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1
Hua, Renyi. "The role of chemokines/chemokine receptors in labour". Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9847.
Testo completoAbstract (sommario):
Human labour is shown to be an inflammatory process, which involves a marked leukocyte infiltrate into myometrium during labour. My study focused on the role of chemokines, key mediators of leukocyte trafficking, in labour. Previous gene array data obtained from human labouring myometrium showed that the mRNA expression of the following chemokines was increased in term labouring myometrium, CCL2, CCL20, CXCL1, CXCL5, CXCL8. I decided to focus on myometrial expression of these chemokines and also to include CCL5, another important chemokine. My data confirmed that the expression of human myometrial chemokines was increased in labour and that their expression was up regulated by cytokines and mechanical stretch via NFKB and MAPK, but decreased by prostaglandins and oxytocin via PLC. I also studied the expression of myometrial chemokine receptors, which may mediate some of the effects of chemokines on myometrial function and/or act as decoys, minimising the effects of locally produced chemokines. I found that the expression of the chemokine receptors decreased with the onset of labour, mainly through the action of prostaglandins and oxytocin. I then used the established model of LPS-‐induced preterm labour (PTL) in the mouse and found that chemokines and cytokines both increased in the myometrium and placenta. CCL2 is consistently increased with human labour and has been shown to be important in rodent parturition too. I therefore studied the impact of LPS in the CCR2 (the main receptor for CCL2) knockout mouse. There was less inflammation in both the myometrium and placenta and a better pup survival rate in the CCR2-/- mouse. However, the PTL was not delayed, suggesting that CCR2 is not essential for the induction of PTL labour by LPS in the mouse. I then turned my attention to CCL20, which acts only via CCR6. It is known to drive dendritic cell recruitment and I found that its expression was increased with labour, while that of its receptor was reduced. Functionally, I found that CCL20 up-regulated the myometrial expression of chemokines. Next I used the LPS-induced preterm labour model in the mouse and found that CCR6 knockout delayed LPS-induced preterm delivery and improved pup survival. These findings were associated with much lower inflammation in myometrium and plasma. These data suggest that CCR6 could be a therapeutic target in the management of PTL. Chemokines play an important role both in the induction of term labour and in infection induced PTL. Chemokine inhibitors may delay the onset of PTL and improve the fetal outcome.
2
Wong, Jeffrey K. W. "Chemokines and chemokine receptors in islet xenograft rejection". Thesis, The University of Sydney, 2006. https://hdl.handle.net/2123/28055.
Testo completoAbstract (sommario):
This project investigates the role of chemokine and chemokine receptors in a model
of CD4 T cell dependent cellular xenograft rejection, specifically the transplantation
of fetal pig pancreas tissue to the renal subcapsular space of mice.
Chemokines and chemokine receptor gene expression was assessed by cDNA arrays,
and confirmed by multi-probe ribonuclease protection assay. Immunostaining for a
selected chemokine, RANTES was performed to demonstrate upregulation at the
protein level.
These methods were applied to several different models to dissect the role
Chemokines and their receptors in this process. Comparisons were made with: an
allografi model, a model where indefinite xenograft survival could be achieved by
short term costimulatory blockade with CTLA4-Fc and MR1, and an
immunodeficient mouse recipient (RAG—1 KO, lacks B and T cells) that was
reconstituted with either unfractionated leucocytes or purified CD4 T cells.
The main findings were:
1. Allograft rejection and cellular xenografi rejection are THl type CD4 T cell
dependent processes as shown by the common T cell chemokine genes (Ltn,
IP-lO, and Mig) expressed in both models; however macrophages are the
main effector cell in cellular xenografi rejection as evidenced by the selective
upregulation of MCP-l and its receptor CCR2, as well as other macrophage
markers
2. Of the Chemokines / receptors upregulated in this model of cellular xenograft
rejection (Ltn, IP-lO, MCP-l, RANTES, MIP-lB, eotaxin) only MCP-l and
IP-lO are CD4 T cell dependent, while Ltn expression is dependent upon a
non-CD4 T cell leucocyte subset.
3. CTLA4-Fc and MR1 therapy resulted in indefinite fetal porcine islet survival
and function in diabetic immune competent wild type C57BL/6 mice. This
treatment suppresses the early upregulation of chemokines and chemokine
receptors seen in untreated animals, and this corresponds with a significant
reduction CD4 T cell and macrophage grafi infiltration at these time points,
consistent with a role for select chemokine / receptors in the mechanism by
which this therapy leads to indefinite graft survival.
4. In addition we studied the functioning of fetal porcine islet tissue in diabetic
mice and found they developed and controlled glucose metabolism in a piglike
manner, and different to normal mice, and thus conclude the development
and function of fetal tissue in cross species transplantation is dependent upon
the origins of the progenitor cells and not the xenogeneic environment i.e.
nature not nurture (in this case anyway).
We conclude that select chemokines and their receptors are important factors in the
recruitment of effector cells mediating graft rejection in this model of cellular
xenograft rejection and these chemokine pathways and networks may represent
potential future therapeutic targets.
3
Mowafi, Frida. "Chemokines and chemokine receptors during viral infections in man /". Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-420-4/.
Testo completo
4
Davis, Christopher Nathan. "Mammalian and viral chemokines provide insight into the mechanism of chemokine receptor activation". [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0006481.
Testo completo
5
Wang, Jixin. "Bioinformatic analysis of chicken chemokines, chemokine receptors, and Toll-like receptor 21". Texas A&M University, 2006. http://hdl.handle.net/1969.1/4212.
Testo completoAbstract (sommario):
Chemokines triggered by Toll-like receptors (TLRs) are small chemoattractant
proteins, which mainly regulate leukocyte trafficking in inflammatory reactions via
interaction with G protein-coupled receptors. Forty-two chemokines and 19 cognate
receptors have been found in the human genome. Prior to this study, only 11 chicken
chemokines and 7 receptors had been reported. The objectives of this study were to
identify systematically chicken chemokines and their cognate receptor genes in the
chicken genome and to annotate these genes and ligand-receptor binding by a
comparative genomics approach. Twenty-three chemokine and 14 chemokine receptor
genes were identified in the chicken genome. The number of coding exons in these genes
and the syntenies are highly conserved between human, mouse, and chicken although the
amino acid sequence homologies are generally low between mammalian and chicken
chemokines. Chicken genes were named with the systematic nomenclature used in
humans and mice based on phylogeny, synteny, and sequence homology. The independent nomenclature of chicken chemokines and chemokine receptors suggests that
the chicken may have ligand-receptor pairings similar to mammals.
The TLR family represents evolutionarily conserved components of the patternrecognizing
receptors (PRRs) of the innate immune system that recognize specific
pathogen-associated molecular patterns (PAMPs) through their ectodomains (ECDs).
TLR's ECDs contain 19 to 25 tandem copies of leucine-rich repeat (LRR) motifs. TLRs
play important roles in the activation of pro-inflammatory cytokines, chemokines and
modulation of antigen-specific adaptive immune responses. To date, nine TLRs have
been reported in chicken, along with a non-functional TLR8. Two non-mammalian
TLRs, TLR21 and TLR22, have been identified in pufferfish and zebrafish. The
objectives of this study were to determine if there is the existence of chicken genes
homologous to fish-specific TLRs, and if possible ligands of these receptors exist. After
searching the chicken genome sequence and EST database, a novel chicken TLR
homologous to fish TLR21 was identified. Phylogenetic analysis indicated that the
identified chicken TLR is the orthologue of TLR21 in fish. Bioinformatic analysis of
potential PAMP binding sites within LRR insertions showed that CpG DNA is the
putative ligand of this receptor.
6
Teleshova, Natalia. "Studies on co-stimulatory molecules, chemokines and chemokine receptors in neuroimmunological diseases /". Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4781-3/.
Testo completo
7
Maru, Seema V. "The role of chemokines and chemokine receptors in astrocytes and astrocytoma biology". Thesis, Open University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427496.
Testo completo
8
Brozyna, Sheree. "The role of chemokines and chemokine receptors in chronic obstructive pulmonary disease (COPD) /". Title page and abstract only, 2005. http://web4.library.adelaide.edu.au/theses/09SB/09sbb8859.pdf.
Testo completo
9
Schweneker, Marc. "Identification and characterization of two novel proteins interacting with the chemokine- and HIV-1 co-receptor CCR5". [S.l.] : [s.n.], 2004. http://www.diss.fu-berlin.de/2004/22/index.html.
Testo completo
10
Fouillet, Antoine. "Cytokines regulation of chemokine and chemokine receptor in relation to multiple sclerosis". Thesis, Sheffield Hallam University, 2008. http://shura.shu.ac.uk/19675/.
Testo completoAbstract (sommario):
Expression of chemokines CXCL10 and CCL2 is elevated within inflammatory lesions in the central nervous system (CNS) of multiple sclerosis (MS) patients, particularly in astrocytes. These chemokines play a critical role in the recruitment of inflammatory cells into the CNS during inflammation. However, the cerebrospinal fluid of MS patients also shows high levels of CXCL10 at the time of relapse but by contrast CCL2 is decreased. In the present study, the mechanisms controlling the synthesis and release of these two chemokines in MS were assessed in vitro using primary human brain astrocytes isolated from MS and non-MS individuals. Pro-inflammatory cytokines (interleukin-1beta , tumour necrosis factor and interferon-gamma) increased the expression of both CCL2 and CXCL10 by astrocytes at the mRNA and protein level, as determined by real time PCR and enzyme linked immunosorbent assays (ELISA), respectively. CCL2 binding to astrocytes was then determined to evaluate any autocrine action on astrocytes in a single astrocyte preparation. CCL2 bound constitutively and following cytokine treatment. CCL2-binding was not the result of the interaction with its receptor since astrocytes did not express CCR2 on this astrocyte culture. CCR2-independent binding of CCL2 was confirmed by the absence of intracellular signalling, evidenced by the lack of calcium influx as well as of Erk and Akt phosphorylation, in CCL2-treated astrocytes. Even though astrocytes expressed CXCR3, similar negative results on calcium influx and downstream signalling pathways were observed for CXCL10. D6 chemokine decoy receptor expression was then assessed in vitro and in situ to further investigate the mechanism(s) of chemokine binding to astrocytes. Cultured astrocytes constitutively expressed the D6 decoy receptor at the mRNA and protein level, but levels were unchanged following cytokine treatment. D6 was expressed in situ in MS normal appearing white matter and in control brain tissue, at both the mRNA and protein level. D6 expression was detected on neurons and microglia but not astrocytes using imunohistochemical methods. Incubation of frozen brain sections with biotinylated CCL2 resulted in partial co-localisation with D6 staining. Altogether, these results suggest a role for astrocytes in regulating inflammation through synthesis and secretion of CCL2 and CXCL10. Subsequently, CCL2 binding to astrocytes, either by binding to D6 decoy receptor or by alternative mechanisms, may establish a chemokine gradient in the CNS, and direct the migration of leukocytes.
11
Waters, Victoria Hannah. "The chicken chemokine repertoire". Thesis, Royal Veterinary College (University of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572437.
Testo completo
12
Lalani, Alshad Sadrudin. "Poxvirus chemokine binding proteins". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0019/NQ46868.pdf.
Testo completo
13
Rahimpour, Rahbar. "Regulation of chemokine and chemokine receptor expression and function during the inflammatory response". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/NQ31108.pdf.
Testo completo
14
Topping, Joanna Ruth. "Regulation of circulating chemokine concentrations and bioactivity by glycosaminoglycans and chemokine binding proteins". Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407377.
Testo completo
15
Moyano, Clara. "Elucidating the signalling mechanisms of the CC chemokine receptor 5 upon chemokine stimulation". Thesis, University of East Anglia, 2011. https://ueaeprints.uea.ac.uk/33333/.
Testo completo
16
Simmons, Graham. "Human immunodeficiency syndrome virus type 1 cell tropism and inhibition by chemokines and chemokine analogues". Thesis, Institute of Cancer Research (University Of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368041.
Testo completo
17
Gaspar, Maria Manuela Carvalho. "Expression of chemokine and chemokine receptor networks during rejection and induction of transplantation tolerance". Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413973.
Testo completo
18
Cavalcante, GalylÃia Menezes. "Study of expression of systems CXCR4-CXCL12/SDF-1, CCR7-CCL21 and Ki-67 in the oral squamous cell carcinoma and their association with clinicopathological factors,nodal metastases and survival". Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11989.
Testo completoAbstract (sommario):
Chemokines are responsible for the directed migration of leukocyte chemotactic cytokines, coordinating cell movement during inflammation and the transport of hematopoietic cells. In addition to leukocytes, chemokine receptors are also found in neoplastic cells and tumors associated with stromal cells. Among chemokines, and the CXCR4/CXCL12 CCR7/CCL21 systems have been shown the involvement of lymph node metastases or distant metastases in different cancers. Thus, aim of this study was to evaluate the expression of CXCR4, CXCL12, CCR7, CCL21 and Ki-67 in oral squamous cell carcinoma (SCC) and to correlate these markers with clinicopathological indicators, lymph node metastasis and survival. We conducted a survey of reports and paraffin blocks of excisional biopsies of patients with SCC treated at the Hospital Haroldo JuaÃaba (2001-2009). Data on anatomic location of the lesion, sex, age, patient survival, degree of histological differentiation of the tumor, tumor stage and presence or absence of lymph node metastasis, lymphovascular and perineural invasion, nuclear grade and depth of invasion were collected. For immunohistochemical analysis, followed by the technique of streptavidin-biotin-peroxidase using the anti-CXCR4, anti-CXCL12, anti-CCR7, anti-CCL21 and Ki-67 antibody. Histological sections were photomicrographed in 10 fields chosen randomly and measured for the number of labeled tumor cells and determined the percentage of each labeling antibody. The marking of CXCR4 was detected in the cytoplasm and nucleus, CXCL12, CCR7 and CCL21 were only cytoplasmic, their expression was observed in 18 (60%) 8 (22.66%) 16 (53.3%) and 3 (12%) cases, respectively. We found a significant positive association between lymphovascular invasion and immunostaining of CXCR4 (p = 0.007) and CCR7 (P = 0.01) and among these cases metastasis was present in 62.5% and 37.5%, respectively. When in combination with Ki67, we found a significant positive correlation between CXCR4 (p = 0.0086), CXCL12 (p = 0.036) and CCR7 (p = 0:04). Among patients CXCR4 + over 111 months, only 38.4% were alive (p = 0.845), whereas both patients CCR7 + (p = 0.398) as well as CXCR4 +, and CCR7 + (p = 0.441) after 62 months, everyone had already died. We conclude that these chemokines are associated with lymphovascular invasion and cell proliferation, perhaps favoring the development of metastasis and poor prognosis.As quimiocinas sÃo citocinas quimiotÃticas responsÃveis pela migraÃÃo direcionada de leucÃcitos, coordenando o movimento celular durante a inflamaÃÃo e o transporte de cÃlulas hematopoiÃticas. AlÃm dos leucÃcitos, os receptores de quimiocinas tambÃm sÃo encontrados em cÃlulas neoplÃsicas e em tumores associados com cÃlulas estromais. Dentre as quimiocinas, os sistemas CXCR4/CXCL12 e CCR7/CCL21 tÃm sido demonstrado no envolvimento de metÃstases linfonodais ou à distÃncia em diferentes tipos de cÃncer. Dessa forma, foi objetivo desse trabalho avaliar a expressÃo de CXCR4, CXCL12, CCR7, CCL21 e Ki-67 em carcinoma de cÃlulas escamosas orais (CEC) e correlacionar estes marcadores com indicadores clÃnicopatolÃgicos, metÃstase linfonodal e sobrevida. Realizou-se um levantamento de laudos e blocos parafinados de biopsias excisionais de pacientes portadores de CEC tratados no Hospital Haroldo JuaÃaba (2001 a 2009). Foram coletados dados sobre localizaÃÃo anatÃmica da lesÃo, sexo, idade, sobrevida do paciente, grau de diferenciaÃÃo histopatolÃgica do tumor, estadiamento tumoral e presenÃa ou ausÃncia de metÃstase linfonodal, invasÃo linfovascular e perineural, grau nuclear e profundidade de invasÃo. Para reaÃÃo de imunohistoquÃmica, seguiu-se a tÃcnica da estreptavidina-biotina-peroxidase, utilizando os anticorpos anti-CXCR4, anti-CXCL12, anti-CCR7, anti-CCL21 e Ki-67. As secÃÃes histolÃgicas foram fotomicrografadas em 10 campos escolhidos aleatoriamente e quantificadas quanto ao nÃmero de cÃlulas tumorais marcadas e determinado o percentual de marcaÃÃo de cada anticorpo. A marcaÃÃo de CXCR4 foi detectada em citoplasma e nÃcleo, CXCL12, CCR7 e CCL21 tiveram marcaÃÃo apenas citoplasmÃtica, sendo observada suas expressÃes em 18 (60%), 8 (22,66%), 16 (53,3%) e 3 (12%) casos, respectivamente. Encontrou-se uma associaÃÃo significativa positiva entre a invasÃo linfovascular e a imunomarcaÃÃo do CXCR4 (p=0.007) e CCR7 (p=0.01) e dentre esses casos a metÃstase esteve presente em 62,5% e 37,5%, respectivamente. Quando em associaÃÃo com o Ki67, encontrou-se uma correlaÃÃo positiva significante entre o CXCR4 (p=0.0086), CXCL12 (p=0.036) e CCR7 (p=0.04). Dentre os pacientes CXCR4+, ao longo de 111 meses, apenas 38,4% estavam vivos (p=0.845), ao passo que tanto para pacientes CCR7+ (p = 0.398), quanto CXCR4+ e CCR7+ (p = 0.441), apÃs 62 meses, todos haviam ido a Ãbito. Conclui-se que essas quimiocinas estÃo associadas com a invasÃo linfovascular e proliferaÃÃo celular, talvez favorecendo o desenvolvimento de metÃstases e um pior prognÃstico.
19
Kanazawa, Nobuo. "Fractalkine and macrophage-derived chemokine : T cell attracting chemokines expressed in T cell area dendritic cells". Kyoto University, 2000. http://hdl.handle.net/2433/180886.
Testo completo
20
Eltayeb, Sana. "Chemokine receptor expression and function in experimental autoimmune neuroimflammation /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-197-5/.
Testo completo
21
Dalton, Richard S. J. "Chemokine and chemokine receptor gene expression in human PBMCs in the early renal post-transplant period". Thesis, University of Southampton, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418008.
Testo completo
22
Subileau, Eva-Anne. "Chemokine and chemokine receptor expression by human brain endothelium : an 'in vitro' and 'in situ' study". Thesis, Open University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434967.
Testo completo
23
Arnatt, Christopher Kent. "DEVELOPMENT OF ANTAGONISTS TARGETING CHEMOKINE RECEPTOR CCR5 AND THE CHEMOKINE RECEPTOR CCR5 – MU OPIOID RECEPTOR HETERODIMER". VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/517.
Testo completoAbstract (sommario):
The chemokine receptor CCR5 (CCR5) plays an integral role within the inflammatory network of cells. Importantly, CCR5 is a mediator in several disease states and can be targeted using small molecule antagonists. Within this work, CCR5’s role in prostate cancer and HIV/AIDS has been exploited in order to develop potential therapeutics and probes. First, a series of novel compounds was designed by using pharmacophore-based drug design based upon known CCR5 antagonists and molecular modeling studies of the CCR5 receptor’s three-dimensional conformation. Once synthesized, these compounds were tested for their CCR5 antagonism and their anti-proliferative effects in several prostate cancer cell lines. The data from both the calcium mobilization studies and the anti-proliferation studies suggests that the compounds synthesized have activity as CCR5 antagonists and as anti-proliferative agents in certain prostate cancer cell lines. In addition, a bivalent ligand containing both a mu opioid receptor (MOR) and a CCR5 antagonist pharmacophore was designed and synthesized in order to study the pharmacological profile of the putative CCR5-MOR heterodimer and its relation with NeuroAIDS. The structural-activity relationship between the bivalent ligand and the heterodimer was studied with radio-ligand binding assays, functional assays, HIV-1 fusion assays, cell fusion assays, and in silico molecular dynamics. The subsequent bivalent ligand was proven to be a potent inhibitor in both an artificial cell fusion assay mimicking HIV invasion and a native HIV-1 invasion assay using live virus. In all, two novel sets of compounds were synthesized that targeted either CCR5 or the CCR5-MOR heterodimer. For the CCR5 antagonists, as leads for prostate cancer therapeutics, further work needs to be done to ascertain and develop their structure-activity-relationship. This library of novel compounds was shown as promising leads as CCR5 and anti-prostate cancer agents. The bivalent ligand targeting the CCR5-MOR heterodimer proved to be a potent and tissue-specific inhibitor for neuroAIDS where the known treatment, maraviroc, is less efficacious and fails to inhibit virus entry in the presence of morphine. Both projects illustrate the roles that CCR5 plays in these two unique diseases.
24
Franciszkiewicz, Katarzyna. "The role of chemokines and chemokine receptors in shaping the effector phase of anti-tumor immune response". Paris 7, 2010. http://www.theses.fr/2010PA077015.
Testo completoAbstract (sommario):
La réponse immunitaire antitumorale nécessite la mise en place de mécanismes effecteurs dépendant des lymphocytes T CD8+ cytotoxiques spécifiques. Cependant, leur présence n'est pas toujours suffisante pour induire une régression tumorale dépendant de plusieurs étapes: la migration des lymphocytes T au site tumoral, l'infiltration, l'établissement de contacts avec le cible cancéreuse et l'activation in situ. Les chimiokines sont impliquées dans la circulation des cellules immunocompétentes. Bien que leur rôle dans la progression tumorale soient bien établi, les chimiokines sont également responsable de la modulation du microenvironnement tumoral permettant l'infiltration des lymphocytes et la potentialisation de leurs fonctions effectrices. Nous avons démontré que les effecteurs T cytotoxiques peuvent être recrutés par la tumeur autologue de façon dépendante du récepteur aux chimiokines CCR5. Une fois dans microenvironnement tumorale riche en TGF-β, ils subissent un processus d'adaptation résultant en l'induction de l'expression du récepteur aux chimiokines CCR6 et de l'intégrine aEβ7, ainsi qu'en la potentialisation de leur activité cytotoxique. L'engagement de l'intégrine aEβ7 conduit au recrutement de CCR5 dans la synapse immunologique, provoquant ainsi la désensibilisation des lymphocytes T au gradient de CCL5. Nos travaux ont mis en évidence le rôle majeur des chimiokines dans le développement de la réponse immunitaire antitumorale dépendante de lymphocytes T cytotoxiques. Dans cette optique, l'identification des mécanismes moléculaires induits par les chimiokines correspond à un enjeu important pour l'optimisation des protocoles d'immunothérapie antitumoraleThe immune system-mediated eradication of cancer cells requires effector mechanisms associated with the presence of tumor-specific T cells. However, the successful generation of tumor-specific effector cells does not necessarily result in tumor regression. Cytotoxic T lymphocytes (CTL) must first be able to migrate to tumor sites, traverse the interstitial space and fmally interact with their target resulting in triggering of effector fonctions. Chemokines are involved in circulation of immunocompetent cells. Although some of them are known to contribute to tumor progression, others are responsible for changes in the tumor microenvironment that allow the infiltration of lymphocytes. In this study, we demonstrate that CTLs can be efficiently recruited into the tumor in a CCR5-dépendent manner. Once in the TGF-pl-rich autologous tumor site, they undergo an intratumoral adaptation process resulting in upregulation of the chemokine receptor CCR6 and the integrin aEß7 as well as the enhancement of T-cell receptor (TCR)-mediated cytotoxicity. The engagement of aEβ₇ leads to CCR5 recruitment at the IS and reduced T-cell responsiveness to a CCR5 ligand chemotactic gradient, suggesting a role of aEß7 in T-cell rétention at the tumor by a CCR5-dépendent mechanism. Altogether, these results show an important role of the chemokine/chemokine receptor network at multiple levels of CTL-mediated antitumor immune response. In consequence, the identification of chemokine-medjated molecular mechanisms can be important for the development of innovative immunotherapeutic approaches and may offer new opportunities to optimize existing protocols of cancer therapy
25
Law, Yuet Ching. "Specific Compartmentalization of IgA ASCs in Mouse Salivary Glands via Differential Expression of Chemokines and Chemokine Receptors". BYU ScholarsArchive, 2008. https://scholarsarchive.byu.edu/etd/1952.
Testo completoAbstract (sommario):
The mucosal system, which forms a barrier between internal organ systems and the external environment, is frequently exposed to pathogenic microorganisms. Immunoglobulin A (IgA) antibody secreting cells (ASCs) localize in the lamina propria, and produce IgA antibodies which help protect mucosal tissues. The concept of a common mucosal immune system in which IgA ASCs have the ability to populate any mucosal site has been proposed (1, 2). However, recent research has suggested that IgA ASCs primed in different mucosal sites might possess different sets of chemokine receptors, and therefore migrate specifically to particular mucosal locations (3). In this study, the specific compartmentalization of IgA ASCs in two mouse salivary glands: sublingual gland (SLG), and submandibular gland (SMG) was studied. It was observed that SLG had 12 times more IgA ASCs per gram of gland than that of SMG (p<0.01). This suggested that IgA ASCs migrated to the two salivary glands with different efficiencies. Since the migration of lymphocytes is mediated by interactions between tissue specific chemokines and chemokine receptors, I hypothesized that the specific compartmentalization of IgA ASCs in the SLG and SMG was mediated by the differential expression of IgA ASC attracting chemokines. Quantitative PCR was used and showed that SLG expressed high levels of CCL28 and its receptor CCR10, which correlated to the distribution of IgA ASCs in the two salivary glands. In agreement with QPCR data, reduced levels of IgA ASCs were found in the SLG of CCR10 deficient mice when compared to wild type (WT) mice. Adoptive transfer of CCR10 deficient mice with WT spleen cells reconstituted the WT phenotype. It was therefore concluded that the interaction between CCL28 and CCR10 play an important role in mediating the migration of IgA ASCs into SLG. These results suggested that the accumulation of IgA ASC to distinct salivary glands is a highly selective process. These data also suggested that homing within mucosal sites is not common but rather a highly regulated process with specific subsets of cells homing to different tissues within the mucosal immune system.
26
Dobner, Bianca Carola [Verfasser]. "Chemokine bei Aderhautmelanomen / Bianca Carola Dobner". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023232022/34.
Testo completo
27
Lanati, Silvia. "Chemokine-mediated metastasis in malignant melanoma". Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.654112.
Testo completoAbstract (sommario):
Malignant melanoma is the most lethal form of skin cancer due to the metastatic spread of the disease. Chemokines have been shown to play a key role in the metastatic cascade. The chemokine receptor CCR7 and its ligand CCL21 were shown to be involved in migration of CCR7 expressing melanoma cells towards a gradient of CCL21 released by lymphatic endothelial cells (LEC) and promote metastasis at the draining lymph node (LN) in in vivo tumour models. I therefore tested the hypothesis that growth of CCR7 -expressing tumours towards LEC is CCL21-dependent in vivo, that LECs promoted this growth through a chemokine-mediated mechanism without increasing the lymphatic clearance at the front of the tumour and that a recombinant human antibody, namely Chemotrap-1, that binds soluble CCL21, could inhibit chemokine-mediated lymphatic metastasis in vivo. I used in vitro migration assays in a modified Boyden chamber and an in vivo mouse model of directional tumour growth and tumour metastasis to determine the chemokine-mediated ability of melanoma cells to migrate and to test the effect of inhibitory antibodies. During the study on Chemotrap-1, I tested the binding affinity for the chemokine ligand CXCL 12, using specifically designed ELlSAs and tested the affinity for CXCL 12 in vitro and in vivo by migration assays. CCR7 was endogenously expressed in all melanoma cells examined, its overexpression promoted in transit metastasis in vivo and a CCL21 neutralising antibody inhibited its migratory potential. LEC depots in vivo did not promote any increase in lymphatic clearance that would have altered the directional tumour growth of subcutaneous melanoma tumours. Chemotrap-1 inhibited in vitro cell migration, LN metastasis in vivo and it also bound to CXCL 12. These results show the key role of the CCR7/CCL21 axis in lymphatic metastasis in malignant melanoma and highlight the therapeutic potential of Chemotrap-1 to target lymphatic metastasis CCL21- and CXCL 12-mediated.
28
Mills, Shirley. "Chemokine signalling in malignant cell migration". Thesis, University of East Anglia, 2018. https://ueaeprints.uea.ac.uk/69973/.
Testo completoAbstract (sommario):
Communication within and between cells is called signalling; elucidation of cell signalling in diseases, especially metastatic cancers, creates opportunities for developing therapeutic interventions. Signalling initiation occurs when a cell surface receptor binds a ligand; the signal then transmits via phosphorylation events through cytosolic signalling proteins to nuclear or effector proteins that orchestrate a cellular response. G-protein coupled receptors (GPCRs) are one type of receptor; a sub-family of GPCRs are chemokine receptors, their ligands, chemokines, can trigger directional migration. Homeostatic chemokine-triggered migration can be hijacked by cancer cells to facilitate metastasis. This study explored various poorly understood aspects of chemokine signalling that may support metastasis with the aim of identifying therapeutic targets. Methodology employed THP-1, Jurkat and MCF7 cell-lines, the manipulation of signalling by antagonists, siRNA knockdown or plasmid modification, followed by calcium and chemotaxis assays, protein visualisation using immunofluorescence, flow cytometry and western blot. Investigations found that in THP-1 cofilin phosphorylation temporally relates to CXCL12-stimulation and to chemotactic migration. In THP-1, but not Jurkat, JAK2 and STAT3 signalling support chemotaxis to CXCL12 and CCL2. Various NSAIDs, Aspirin and Paracetamol drug-specifically influenced chemokine-induced migration and cofilin activity. Rac1, FAK/Pyk2 and Pi3K were found important for chemotaxis to CXC- but not CC-chemokines and to modulate cofilin phosphorylation. Rac1 inhibitor NSC23766 was found to compete with CXCR4 ligands. Many signalling proteins involved in cancer, including GRKs, Src, Raf, MEK, ERK, Cdc42, ROCK, β-catenin and p38MAPK were shown to positively influence chemotactic migration, also Arrestin-2 to support chemotaxis to CXCL12, and Arrestin-3 chemotaxis to CCL3. Dynamin inhibitors and siRNA knockdown produced chemokine, cell type, and dynamin domain-specific responses, Dynamin's G-domain being important for CXCL12- and PH domain for CCL3-induced migration. PKC's role in malignancies was found contradictory and isoform specific; PKCε and PKCδ supporting chemotaxis to CXCL12 but not CCL3, whereas PKCα and PKCζ influenced migration to both CXCL12 and CCL3. This thesis offers novel insights into the complexities of chemokine-induced migration. It examines many key signalling proteins implicated in cancer; reports that NSC23766 offers promise as a lead compound for developing CXCR4 biased antagonists; and offers possible mechanisms, through cofilin phosphorylation and effects on cell migration, for the mixed epidemiology reported for different NSAID's with respect to their influences on cancer incidence and progression, and suggests Ibuprofen may offer anti-metastatic efficacy.
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Khan, Abid. "CXCR4 chemokine receptor antagonists : new metallodrugs". Thesis, University of Hull, 2009. http://hydra.hull.ac.uk/resources/hull:10418.
Testo completoAbstract (sommario):
Chemokine receptors are a target of growing interest for new therapeutic drugs, as their role in multiple disease states has been demonstrated. The CXCR4/ CXCL12 pairing has been implicated in HIV and cancer, as well as chronic inflammatory diseases, including asthma and rheumatoid arthritis. HIV uses CXCR4 or CCR5 receptors in the key binding step of the infection process, leading to the idea that drugs could be developed to block this interaction. Cancer metastasis has also been linked to cellular communication via the chemokine pathways and hence, receptor antagonists could potentially inhibit this important pathway of disease progression. Small synthetic CXCR4 antagonists exist including AMD3100 (Mozobil®/Plerixafor), which has been identified as a potent CXCR4 antagonist exhibiting anti-HIV, anti-inflammatory and anti-tumour activity. Configurationally restricted analogues of AMD3100 complexed to metal ions have improved binding characteristics compared to AMD3100 and its metal complexes. Herein we report the binding of a new class of cyclen, cyclam and tris-cyclam based complexes in vitro. Compounds competed effectively in anti-CXCR4 competition assays with the tricyclam linear complex displaying improved binding characteristics. The difference in activity of the compounds is discussed in relation to the different possible binding interactions that are occurring. Furthermore, a monocyclam derivative conjugated to biotin competed effectively in competition with a CXCR4 mAb, however could not directly be detected via a fluorescent conjugated streptavidin molecule. Our most potent compound to date, copper(II) cross-bridged bicyclam was found to have a significant higher relative residence time in CXCR4 compared to AMD3100 and copper(II) AMD3100 in vitro. Moreover, copper(II) cross-bridged bicyclam was able to totally block CXCL12 induced and partially block serum induced, invasion of CXCR4 positive cancer cells with a higher potency than AMD3100 and copper(II) AMD3100. This shows the potential of using such a drug in the clinic. Using CXCR4 mutants, it has been shown that CXCR4 defective degradation and recycling increases invasion in breast cancer cells. Moreover the development of a multicellular tumour spheroid (MTS) is reported that could be used as a preclinical model in the evaluation of the anti-cancer activity of CXCR4 antagonists.
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Barker, Catriona. "Modulation of chemokine function during inflammation". Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2754.
Testo completoAbstract (sommario):
Oxidative stress is a key feature of inflammatory diseases. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated by many cell types during inflammation. ROS are known to induce chemokines, however it is increasingly apparent that RNS also impact on inflammation. This study was designed to investigate the effects of tissue stress on both chemokine production and function. How stress alters chemokine production in epithelium was established by qPCR. A distinct tissue, stress and chemokine specific response was elicited; of those studied, CXCL8 showed the greatest induction. The chemokines produced by epithelial cells were functional but post-translational modification occurred and so these chemokines may not have their predicted function. The effects of stress in vivo were also assessed. Immunohistochemistry showed association between RNS activity and ischaemic time in a model of kidney ischaemia-reperfusion injury. These observations were extended to human inflammatory liver disease, with increased RNS activity at sites of inflammation, a situation in which chemokines such as CCL2 are also present. RNS also modulates inflammation by post-translational modification. CCL2 was nitrated by RNS creating a chemokine, nCCL2, with decreased chemotactic activity in a diffusion gradient. Similar results were seen for nCCL5 and nCXCL8. Recruitment of HEK-CCR2b cells was decreased following CCL2 nitration and radio-ligand binding experiments confirmed there was some loss of receptor binding. However, the biological significance of this was uncertain. Glycosaminoglycan interactions were prevented by CCL2 nitration as was proportion of transendothelial migration. The ability of nitration to decrease the chemotactic potential of CCL2 was confirmed by in vivo assays. These data show the complexities of the chemokine system. Increased chemokine production by oxidative stress and concurrent modification of those chemokines by RNS represents a powerful paradigm for the regulation of inflammation.
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Wavre, Silene Tuija. "Endocytic regulation of chemokine receptor expression". Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1446114/.
Testo completoAbstract (sommario):
The activity of stimulated cell surface signalling receptors is frequently regulated by endocytosis, which provides a mechanism to internalise and either degrade or reprogram the protein. Clathrin-mediated endocytosis (CME) is one of the principal mechanisms responsible for these events. Although clathrin and many of its associated proteins are relatively well characterised, many aspects of how CME operates are yet to be established. In particular, the early steps of internalisation, the formation of clathrin-coated pits (CCPs) and the mechanism by which receptors are recruited into CCPs remain controversial. This thesis investigates the early events of CME occurring at the plasma membrane using as a model various cell lines expressing CC Chemokine receptor 5 (CCR5), a G-protein coupled receptor (GPCR). Upon agonist binding, CCR5 undergoes rapid phosphorylation by a GPCR kinase (GRK) and protein kinase C (PKC) on four C-terminal serines, p-arrestin is subsequently recruited to the receptor, abrogates CCR5 interaction with the G- protein and links the receptor to the endocytic machinery by binding to AP-2 and clathrin. Using confocal immunofluorescence microscopy and electron microscopy, I show that, on agonist binding, CCR5 relocates in the plasma membrane and clusters into flat clathrin lattices. CCPs were observed to invaginate at the edge of these lattices and proteins from the endocytic machinery were identified by immunolabelling within these domains. As C-terminal serine phosphorylation has been found to be important for efficient agonist-induced internalisation of CCR5, the requirement for specific serines for plasma membrane relocation, association with clathrin lattices and endocytosis were analysed. A mutant lacking all serines failed to be recruited into flat clathrin lattices. Further analysis showed that specific GRK phosphorylation of CCR5 was sufficient for this recruitment, suggesting a distinct role for different kinases in receptor desensitisation and internalisation. This study brings new insights into the mechanism of recruitment of activated GPCRs into CCPs and reveals the importance of flat clathrin lattices in the formation of endocytic clathrin-coated vesicles and CME. Part of the results presented in this thesis have been published (Signoret et al., 2005) (see appendix).
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Petersen, Desiree C. "The role of chemokine and chemokine receptor genes in genetic susceptibility to HIV infection in South Africa". Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53158.
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Escher, Sylvia E. "Untersuchungen zur Struktur, Aktivitätsbeziehung des humanen CC-Chemokins HCC-2". [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=958876290.
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Cornelissen, Gesine. "Integrierte Bioprozessentwicklung zur Herstellung pharmakologischer wirksamer Proteine mit Pichia pastoris /". Düsseldorf : VDI-Verl, 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=012990697&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Nüßeler, Elke. "Charakterisierung des Chemokinrezeptor-ähnlichen orphan-Rezeptors CXCR1-like der Maus". [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-55569.
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Popović, Milan. "Expression and function of thrombin receptors (PAR1, PAR3 and PAR4) in human umbilical vein endothelial cells: thrombin-mediated CX3CL1 expression". [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-63323.
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Thapa, Manoj. "Chemokines and chemokine receptors that mediate immune defense to genital herpes simplex virus type 2 (HSV-2) infection". Oklahoma City : [s.n.], 2008.
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38
Duchesnes, Cecile Emmanuelle. "Molecular characterisation of the chemokine receptor CCR3". Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407171.
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Martinelli, Roberta. "Molecular characterisation of the chemokine receptor CCR2". Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398841.
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Wilson, Shirley Risk. "Oligomerisation of chemokine receptors CXCR1 and CXCR2". Thesis, University of Glasgow, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418346.
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Sherwood, Joanna. "ELR+ CXC chemokine signalling in cartilage homeostasis". Thesis, Queen Mary, University of London, 2011. http://qmro.qmul.ac.uk/xmlui/handle/123456789/2447.
Testo completoAbstract (sommario):
The production of ELR+ CXC chemokines is widely studied in arthritis and has been postulated to contribute to the inflammatory phenomena that eventually lead to cartilage breakdown. Healthy articular chondrocytes also express CXC chemokines and chemokine receptors, however their purpose within cartilage is unclear because chondrocytes are encased within a dense avascular extracellular matrix and are not known to migrate in vivo. This study reveals a novel homeostatic function of signalling via CXCR1 and CXCR2 in articular cartilage. Confocal microscopy confirmed the localisation of CXCR1/2 in both in vitro cultured chondrocytes and in human articular cartilage explants at the cell membrane as well as within the cytoplasm, as expected considering the internalisation and recycling of these receptors. Calcium mobilisation assays proved that chondrocyte CXCR1/2 are functional and show a higher redundancy than that found in human neutrophils. Disruption of CXCR1/2 signalling at receptor level or by downstream G-protein inhibition resulted in a reduced extracellular matrix sulphated glycosaminoglycan content, and reduced expression of the cartilage differentiation markers COL2A1, Aggrecan, and SOX9, showing that CXCR1/2 signalling is required for the phenotypic stability of adult articular chondrocytes. In normal cartilage, CXCL6 and CXCL8 are present within the cartilage matrix. CXCL8 is bound to heparan sulphate proteoglycans, whilst CXCL6 is sequestered by an as of yet unidentified alternative matrix interaction, contributing to the determination of the chemokine signalling domain. In vivo analysis of CXCR2 knockout mouse knee joints revealed that mice lacking CXCR2 have significantly thinner epiphyseal growth plates and medial tibial plateaus, suggesting that CXCR signalling may be required in cartilage during periods of high chondrocyte turnover. Pharmacological modulation of the CXCR1/2 signalling pathway may allow for the selective inhibition of catabolic inflammatory responses whilst preserving CXCR1/2 maintained chondrocyte phenotypic homeostasis in articular cartilage.
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CAGLIANI, ROBERTA. "NANOBIOINTERACTIONS: CHEMOKINE MEDIATED SELECTIVE TARGETING OF NANOPARTICLES". Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/1000880.
Testo completoAbstract (sommario):
A major challenge in nanomedicine is the preparation of nano-tools with the ability to selectively targeting diseased tissues. Functionalization of nanoparticles (NPs) by conjugation with specific ligands possessing the inherent ability to bind only cell subsets confer “smartness” to NPs. Due to their small sizes, nanostructures exhibit unique physicochemical and biological properties, such as enhanced reactive area as and the ability to cross tissue barriers, making them a favorable material for biomedical applications. NPs vary in size ranging from 5 to 500 nm. Through the manipulation of size, surface chemistry and material structure, NPs can be tailored to carry therapeutic or imaging agents for delivery to specific tissues. In particular, surface functionalization can modify NP interaction with the immune system cells and the acquisition of stealth or specific-targeting properties. NP surface decoration with peptide moieties is one of the most efficacious cell-targeting strategies. In the first part of my PhD project, I focused on NP surface functionalization with stable proteins that interact with different immune cells in a selective manner. I used chemokines (chemo-attractant cyto-kines) due to their role in physiological and pathological binding and regulation of immune cells, as well as their structural stability in biological media. I modified a prototype SiO2-NP surface with the chemokine CXCL5, adsorbed or covalently bound, to precisely targeting CXCR2+ immune cells. The development of CXCL5-NPs and the discovery of their targeting properties provide novel results. Specifically, these protein-decorated nano-tools showed enhanced uptake and precise receptor-mediated cell subset localization. Moreover, given the crucial role of CXCR2 in inflammatory responses and cancer biology, CXCL5-NPs pave the way to prepare new delivery systems with increased capabilities and potential modulation of immune responses.
In the second part of my PhD project, I evaluated the effects of PtNPs on HL60 and differentiated HL60 cells in immune responses and inflammatory diseases. Reactive Oxygen Species (ROS) removing activity within cells is often achieved with different catalytic nanomaterials. Among them, PtNPs attract great attention due to their efficient catalysis and good degree of cyto-compatibility, but information about their effects on the human immune system is still missing. Further investigation using undifferentiated and differentiated neutrophil-like HL60 confirmed the harmlessness and non-cytotoxicity of PtNPs with non-adherent innate immune cells, contributing to the knowledge of PtNP interaction with immune cells in view of their potential applications in nanomedicine.
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Khan, Nouman Ullah. "The effect of chemokines on T regulatory cells following heart transplantation". Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/the-effect-of-chemokines-on-t-regulatory-cellsfollowing-heart-transplantation(6b5b194d-f2fd-4869-9b22-95ce099ac3ed).html.
Testo completoAbstract (sommario):
Heart transplantation (HTx) is now an established therapy for end-stage cardiac failure not responding to medical treatment. Recent decades have seen improved outcome following HTx due to more effective and targeted immunosuppressive therapy. However, acute and chronic rejection remains a major cause of morbidity and mortality. At the same time, immunosuppressive strategies are associated with significant side effects, including development of tumours. Hence, the induction of immunologic tolerance to alloantigen is considered the “holy grail” of transplant research. T regulatory cells (Tregs) are a subset of T cells that appear to suppresscytotoxic cell and initiate tolerance to foreign tissues. The Tregs suppresscytotoxic cells through specific cytokine pathways and cell-cell contact. In-vivo T reg migration has been a matter of debate in recent years. Treg trafficking is governed by chemokines, which are small secreted proteins, acting via their distinct trans-membrane serpentine receptors. Experimental work has demonstrated an involvement of distinct chemokine pathways in Tregs migration and localization following cardiac transplantation; however, there is paucity of data in humans. I investigated the effects of chemokines on Tregs in heart transplant recipients through a series of observational studies. My study demonstrated that acute rejection following heart transplantation is associated with a significant elevation of peripheral blood Th1 chemokine levels. I hereby further show that peripheral blood Treg counts in stable heart transplant recipients are not affected by immunosuppression but are significantly lower in patients taking statins. I have demonstrated via in-vitro chemotaxis assays a specific pattern of chemotactic response for Tregs and the effector T cells. Using double immunofluorescence staining and immunostaining, I show for the first time that Tregs may migrate to the allograft under the influence of CCL17.
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Jansma, Ariane L. "Structural and functional analysis of the chemokine CCL27 and the expression and purification of silent chemokine receptors D6 and DARC". Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3386768.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed February 4, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 196-206).
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González, Motos Víctor [Verfasser]. "Discovery and characterization of a novel chemokine binding protein of varicella zoster virus that enhances chemokine activity / Víctor González Motos". Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2017. http://d-nb.info/1150192194/34.
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McClure, Charles Patrick. "HIV-1 in the genital tract". Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275163.
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Lipfert, Jana. "Die Rolle und Funktionsweise der Chemokinrezeptoren CXCR4 und CXCR7 in Mikroglia und Astrozyten". Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-118858.
Testo completoAbstract (sommario):
Das Chemokin SDF-1 spielt eine wichtige Rolle bei der Hämatopoese, bei Immunreaktionen sowie bei der Entwicklung des Herzens, der Extremitätenmuskulatur und des zentralen und peripheren Nervensystems. Lange Zeit galt CXCR4 als der einzige Chemokinrezeptor für SDF-1, bis vor wenigen Jahren CXCR7 als ein alternativer Rezeptor für SDF-1 identifiziert wurde. Da alle Zelltypen des zentralen Nervensystems (ZNS) sensitiv für SDF-1 sind, sollte in dieser Arbeit die Funktion der beiden Rezeptoren in primärer Mikroglia und primären Astrozyten untersucht werden. Bisher konnte CXCR7 nur als Scavenger-Rezeptor für SDF-1 oder als atypischer Chemokinrezeptor nachgewiesen werden.
Die Untersuchungen ergaben einen mitogenen und chemotaktischen Effekt von SDF-1 auf primäre Mikroglia, wobei sowohl CXCR4 als auch CXCR7 für das SDF-1-Signalverhalten essentiell sind. Nach Aktivierung von Mikroglia in vitro und in vivo wurden beide Rezeptoren verstärkt expremiert. In primären Astrozyten ergab sich ein ligandenabhängiges Signalverhalten von CXCR7. So führte die Bindung von SDF-1 an CXCR7 zu einer Aktivierung von G-Proteinen, während die Kopplung von interferon-inducible T cell alpha chemoattractant (I-TAC), als zweiten Liganden von CXCR7, eine Signalweiterleitung über ß-Arrestin2 zur Folge hatte. Zudem konnte die G-Protein-gekoppelte Rezeptorkinase (Grk)2 als ein positiver Regulator des SDF-1-CXCR7-Signalverhaltens in Astrozyten identifiziert werden.
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Chu, Sok-fan. "Association between [beta]-Chemokine gene polymorphisms and tuberculosis". Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B35736136.
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Böcker, Sophia. "GPI-verankerte Chemokine als Adjuvantien in der Tumortherapie". Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-158566.
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Millette, Roxanne. "The effect of chemokine CCL19 on B lymphocytes /". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79051.
Testo completoAbstract (sommario):
B-T lymphocyte interaction within lymphoid tissues following antigen exposure is a crucial step in the generation of high affinity antibody. Due to its expression pattern and specificity for B lymphocytes, CC Chemokine Ligand 19 (CCL19) may help initiate the adaptive humoral immune response following antigen exposure. Here we show CCL 19 induced [Ca2+]i mobilization, chemotaxis and rescue from apoptosis in B lymphocytes. Because CCL19 is constitutively expressed, we studied the expression and signalling properties of its corresponding chemokine receptor, CC chemokine receptor 7 (CCR7) in various B cell populations. We found that CCL19 responsive CCR7 + cells belonged to distinct B lymphocyte populations at particular stages of maturation and that BCR crosslinking alone was insufficient to modulate CCR7 expression and CCL19 responsiveness. CCL19 induced signal transduction events were Galphai dependent. We found that CCL19 stimulation could desensitize the CCR7 receptor to further CCL19 stimulation, but did not interfere with other key B cell activation signals such as BCR and PAF. Our results implicate CCL19 in B lymphocyte activation, migration, and survival.