perfil de citocinas e o fenótipo das células T CD4+ e CD8+ multifuncionais (produtoras de IFN-γ, IL-2 ou TNF-α) de memória efetora e central foram analisados. Observamos que as lesões de HT expressaram mais células CD4+IL-17A+ do que as de HV. Níveis mais elevados de IFN-γ sérico foram detectados em pacientes com as formas HT e em MB que apresentavam reações hansênicas (MB RH+). Concentrações mais elevadas de IL-17A e IL-1β foram observadas nos soros de pacientes PB do que em MB. As análises das células ex vivo por citometria de fluxo revelaram maior frequência de células Th17 nos pacientes com hanseníase tuberculóide (HT) em comparação com aqueles com hanseníase virchowiana (HV). Estes resultados indicam que a resposta Th17 está associada a uma resposta inflamatória efetiva que se apresenta nas formas PB, mas não estão associadas à resposta inflamatória durante as reações hansênicas. A resposta Th1 também está associada às formas PB, entretanto altos níveis de IFN-γ foram associados também aos episódios de reação hansênica. As análises multiparamétricas por citometria de fluxo revelaram maior frequência de células T multifuncionais antígeno-específicas em CCS, do que em pacientes com hanseníase. Nossos dados indicam que controles contactantes, quando estimulados com antígenos brutos e com o ML2028 recombinante, produziram mais células T multifuncionais e isto sugere que estas células proporcionam uma resposta imunológica mais eficaz contra a infecção por M. leprae, podendo explicar a ausência de doença nesses indivíduos. Estes dados sugerem que esses antígenos são capazes de induzir uma resposta protetora e indutora de células T multifuncionais de memória e abrem perspectivas para o desenvolvimento futuro de imunoprofilaxia com estes antígenos de M. leprae. Além disso, o estudo dá suporte à busca de induzir uma resposta Th1 e Th17 em indivíduos em risco de adquirir a doença, mesmo que haja uma proteção parcial, pois neste caso haveria uma proteção contra formas mais graves MB, e reduziria também a transmissão da doença. Esta tese é composta por um artigo aceito para publicação sobre a resposta de células Th17 e Th1 nas formas clínicas da hanseníase e outro submetido sobre a resposta a antígenos recombinantes de M. leprae na indução de células T multifuncionais.
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McGovern, J. "The influence of biologic therapy on the capacity of regulatory T cells to restrain Th17 responses". Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1363638/.
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The importance of IL-17 is underscored both by its resistance to control by regulatory T cells (Treg) and the propensity of Treg to produce this highly inflammatory cytokine. I addressed whether Th17 cells are inhibited by Treg from anti-TNF treated rheumatoid arthritis (RA) and psoriatic arthritis patients (PsA) and defined the underlying mechanisms. Th17 responses were inhibited by Treg isolated from RA patients responding to the anti-TNF antibody adalimumab, but not by Treg from healthy individuals or patients with active RA. Furthermore, in patients with RA, response to adalimumab therapy was associated with a reduction in RORC+ Th17 cells and an increase in FOXP3+ Treg lacking Helios and CD62L expression. These Treg suppressed Th17 cells through inhibition of monocyte-derived IL-6, but independently of IL-10 and TGF-ß, which mediated suppression of Th1 responses. Surprisingly, therapy with the anti-IL-6 receptor, tocilizumab, did not result in a reduction in RORC+ cells in RA patients. Rather, tocilizumab reduced T cell IL-21 production, which was associated with a diminished memory B cell population. The acquisition of IL-17 suppressor function by Treg was not observed in RA patients responding to etanercept, a modified TNF receptor, or in PsA patients treated with either adalimumab or etanercept. Moreover, response to therapy was not associated with an increase in Treg number in these patients. In RA patients treated with etanercept the inability of Treg to suppress Th17 responses was associated with high levels of IL-17 production and high levels of RORC+ Th17 cells ex vivo. In contrast, there was a reduction in IL-17 production and RORC+ Th17 cells ex vivo in PsA patients treated with both adalimumab and etanercept. Furthermore, depletion of Treg from PBMC showed that Treg from healthy controls, patients with active PsA and PsA patients responding to adalimumab can modulate the production of IL-22, a key cytokine in inflammatory skin disorders. However, PsA patients responding to etanercept have an impaired ability to regulate production of this cytokine. In conclusion, the induction of IL-17 suppressing Treg by anti-TNF is both therapy and disease specific. These data provides a rationale for the therapeutic benefit of switching between different anti-TNF agents. Furthermore, the induction of highly potent Treg may offer an explanation as to why patients treated with adalimumab have an increased risk of developing Mycobacterium tuberculosis (TB).
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Ghannam, Soufiane. "Les lymphocytes Th17 humains : modulation de leur fonction effectrice par les cellules souches mésenchymateuses et caractérisation de leurs propriétés migratoires". Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON1T023.
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Les lymphocytes Th17 forment une population de cellules T CD4+ pro-inflammatoires, impliqués non seulement dans l'élimination d'agents pathogènes, mais ayant aussi un rôle délétère dans l'induction de maladies inflammatoires chroniques. Ils expriment spécifiquement le récepteur de chimiokines CCR6, qui a pour ligand le CCL20 mais aussi les β-defensine-1, 2 et 3, peptides ayant une activité antimicrobienne. Les cellules souches mésenchymateuses (CSMs) représentent une population cellulaire hétérogène exerçant diverses propriétés immunomodulatrices.Les résultats obtenus dans ce travail de thèse montrent que l'environnement inflammatoire contribue à augmenter l'adhésion des lymphocytes Th17 aux CSMs, et qu'elle est régulée par l'interaction du CCR6 avec ses ligands ; que les CSMs exercent, en partie via la sécrétion de PGE2, des effets anti-inflammatoires en faisant acquérir un phénotype régulateur aux lymphocytes Th17 différenciés, soulignant ainsi la plasticité de ces derniers.De plus, nous avons montré que les lymphocytes Th17 activés par l'antigène produisent du CCL20 et induisent, via la production de l'IL-17 et de l'IL-22, la sécrétion d'hBD-2, mais pas celle des hBD-1 et 3, par des kératinocytes épidermiques humains et de la peau reconstituée; que le CCL20, ainsi que la hBD-2, induisent l'arrêt de ces cellules sur l'endothélium enflammé in vitro en conditions de cisaillement. Finalement, l'activation spécifique d'antigène des lymphocytes Th17 entraîne une perte de l'expression de CCR6, ce qui provoque ainsi un état transitoire de non réponse à une nouvelle stimulation de ces cellules avec les ligands de CCR6, permettant leur migration ultérieure hors du tissu enflamméTh17 cells form a population CD4+ T cells with strong pro-inflammatory properties that are not only involved in the clearance of pathogens, but also play a deleterious role of in the pathogenesis of inflammatory disease. Th17 cells specifically express CCR6, a chemokine receptor that binds to its unique chemokine ligand, CCL20, as well as to human β-defensin (hBD)-1, 2 and 3, peptides with anti-microbial activity. Mesenchymal stem cells (MSC) represent a heterogenous population that exert broad immunomodulatory effects.The results from the studies carried out during this thesis show that the inflammatory environment contributes to increased adhesion of Th17 cells to MSCs, which is mediated via the interaction of CCR6 with its ligands, and that MSCs exert, in part via the secretion of PGE2, anti-inflammatory effects through the induction of a T regulatory cell phenotype in fully differentiated tissue-infiltrating Th17 cells, thereby underscoring the plasticity of the latter cells.Furthermore, the results show that antigen-activated Th17 cells produce CCL20 and induce, via the production of both IL-17 and IL-22, the secretion of hBD-2, but not 1 and 3, by normal human epidermal keratinocytes and reconstituted skin, and that CCL20, as well as hBD-2, induce arrest of these cells onto inflamed endothelium in vitro under conditions of shear stress. Finally, antigen-specific activation of Th17 cells also causes a loss of CCR6 expression from their cell surface and thus results in a transitory state of non-responsiveness to further stimulation of these cells with CCR6 ligands, which is likely to permit their subsequent migration out of inflamed tissue
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Debock, Isabelle. "Study of the development of Th17-type immune response in early life". Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209700.
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Par rapport à l’adulte, le nouveau-né présente une susceptibilité accrue aux agents infectieux et au développement d’allergies. Une polarisation de l’immunité acquise vers des réponses de type Th2, productrices d’IL-4, d’IL-5 et d’IL-13, et un défaut de réponses immunes de type Th1, sécrétant de l’IFN-γ, peuvent rendre compte de ce statut immunitaire particulier. De plus, un retard de production et de maturation des anticorps, caractéristiques de l’immunité humorale, s’observe en début de vie. Récemment, de nouveaux lymphocytes T auxiliaires ont été décrits, les lymphocytes Th17, producteurs d’IL-17A, d’IL-17F et d’IL-22, d’une part, et les lymphocytes Tfh, sécrétant de l’IL-21 et exprimant CXCR5, ICOS et PD-1, d’autre part. La différenciation des lymphocytes Th17 dépend de la présence d’IL-6 ou d’IL-21 et de TGF-β, et est inhibée par l’IL-4 ;tandis que les lymphocytes Tfh sont induits en présence d’IL-21, d’IL-6 et du répresseur transcriptionnel Bcl6. Alors que les lymphocytes Th17 sont associés à des réponses inflammatoires par le recrutement de neutrophiles, les lymphocytes Tfh aident les lymphocytes B à produire des anticorps de haute affinité.
L’objectif principal de notre travail est l’étude du développement potentiel de réponses de type Th17 chez le nouveau-né de souris soumis à une stimulation allogénique et au manque d’IL-4. De plus, l’existence potentielle de lymphocytes Tfh induits chez le nouveau-né immunisé avec un vaccin constitué d’ovalbumine de poulet et d’Alum, sera investiguée.
Dans notre modèle de tolérance néonatale, l’immunisation de nouveau-nés BALB/c à l’aide de cellules spléniques semi-allogéniques F1 (AJAX x BALB/c) induit une polarisation de type Th2, associée à l’établissement d’un chimérisme lymphoïde et à l’acceptation d’une greffe de peau présentant les alloantigènes rencontrés à la naissance. Des nouveau-nés soumis à cette immunisation allogénique et à la privation d’IL-4, réalisée par l’utilisation d’anticorps monoclonaux ou de souris IL-4-/-, rejettent de façon aiguë les greffons de peau et présentent une proportion réduite de cellules chimériques. Cette rupture de la tolérance néonatale est associée à l’inhibition de la réponse allospécifique de type Th2 et au développement de lymphocytes Th17 alloréactifs, produisant de l’IL-17A. L’inhibition de la voie Th17 ne conduit toutefois pas à l’acceptation des allogreffes de peau. Par contre, la neutralisation de l’IL-6 ou de l’IL-17A et la réduction du nombre de neutrophiles restaurent la proportion de cellules chimériques présentes dans la rate, démontrant que la réponse de type Th17 allospécifique néonatale contrôle le chimérisme lymphoïde.
En réponse au vaccin OVA-Alum, les nouveau-nés présentent une proportion accrue de lymphocytes Tfh CXCR5+ PD-1+, bien que cette proportion lymphocytaire soit significativement diminuée par rapport aux adultes. Les lymphocytes Tfh néonataux expriment en outre des taux moindres des ARNm d’IL-21, d’IL-4 et de Bcl6, suggérant que la génération de lymphocytes Tfh est altérée en début de vie. En parallèle, les titres et la maturation des anticorps produits suite à la vaccination sont réduits chez les nouveau-nés, en comparaison avec les adultes. Cependant, qu’ils soient déficients en IL-4 ou non, des lymphocytes T CD4+ néonataux activés in vitro en présence d’IL-6 induisent une production d’anticorps par des lymphocytes B compétents, suggérant qu’il n’y a pas de défaut intrinsèque des lymphocytes T du nouveau-né à développer une capacité d’aide aux lymphocytes B.
En conclusion, nous avons montré que la polarisation de type Th2 néonatale inhibe la différenciation de lymphocytes Th17 alloréactifs contrôlant le rejet de cellules allogéniques, un mécanisme pouvant intervenir dans la relation immunitaire entre la mère et l’enfant. Nos résultats indiquent également que le nouveau-né est capable de différencier des lymphocytes Tfh, bien que le développement de ces derniers semble réduit. \
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished