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Jonker, M. A., Y. Sano, A. Heneghan, J. Hermsen, and K. Kudsk. "P099 PARENTERAL NUTRITION ELIMINATES SMALL INTESTINE MUCOSAL IMMUNE REPONSE TO INJURY." Clinical Nutrition Supplements 4, no. 2 (January 2009): 67. http://dx.doi.org/10.1016/s1744-1161(09)70149-8.
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Corrêa, R. B., M. Puccioni-Sohler, S. A. P. Novis, M. S. P. Oliveira, and M. S. M. Carvalho. "5-04-06 Profile of cellular immune reponse among HAM/TSP patients in Rio de Janeiro." Journal of the Neurological Sciences 150 (September 1997): S277. http://dx.doi.org/10.1016/s0022-510x(97)86229-6.
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Khalil, Maged, Zili He, Ashish Sangal, Aref Agheli, Alka Arora, Theresa Dumlao, Seema Naik, Elizabeth Chiu, Madhumati Kalavar, and William Steier. "High Dose Glucocorticoids Potentiate the Reponse to Erythropoietin." Blood 108, no. 11 (November 16, 2006): 3775. http://dx.doi.org/10.1182/blood.v108.11.3775.3775.
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Abstract Introduction: The role of steroids in mammalian erythropoiesis has remained not well defined. At our institution, we have observed cases in which it appears that there is a synergism between Erythropoietin factor and glucocorticoids. In three cases, the patients were being treated for anemia that was slow to respond to erythropoietin, but then had a sudden quick rise in Hemoglobin following concomitant therapy with Glucocorticoids. Case #1 is a 32 year-old black female, with SLE for more than 20 years, lupus nephropathy, end-stage renal disease on maintenance Hemodialysis, for the last 5 years, chronic anemia secondary to renal failure, and thrombocytopenia due to lupus. The patient was treated with prednisone 20 mg daily as a maintenance therapy for her SLE and erythropoietin (procrit) 10,000 units injection three times a week, during each session of hemodialysis. On April 27th patient was switched over from prednisone 20mg daily to dexamethasone 6mg orally every 12 hours for 4 does followed by prednisone 40 mg orally every day for worsening thrombocytopenia. A robust rise in hemoglobin level was noticed, from 7.5gm/dl to 17.5 gm/dl within a month from the date started on high dose glucocorticoids a long with procrit. Complete work up for secondary polycythemia was all negative. Procrit was discontinued while prednisone 40mg/day was continued, hemoglobin level decreased to 14.8 g/dl, and platelet count remain stable above 150/CMM. Case #2. A 52 years old female who was diagnosed with stage 111B NSCLC treated with chemo radiation. During the period of chemo radiation hemoglobin level remained between 9–10gm/dl on procrit 40,000 units once per week. Before completion of the Chemotherapy patient developed brain metastasis treated with whole brain irradiation, Dexamethasone 4mg every 6 hours and Dilantin 100mg orally daily for seizure prophylaxis. Three weeks after starting dexamethasone hemoglobin level increased to 17 gm/dl without any obvious reason. Complete work up for secondary polycythemia was all negative. Case #3. is a 42 year old female, with HIV/AIDS (CD4<20) not on any HAART medications, Chronic anemia treated with procrit 10,000 units three times a week for six months and Feso4 325 mg tablets three times a day with hemoglobin base line around 8.00 gm/dl and Seizure. Was admitted on 12/28/05 with odynophagia, cough and shortness of breath was treated for oropharyngeal candidiasis and PCP pneumonia with Bactrim IV, Nystatin, Diflucan and Methylprednisolone 125 IV daily on 12/28/06 changed later to Prednisone 20mg orally once daily from 12/30/06 until 1/27/06. While the patient on both Glucocorticoids and procrit we notice the increased of hemoglobin from 7.7 gm/dl on 12/29/05 to 12gm/dl on 1/27/06. All other causes of secondary polycythemia have been ruled out. Conclusion: The reason for the inordinate rise in hemoglobin after starting corticosteriods could be explained by the action of corticosteriods on an immune component of the anemia, to a synergistic effect with erythropoietin on erythropoiesis through a shared mechanism or to a coincidental factor(s) unrelated to either drugs. Whatever the mechanism, When corticosteriods are prescribed for patient on erythropoietin they should be closely monitored for the development of erythrocytosis. Cautious use of glucocorticoids should be considered in patients who are refractory to erythropoietin.
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Purow, Benjamin. "Repurposing existing agents as adjunct therapies for glioblastoma." Neuro-Oncology Practice 3, no. 3 (September 30, 2015): 154–63. http://dx.doi.org/10.1093/nop/npv041.
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AbstractNumerous non-oncologic medications have been found in the last decade to have anti-cancer properties. While the focus in oncology research should clearly remain on deriving new therapeutic strategies, repurposing these existing medications may offer the potential to rapidly enhance the effectiveness of treatment for resistant cancers. Glioblastoma, the most common and lethal brain cancer, is highly resistant to standard therapies and would benefit from even minor improvements in treatment. Numerous agents already in the clinic for non-cancer applications have been found to also possess potential against cancer or specifically against glioblastoma. These include agents with activities affecting oxidative stress, the immune reponse, epigenetic modifiers, cancer cell metabolism, and angiogenesis and invasiveness. This review serves as a guide for potential ways to repurpose individual drugs alongside standard glioblastoma therapies.
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Siolas, Despina, Jane Cullis, Antonina Avanzi, Kate Byrne, Lawrence P. Leichman, Robert H. Vonderheide, and Dafna Bar-Sagi. "Antitumor activity and immune reponse in CD40 immunotherapy with gemcitabine and nab-paclitaxel in an orthotopic pancreatic cancer mouse model." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 271. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.271.
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271 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. A Phase I trial of CD40 immunotherapy in combination with gemcitabine demonstrated the combination was safe and achieves tumor responses in patients with pancreatic ductal adenocarcinoma. We investigated the effectiveness of gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy in an orthotopic pancreatic mouse model. Methods: Pancreatic cells obtained from a KrasG12D;Trp53R172H (KPC) genetically engineered mouse were cultivated in cell culture and surgically implanted into the pancreata of immunocompetent syngeneic C57/Bl6 mice allowing for tumor formation in situ. Two weeks after KPC cell implantation, mice were treated with 120 mg/kg gemcitabine and 120 mg/kg nab-paclitaxel by intraperitoneal injection. Forty eight hours after chemotherapy administration, mice were treated with 100 ug of FGK45 CD40 immunotherapy. Mouse tumors and spleens were harvested from euthanized mice ten days after drug treatment. Tumor and spleens were analyzed histologically and by flow cytometry. Results: Mice treated with combination chemotherapy and immunotherapy had a significant reduction in tumor volume in comparison to vehicle treated mice. Combination chemotherapy did not cause a significant decrease in tumor volume. No changes were seen in stromal remodeling using trichrome histological staining. Mice treated with CD40 immunotherapy had an increase in spleen size indicating an immune response. Histological and flow cytometry analysis revealed an increase in CD45+ cells in the tumors of the CD40 immunotherapy treated samples in comparison to chemotherapy alone. Conclusions: CD40 immunotherapy in combination with gemcitabine and albumin-bound paclitaxel has significant antitumor activity in an orthotopic pancreatic cancer mouse model provoking an immune response in the tumors. Future experiments will focus on identifying immune mediators critical for drug efficacy.
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Hessel, L., A. Garbarg-Chenon, J. L. Fontaine, G. Lasfargues, H. F. Clark, S. Plotkin, and F. Bricout. "Etude de la reponse immune au vaccin rotavirus vivant attenue, souche WC3, chez des enfants de 2 A 12 mois." Médecine et Maladies Infectieuses 19, no. 11 (November 1989): 627. http://dx.doi.org/10.1016/s0399-077x(89)80071-x.
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Lechner, Franziska, John Sullivan, Hans Spiegel, Douglas F. Nixon, Belinda Ferrari, Andrew Davis, Bill Borkowsky, et al. "Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1400 (August 29, 2000): 1085–92. http://dx.doi.org/10.1098/rstb.2000.0646.
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Hepatitis C virus (HCV) infection is a major public health problem, affecting an estimated 3% of the world's population, and over 10% in some countries. Infection in most cases becomes persistent, and can lead to hepatic inflammation, fibrosis and liver failure. The T lymphocyte reponse, in particular that mediated by cytotoxic T lymphocytes (CTLs), is likely to be involved in determining the outcome of infection, although its overall role is not clear. The use of major histocompatibility complex (MHC) class I peptide tetrameric complexes (tetramers) to study antiviral CTL responses has revolutionized our approach to the study of human infection. We have used a panel of MHC class I tetramers to analyse immune responses in HCV–infected individuals at various stages of disease. We find that the CTL response against HCV is vigorous in its early phases but dwindles over time both in terms of lymphocyte number and function. A number of potential explanations for this ‘CTL failure’ are discussed.
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Boussoffara, Thouraya, Mohamed Samir Boubaker, Melika Ben Ahmed, Mourad Mokni, Ikram Guizani, Afif Ben Salah, and Hechmi Louzir. "Histological and immunological differences between zoonotic cutaneous leishmaniasis due to Leishmania major and sporadic cutaneous leishmaniasis due to Leishmania infantum." Parasite 26 (2019): 9. http://dx.doi.org/10.1051/parasite/2019007.
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Lesion features in cutaneous leishmaniasis (CL) depend on the infecting Leishmania species as well as on host immune reponse. In this study, we evaluated the histological and immunological differences between two forms of CL described in Tunisia: zoonotic cutaneous leishmaniasis (ZCL) caused by L. major and sporadic cutaneous leishmaniasis (SCL) caused by L. infantum. Histological analysis showed a mild to moderate infiltrate within ZCL lesions. In contrast, massive infiltration of the dermis was observed within SCL lesions. Contrary to ZCL, infiltrates within SCL lesions were organized and showed granuloma composed of macrophages and lymphocytes. In addition, immunohistochemical analysis showed a predominance of CD4+ T cells within both CL forms. Furthermore, expression of interferon-γ, interleukin (IL)-10, IL-8, IL-13 and monocyte chemotactic protein (MCP)-1 was evaluated using real-time quantitative polymerase chain reaction (RT-qPCR). MCP-1 and IL-10 were expressed at comparable levels in ZCL and SCL lesions. Interestingly, IL-8 mRNA levels were significantly higher in ZCL lesions compared to SCL lesions, but interferon-γ was significantly higher in SCL lesions than in ZCL lesions.
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Pratiwi, Rahma Indah, Jusak Nugraha, Betty Agustina Tambunan, and Francisca Srioetami Tanoerahardjo. "Respons Sitokin TNF-Α Dan Il-4 Pasca Stimulasi Antigen Fusi Resat-6-CFP-10." Buletin Penelitian Kesehatan 46, no. 1 (July 4, 2018): 53–60. http://dx.doi.org/10.22435/bpk.v46i1.57.
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AbstractProtective immunity of tuberculosis (TB) infection is highly dependent on the balance of Th1 and Th2cytokines. TNF-α cytokines produced by Th1 cell retain a latent status, and IL-4 produced by Th2 aidsin the production of antibodies. The recent development of the vaccine candidates shows that rESAT-6-CFP-10 fusion antigen is specific to induce protective immune responses. The objective of the study wasto determine the immune response. This study used a quasi experimental design in the laboratory in vitrowith cultured PBMC of patients with new cases of pulmonary TB, latent TB and healthy individuals.Examination of TNF-α and IL-4 levels was done by ELISA. The highest TNF-α mean levels were 866,05in the latent TB group, compared to 814,56 in active TB and 414,58 in healthy individuals, but they werenot significantly different. The highest IL-4 mean levels were 1,39 in the active TB group, compared to0,88 in latent TB and 0,74 in healthy individuals, but they were not significantly different. High levels ofTNF-α and low levels of Il-4 in latent TB post-stimulation of rESAT-6-CFP-10 fusion antigen show thatthe candidate vaccine is capable of providing protective reponse against Mycobacterium tuberculosisinfection.Key words : TNF-α, IL-4, PBMC, ELISA, rESAT-6-CFP-10
AbstrakImunitas protektif terhadap infeksi tuberculosis sangat bergantung terhadap keseimbangan sitokinT-helper (Th)-1 dan Th2. Sitokin TNF-α yang disekresi oleh sel Th1 mampu mempertahankan status laten,dan IL-4 yang disekresi oleh Th2 membantu produksi antibodi. Pengembangan kandidat vaksin terbaruyaitu antigen fusi rESAT-6-CFP-10 bersifat spesifik terhadap respons imun protektif. Tujuan penelitianini untuk mengetahui respons imun seluler melalui kadar TNF-α dan IL-4 pasca stimulasi antigen fusirESAT-6-CFP-10. Penelitian ini menggunakan desain eksperimen semu di laboratorium secara in vitropada kultur PBMC. Pemeriksaan kadar sitokin TNF-α dan IL-4 dengan metode ELISA. Rerata kadarTNF-α pasca stimulasi paling tinggi ditemukan pada kelompok TB laten 866,05, dibandingkan TBaktif 814,56 dan orang sehat 414,58, tetapi tidak berbeda bermakna. Reratakadar IL-4 pasca stimulasipaling tinggi ditemukan pada kelompok TB aktif, dibandingkan TB laten dan orang sehat, tetapi tidakberbeda bermakna. Kadar TNF-α yang tinggi dan kadar IL-4 yang rendah pada TB laten pasca stimulasiantigen fusi rESAT-6-CFP-10 menunjukkan bahwa kandidat vaksin mampu memberikan repons protektifterhadap infeksi Mycobacterium tuberculosis secara invitro.Kata kunci : TNF-α, IL-4, PBMC, ELISA, rESAT-6-CFP-10.
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Ghanmi, Z., M. Rouabhia, O. Othmane, and P. A. Deschaux. "5.3 Effects of metal ions on cyprinid fish immune response: in vitro effects of Zn2+ and Mn2+ on the mitogenic reponse of carp pronephros lymphocytes." Developmental & Comparative Immunology 13, no. 4 (September 1989): 398. http://dx.doi.org/10.1016/0145-305x(89)90115-8.
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Ferrandina, Gabriella, Patricia S. Braly, Corrado Terranova, Vanda Salutari, Caterina Ricci, Francesco Raspagliesi, Domenica Lorusso, et al. "A randomized phase II study assessing an optimized schedule of oregovomab (O) anti-CA125 vaccination with carboplatin paclitaxel (CP) relative to CP alone in front-line treatment of optimally cytoreduced stage III/IV ovarian cancer (EOC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5536. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5536.
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5536 Background: In a phase II study of vaccination schedule in front-line combinatorial treatment of EOC (Braly JIT 2009), simultaneous day infusion dramatically enhanced the magnitude of induced immunity relative to a one week delayed schedule & other schedules historically evaluated. The current study is exploring the clinical & biological effects of the optimized 4 vaccine schedule relative to CP alone. Methods: Stage III/IV EOC patients (pts) optimally debulked to <1cm residual disease with CA125 >2x ULN were randomized to CP+O (cycle 1,3,5, & C5 +12 weeks) vs CP and followed for clinical outcomes and immune reponse. A total of at least 80 evaluable pts were required for 80% power to detect a difference of 45% vs 15% for a primary comparative analysis of induced CA125 specific T cell immunity using an IFN-γ ELISpot. Clinical evaluations and safety were considered secondary endpoints. Results: 97 pts (47 OV+SOC & 50 SOC) were accrued at 13 centers in US & Italy. Analysis of immune markers and long term clinical outcomes is ongoing. The median duration of follow up at time of this analysis was 26 months (m). There was no difference in safety outcomes between the treatment groups. Grade 3-4 toxicity was observed in 24 (52%) CP+O vs 28 (58%) C-P pts. Toxicities were typical of standard IV C-P chemotherapy. K-M Analysis of recurrence free survival (RFS) showed median RFS not estimable for CP+O [95% CI: 21.3, NE] vs 15.4 m [10.9,19.3] for CP (p=0.0009 log rank). In the interim analysis of survival (OS), 4 deaths have been observed in CP+O vs 16 in CP (log rank p=0.0025). Cox proportional hazard analysis finds consistent results across centers, and no imbalance in identified risk factors explanatory for the emerging outcome Conclusions: This study suggests simultaneous day vaccination with O on alternate cycles of front line CP leverages CP associated temporal change in the tumor microenvironment permitting an immune treatment effect to enhance the outcomes achievable with CP alone. This observation will be further characterized in ongoing translational studies and confirmed in a future phase III study. Clinical trial information: NCT01616303.
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Fest, Stefan, Kerstin Hilt, Nicole Huebener, Yan Zeng, Anne Strandsby, Silke Weixler, Gerhard Gaedicke, et al. "GD2 Peptide Mimotope DNA Vaccines for Anti-Neuroblastoma Immunotherapy." Blood 104, no. 11 (November 16, 2004): 1350. http://dx.doi.org/10.1182/blood.v104.11.1350.1350.
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Abstract The tumor-associated antigen disialoganglioside-GD2 is expressed on neuroblastoma and melanoma and is an established target for passive immunotherapy. The aim of this study was to develop an active immunization strategy leading to the induction of a humoral anti-GD2 immune response. However, carbohydrates and glycolipids are T cell-independent antigens (TI) and usually evoke a poor immune response in tumor-bearing hosts. Here, we describe the identification, characterization and in vivo efficacy of cyclic peptides mimicking the structure of glycolipid GD2, i.e. GD2 mimotopes, in order to overcome T-cell independency. First, GD2 peptide mimotopes were identified by biopanning experiments of a phage-display library displaying circular decapeptides against the human/mouse chimeric anti-GD2 antibody (Ab) ch14.18. Thirteen independent phage clones were isolated which bind to ch14.18 with high specificity. Competitive binding of phages expressing GD2 peptide mimotopes to ch14.18 antibody revealed two superior peptide candidates, mimotope A (MA) and and mimotope D (MD), which were subjected to further evaluation. Second, two plasmid DNA minigene vaccines were generated by overlapping PCR encoding for MA and MD, respectively. The plasmids were based on pSecTag2-A also including a kappa leader sequence, a T-cell helper epitope from HIV-1 gp 120 (T1) and a myc-tag. Minigene expression was demonstrated following transfection of COS-7 cells in western-blots and GD2 mimikry was determined in solid phase ELISA experiments. Third, the efficacy of these mimotope DNA vaccines to induce a tumor protective anti-GD2 immune response was tested in the syngeneic NXS2 model of neuroblastoma expressing ganglioside GD2. The DNA vaccination was accomplished with attenuated Salmonella typhimurium (SL 7207) used as an oral vaccine carrier. Only mice receiving the mimotope DNA vaccines revealed a decrease in primary tumor growth by 50% and a dramatic reduction of spontaneous liver metastases with a mean liver weight of 1g in both groups (MA and MD) in contrast to negative controls (3g). Interestingly, mice immunized with KLH conjugated peptide mimotopes A and D revealed an increased rate of s.c. tumor growth and spontaneous liver metastasis with average liver weights of 5 (MA) and 7 (MD), respecively, suggesting the induction of tolerance using this peptide vaccine approach. Finally the highest anti-GD2 humoral immune response was observed in sera of mice from both GD2 mimotope DNA vaccine groups, consistent with the anti-tumor reponse observed in vivo. Based on these data, we belive that GD2 mimotope DNA vaccines may provide a useful strategy for active immunization against neuroblastoma.
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Dhir, Varun. "Mesenchymal Stem Cells: The New Immunosuppressants?" Journal of Postgraduate Medicine, Education and Research 46, no. 2 (2012): 63–68. http://dx.doi.org/10.5005/jp-journals-10028-1015.
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ABSTRACT Mesenchymal stem cells are adult stem cells which can differentiate into cells of mesodermal lineage. osteoblasts, chondroblasts and adipocytes. They have an important property of immunosuppression which is mediated mainly through soluble mediators, like interleukin-1, transforming growth factor-β, nitric oxide, indoleamine 2,3 dioxegenase, etc. They have been shown to suppress both naive and antigen experienced T cells, lead to T cell arrest, and suppress Th1 and Th17 responses. They have also been shown to lead to development of tolerogenic dendritic cells, Th2 response and expansion of T regulatory cells. Importantly, MSCs are cells with a low immunogenic potential and hence have been used both in allogenic as well as xenogenic settings. MSCs have shown efficacy in suppressing the development of autoimmune disease in various animal models, like collagen induced arthritis, MRL-lpr mice, EAE mice, etc. They have been used in small human studies, some of which have shown benefit like in systemic lupus erythematosus. Also, they have been used in graft-verus-host disease in humans with promising results. However, a single randomized controlled trial has been done and, thus, their current status remains investigational. It is hoped that they may become part of the armamentarium to control and abberant or excessive immune reponse. Key messages (1) Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate only in one lineage (mesodermal). (2) They were first discovered in the bone marrow and this remains a common source, followed by adipose tissue. There are other sources: Synovial fluid, umbilical cord blood, amniotic fluid, placenta, fetal liver. (3) MSCs are immunosuppressive, the mechanism of which is not fully elucidated, but involves action on other cells mainly through soluble mediators, like TGFβ, IDO, IL-1, NO, etc. (4) MSCs have shown efficacy in various animal models of autoimmune diseases. There have been small human studies, some of which showed benefit, however, a single randomized controlled trial has been done. (5) MSCs may have a role in autoimmune diseases refractory to treatment or as an add onto prevent treatment side effects. How to cite this article Dhir V. Mesenchymal Stem Cells: The New Immunosuppressants? J Postgrad Med Edu Res 2012;46(2):63-68.
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Limentani, S. A., M. Campone, T. Dorval, E. Tan-Chiu, G. Curigliano, R. De Boer, J. Canon, T. Bachelot, J. Louahed, and V. G. Brichard. "Evaluation of a recombinant HER2 vaccine: Induction of specific antibodies, T-cells and preliminary activity in metastatic breast cancer patients." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 631. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.631.
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631 Background: We designed a vaccine to induce T cells able to recognize epitopes from HER2 and to engender a polyclonal antibody reponse. Methods: The vaccine is a recombinant HER2 protein, including its extra and part of its intra-cellular domains (ECD/ICD), combined with a potent immunologic adjuvant. Cohorts of patients with Stage II/III breast cancer (BC) received 20, 100 or 500 μg in the adjuvant setting. Treatment comprised of six vaccinations over 14 weeks, for the 500-μg dose, recall injections were given on weeks 34 and 38. The trial was extended to include an alternative vaccination schedule: 500 μg on days 0, 28 and 98. In an on-going trial, patients with metastatic BC treated in the first line setting are receiving the 500-μg treatment and being assessed for clinical response. Results: The vaccine was well tolerated, with no symptomatic cardiotoxicity. Antibody (Ab) response against ECD was dose-dependent, with 2/12, 9/14 and 14/15 immune responders in the respective cohorts after four vaccinations. Response was dose-related. Ab isotypes were analyzed in the 500 μg cohort: in 50% of patients, high levels of IgM (30–60%) against ECD were found after four vaccinations. The switch towards IgG was complete in all patients after six vaccinations. The efficacy of booster vaccinations was observed mainly in patients with low IgM after eight weeks. After two vaccinations, Ab titers on the alternative 500 μg vaccination schedule were as high as after four vaccinations utilizing the initial schedule. The anti-ECD antibodies in 11/15 patients (500 μg level) bound HER2-overexpressing breast-cancer cell lines. In sera from 2 patients tested thus far, the gene-expression resembled that of trastuzumab. Assays show that specific T cells were obtained; detailed analysis is continuing. Among metastatic patients, two showed evidence of tumor regression after vaccination. Conclusions: The HER2 vaccine was well tolerated and induced (dose-dependently) anti-ECD Ab that bound the HER2 receptor. Data suggest that the vaccine also induced specific T-cell immunity. The alternative vaccination schedule may increase the Ab titers. This data justifies further evaluation of this vaccine in the phase II/III setting. [Table: see text]
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Kuo, Yuh-Chi, Wei-Jern Tsai, Hsiang-Chen Meng, Wei-Perng Chen, Ling-Yu Yang, and Ching-Yuang Lin. "Immune reponses in human mesangial cells regulated." Life Sciences 68, no. 11 (February 2001): 1271–86. http://dx.doi.org/10.1016/s0024-3205(00)01033-x.
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Bystryn, J. C., R. Oratz, M. Harris, D. Roses, and R. O. Perelman. "Clinically beneficial immune reponses to melanoma vaccine treatment." Melanoma Research 3, no. 1 (March 1993): 30. http://dx.doi.org/10.1097/00008390-199303000-00100.
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Liu, Qi, Momina Mazhar, and Lloyd S. Miller. "Immune and Inflammatory Reponses to Staphylococcus aureus Skin Infections." Current Dermatology Reports 7, no. 4 (September 22, 2018): 338–49. http://dx.doi.org/10.1007/s13671-018-0235-8.
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Parrot, A., G. Voiriot, A. Canellas, A. Gibelin, J. M. Nacacche, J. Cadranel, and M. Fartoukh. "Hémorragies intra-alvéolaires." Médecine Intensive Réanimation 27, no. 4 (July 2018): 331–43. http://dx.doi.org/10.3166/rea-2018-0060.
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L’hémorragie intra-alvéolaire (HIA), maladie rare, est une urgence thérapeutique, car elle peut conduire rapidement vers une insuffisance respiratoire aiguë asphyxiante avec décès. La triade, hémoptysie–anémie–infiltrat radiologique, suggère le diagnostic d’HIA, mais elle peut manquer dans deux tiers des cas, y compris chez des patients en détresse respiratoire. La tomodensitométrie thoracique peut aider dans les formes atypiques. Le diagnostic d’HIA repose sur la réalisation d’un lavage bronchoalvéolaire. Les étiologies en sont très nombreuses. Il importera de séparer, en urgence, les HIA d’origine non immune, avec un dépistage de celles d’origine septique qui doivent bénéficier d’une enquête microbiologique ciblée et cardiovasculaire avec la réalisation d’une échographie cardiaque, des HIA immunes (les vascularites liées aux anticorps anticytoplasme des polynucléaires neutrophiles, les connectivites et le syndrome de Goodpasture), avec la recherche d’autoanticorps et la réalisation de biopsies au niveau des organes facilement accessibles. La biopsie pulmonaire doit rester exceptionnelle. En cas d’HIA immune inaugurale, un traitement par stéroïdes et cyclophosphamide peut être débuté. Les indications du rituximab commencent à être mieux établies. Le bénéfice des échanges plasmatiques est débattu. En cas de réapparition d’infiltrats pulmonaires, chez un patient suivi pour une HIA immune, on s’efforcera d’écarter une infection dans un premier temps.
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De Castro, Nathalie, Maryvonnick Carmagnat, Solen Kernéis, Catherine Scieux, Claire Rabian, and Jean-Michel Molina. "Varicella-Zoster Virus-Specific Cell-Mediated Immune Reponses in HIV-Infected Adults." AIDS Research and Human Retroviruses 27, no. 10 (October 2011): 1089–97. http://dx.doi.org/10.1089/aid.2010.0340.
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Li-Kim-Moy, Jean, Nicholas Wood, Cheryl Jones, Kristine Macartney, and Robert Booy. "Impact of Fever and Antipyretic Use on Influenza Vaccine Immune Reponses in Children." Pediatric Infectious Disease Journal 37, no. 10 (October 2018): 971–75. http://dx.doi.org/10.1097/inf.0000000000001949.
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Han, G., H. Liu, W. Tan, C. Xie, Y. Zhou, X. Wang, and D. Hu. "Differential Activation of Th1/Th2 Immune Reponses in Murine Radiation Induced Lung Injury." International Journal of Radiation Oncology*Biology*Physics 93, no. 3 (November 2015): E510—E511. http://dx.doi.org/10.1016/j.ijrobp.2015.07.1853.
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Arellano, Javier, Carolina Carrasco, and Carolina García. "A report of successful management with simvastatin plus ezetimibe in alopecia areata." Medwave 20, no. 10 (November 30, 2020): e8053-e8053. http://dx.doi.org/10.5867/medwave.2020.10.8053.
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Alopecia areata is a common type of non-scarring alo¬pecia. Although the exact pathogenesis remains elusive, alopecia areata is thought to have a multifactorial etiology described as an interplay of genetic predisposition and environmental exposures. In patients with genetic susceptibility, stress, infection, and microtrauma have been documented to decrease immunosuppressive cytokines that generally maintain the hair follicle's immune privilege. There is currently no curative therapy for alopecia areata, although some treatments can induce hair growth in a percentage of patients. It has been postulated that simvastatin reestablishes the immune privilege, and ezetimibe would provide an immunomodulatory and anti-inflammatory effect. We report a case of a 23 years-old woman with alopecia areata successfully treated with simvastatin/ezetimibe.
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Yan, Qingsheng, Shilpee Dutt, Rong Xu, Katherine Graves, Przemyslaw Juszczynski, John Manis, and Margaret A. Shipp. "The BBAP E3 Ligase Monoubiquitylates Histone H4 at Lysine 91 and Selectively Modulates the DNA Damage Response in Chemotherapy-Resistant Lymphomas." Blood 114, no. 22 (November 20, 2009): 3958. http://dx.doi.org/10.1182/blood.v114.22.3958.3958.
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Abstract Abstract 3958 Poster Board III-894 Although the BBAP E3 ligase and its binding partner, BAL, are overexpressed in chemotherapy-resistant diffuse large B-cell lymphomas (DLBCLs), the role of these proteins in response to DNA damage remains undefined. The BBAP and BAL1 genes are located on chromosome 3q21 in a head-to-head orientation and regulated by the same gIFN-responsive bidirectional promoter. These findings are of note because BBAP and BAL1 are most abundant in DLBCLs with a prominent, but ineffective, immune/inflammatory infiltrate and increased gIFN production. Since BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. The nucleosome consists of eight core histone proteins (two each of H2A, H2B, H3 and H4) encircled by a genomic DNA segment. Individual histone proteins undergo extensive post-translational modifications that are essential for proper chromatin assembly, regulation of chromatin structure and DNA damage repair. We found that the BBAP E3 ligase selectively monoubiquitylated histone H4 lysine 91, interacted with the chromatin-associated histone and protected cells exposed to DNA damaging agents. For these reasons, we visually assessed the role of BBAP in the DNA damage response (DDR) pathway. DNA damage generates double-strand DNA breaks and the relocalization of DDR factors to damaged chromatin with phosphorylated ATM, g-H2AX, and MDC-1 accumulating early in the response, followed by 53BP-1 and BRCA1. BBAP-depletion did not affect the accumulation of the early response factors, ATM, g-H2AX or MDC, to sites of DNA damage. In marked contrast, BBAP-depletion significantly altered the DDR response to the checkpoint mediator, 53BP1. At 1 - 4 hrs following induction of DNA damage, there were significantly fewer 53BP1 foci in BBAP-depleted cells than in controls. Since 53BP1 is recruited to histones via the specific interaction of its tandem tudor domains with mono- and dimethyl H4K20, we next compared BBAP expression, H4 monoubiquitylation and H4K20 methylation in control and BBAP-depleted cells at serial timepoints following DNA damage. In parental or control siRNA-treated Hela cells, DNA damage increased the abundance of BBAP and the respective histone H4 modifications - monoubiquitylated histone H4 and mono- and dimethylated H4K20 – with similar kinetics. However, when BBAP was depleted prior to DNA damage, there was a significant decrease in monoubiquitylated histone H4 and mono- and dimethylated histone H4K20. Taken together, these data directly associate BBAP-mediated monoubiquitylation of histone H4 with the additional histone H4 modifications, H4K20 mono- and dimethylation, necessary for 53BP1 recruitment. PR-Set7/Set8 catalyses the monomethylation of histone H4K20, which is a prerequisite for H4K20 dimethylation. Since histone H4K20 mono- and dimethylation were significantly reduced in BBAP-depleted cells, we next assessed PR-Set7/Set8 levels following BBAP knockdown. BBAP depletion significantly decreased the abundance of chromatin-associated PR-Set7/Set8, providing a likely mechanism for BBAP-associated changes in histone H4K20 methylation and 53BP1 foci formation. BBAP-mediated monoubiquitylation of H4K91 and modulation of an associated DNA damage response may represent a mechanism of gIFN-mediated “immunoediting”, limiting the host reponse against lymphoma. More generally, BBAP's role in decreasing the efficacy of chemotherapy-induced DNA damage responses has implications for the design of more effective treatment regimens. Disclosures: No relevant conflicts of interest to declare.
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Vos, G. J., and P. R. Gardiner. "Parasite-specific antibody reponses of responses of ruminants infected withTrypanosoma vivax." Parasitology 100, no. 1 (February 1990): 93–100. http://dx.doi.org/10.1017/s0031182000060157.
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SummarySera from goats and cattle that were infected with twoTrypanosoma vivaxclones (ILDat 1.2 and ILDat 2.1) derived from different stocks were analysed for antibody activity against the variable surface glycoproteins (VSGs) of the infecting clones by enzyme-linked immune assays (ELISA) and immune lysis. To obtain purified VSG, lysed trypanosomes were separated on dodecyl sulphate-polyacrylamide gels. The gels were copper stained and the VSG protein band was excised from the gel. After destaining, the proteins were electroeluted from the gel slices and used as antigens in ELISA. High titres of IgM and IgG1antibodies and lytic antibodies against the VSG of the infecting clone were detected. The IgG1response appeared about 4 days later than the IgM response. IgG2antibodies were only detected in goats and cattle that were infected with ILDat 1.2. Two goats and two calves that were infected with ILDat 1.2 showed recurrent peaks in lytic activity and of IgM and IgG1antibody activity to the VSG of the infecting variable antigenic type (VAT). Two goats that were infected with ILDat 2.1 showed a similar pattern, but in two other goats there was a recurrent peak only in the IgM class. Recurrent peaks of antibody activity to the VSG of ILDat 1.2 and ILDat 2.1 were not detected in the sera of goats that had been inoculated with irradiated trypanosomes or that had been infected with an unrelatedT. vivaxclone. The recurrence of antibody peaks against the VSG of infecting VATs suggests that trypanosomes with completely or partially identical surface determinants reappear duringT. vivaxinfection of ruminants.
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Fang, Zhu, and Wei Junfang. "A Novel Parameter Optimization Algorithm Based on Immune Memory Clone Strategy." International Journal of Advanced Pervasive and Ubiquitous Computing 4, no. 3 (July 2012): 102–8. http://dx.doi.org/10.4018/japuc.2012070107.
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The performance of support vector machine (SVM) depends on the selection of model parameters, however, the selection of SVM model parameters more depends on the empirical value. According to the deficiency, this paper proposes a parameters optimization method of support vector machine based on immune memory clone strategy (IMC). This method can solve the multi-peak model parameters selection problem better which is introduced by n-folded cross-verification. Tests on standard datasets show that this method has higher precision and faster optimization speed compared with other four methods. The proposed method was applied to bus passenger flow counting. The experimental results show that the method reposed in this paper obtains higher classification accuracy.
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Kostine, Marie, Aurélien Marabelle, Thierry Schaeverbeke, and Maria Kfoury. "Les limites des inhibiteurs de points de contrôle immunitaire et la gestion de leur toxicité." médecine/sciences 35, no. 12 (December 2019): 949–56. http://dx.doi.org/10.1051/medsci/2019191.
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L’immunothérapie représente désormais un des piliers de la prise en charge du cancer, notamment avec l’arrivée des inhibiteurs de points de contrôle (checkpoint) immunitaire (ICI, immune checkpoint inhibitors). Ces anticorps thérapeutiques ciblent ces co-signaux inhibiteurs entre cellules tumorales ou cellules présentatrices d’antigènes et lymphocytes T, activant ou réactivant ainsi une immunité cellulaire T anti-tumorale. Mais la survenue d’une toxicité immunologique, qui peut concerner tous les organes, représente le facteur limitant dans le développement clinique de ces anticorps. La gestion de cette toxicité nécessite une collaboration étroite entre oncologues et spécialistes d’organe, et repose sur l’utilisation de corticoïdes et/ou d’autres immunosuppresseurs, avec l’objectif de contrôler la dysimmunité induite sans perdre l’efficacité anti-tumorale.
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Michel, J. P., M. Cadoz, F. Denis, L. Hessel, M. Mounier, and G. Shiffman. "Comparaison des reponses immunes au vaccin pneumococcique 23 valent entre adultes jeunes et personnes agees." Médecine et Maladies Infectieuses 18 (May 1988): 406. http://dx.doi.org/10.1016/s0399-077x(88)80322-6.
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Wang, Anqi, Lipei Sun, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Kunfeng Sun, et al. "Identification of IFITM1 and IFITM3 in Goose: Gene Structure, Expression Patterns, and Immune Reponses against Tembusu Virus Infection." BioMed Research International 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/5149062.
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As interferon-stimulated genes (ISGs), interferon-inducible transmembrane proteins 1 and 3 (IFITM1 and IFITM3) can effectively inhibit the replication of multiple viruses. Here, goose IFITM1 and IFITM3 were cloned and identified for the first time. The two proteins share the same topological structure and several important sites critical for the antiviral functions in other species are conserved in the goose. Goose IFITM1 and IFITM3 are most closely related to their respective orthologs in ducks; these proteins exhibited high mRNA transcript levels in immune-related tissues, including the thymus, bursa of Fabricius, and Harderian gland, compared to other tissues. Moreover, goose IFITM1 was highly constitutively expressed in gastrointestinal tract tissues, while goose IFITM3 was expressed in respiratory organs. Furthermore, goose IFITM3 was activated in goose peripheral blood mononuclear cells (PBMCs) infected with Tembusu virus (TMUV) or treated with Toll-like receptors (TLRs) agonists, while only the R848 and Poly (I:C) agonists induced significant upregulation of goose IFITM1. Furthermore, goose IFITM1 and IFITM3 were upregulated in the sampled tissues, to some extent, after TMUV infection. Notably, significant upregulation of goose IFITM1 and IFITM3 was detected in the cecum and cecal tonsil, where TMUV was primarily distributed. These data provide new insights into the immune effectors in geese and promote our understanding of the role of IFITM1 and IFITM3 in the defense against TMUV.
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Zhu, Fang, and Jun Fang Wei. "SVM Parameter Optimization Based on Immune Memory Clone Strategy and Application in Bus Passenger Flow Counting." Advanced Engineering Forum 6-7 (September 2012): 694–99. http://dx.doi.org/10.4028/www.scientific.net/aef.6-7.694.
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The performance of support vector machine (SVM) depends on the selection of model parameters, however, the selection of SVM model parameters more depends on the empirical value. According to the above deficiency, this paper proposed a parameters optimization method of support vector machine based on immune memory clone strategy (IMC). This method can solve the multi-peak model parameters selection problem better which is introduced by n-folded cross-verification. Tests on standard datasets show that this method has higher precision and faster optimization speed compared with other four methods. Then the proposed method was applied to bus passenger flow counting. The experimental results show that the method reposed in this paper obtains higher classification accuracy.
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Fang, Zhu, and Wei Junfang. "SVM Parameter Optimization based on Immune Memory Clone Strategy and Application in Bus Passenger Flow Counting." International Journal of Advanced Pervasive and Ubiquitous Computing 4, no. 4 (October 2012): 74–80. http://dx.doi.org/10.4018/japuc.2012100108.
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The performance of support vector mchine (SVM) depends on the selection of model parameters, however, the selection of SVM model parameters more depends on the empirical value. According to the above deficiency, this paper proposed a parameters optimization method of support vector machine based on immune memory clone strategy (IMC). This method can solve the multi-peak model parameters selection problem better which is introduced by n-folded cross-verification. Tests on standard datasets show that this method has higher precision and faster optimization speed compared with other four methods. Then the proposed method was applied to bus passenger flow counting. The experimental results show that the method reposed in this paper obtains higher classification accuracy.
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Kuwata, Takeo, Russell Byrum, Sonya Whitted, Robert Goeken, Alicia Buckler-White, Ronald Plishka, Ranjini Iyengar, and Vanessa M. Hirsch. "A Rapid Progressor-Specific Variant Clone of Simian Immunodeficiency Virus Replicates Efficiently In Vivo Only in the Absence of Immune Reponses." Journal of Virology 81, no. 17 (June 27, 2007): 8891–904. http://dx.doi.org/10.1128/jvi.00614-07.
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ABSTRACT A subset of simian immunodeficiency virus (SIV)-infected macaques progresses rapidly to disease with transient SIV-specific immune responses and high viral loads. Unique SIV variants with convergent Env mutations evolve in these rapid progressor (RP) macaques. To address the pathogenic significance of RP-specific variants, we generated infectious molecular clones from the terminal-phase plasma of an RP macaque. Inoculation of macaques with a representative clone, SIVsmH635FC, resulted in a persistent viremia, comparable to that produced by pathogenic SIVsmE543-3, and a chronic disease with progressive loss of CD4+ T cells. However, SIVsmH635FC did not reproduce the rapid-disease phenomenon. Molecular analyses of viruses from these macaques revealed rapid reversion to the wild-type SIVsmE543-3 sequence at two RP-specific sites and slower reversion at another three sites. SIVsmH635FC infection was not sufficient to cause rapid progression even following coinoculation with SIVsmE543-3, despite acute depletion of memory CD4+ T cells. SIVsmH635FC competed efficiently during primary infection in the coinoculated macaques, but SIVsmE543-3 predominated after the development of SIV-specific immune responses. These data suggest that the replication fitness of the RP variant was similar to that of SIVsmE543-3 in a naïve host; however, SIVsmH635FC was at a disadvantage following the development of SIV-specific immune responses. Consistent with these findings, neutralization assays revealed that SIVsmH635FC was highly sensitive to neutralization but that the parental SIVsmE543-3 strain was highly resistant. This study suggests that the evolution of RP-specific variants is the result of replication in a severely immunocompromised host, rather than the direct cause of rapid progression.
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Pagliuca, Simona, Flore Sicre de Fontbrune, Serena Marotta, Anna Paola Iori, Marie Robin, Gérard Socié, Regis Peffault de Latour, and Antonio M. Risitano. "Aplastic Anemia in the Context of Hemolytic Paroxysmal Nocturnal Hemoglobinuria: Feasibility of Antibody-Based Intensive Immunosuppression during Eculizumab Treatment." Blood 128, no. 22 (December 2, 2016): 5074. http://dx.doi.org/10.1182/blood.v128.22.5074.5074.
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Abstract Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (AA/PNH syndrome) PNH. While classical PNH patients requires anti-complement treatment (eculizumab), the treatment of AA/PNH patients should target their bone marrow failure (BMF) by immunosuppression (IST), or even bone marrow transplantation (BMT). However, in a few patients clinically meaningful AA and hemolysis may be concomitant, eventually justifying both IST and eculizumab. To date there is no standard treatment for this rare condition. Here we investigated the prevalence of this condition based on a large cohort of PNH patients seen at our reference centers at St. Louis Hospital (Paris) and Federico II University (Naples), looking for patients who have received "intensive IST" in combination with eculizumab. Amongst a total of 145 PNH patients seen between 2007 and 2016, we have identified 6 patients who have received intensive IST during eculizumab treatment ; thus, roughly the prevalence of severe BMF associated with hemolysis is around 5%. All the 6 patients have been initially classified as AA/PNH syndrome at time of eculizumab starting, but did not require specific treatment before; they were all on eculizumab treatment at the standard dose of 900 mg fortnightly, with adequate control of intravascular hemolysis. Five of the patients fulfilled the criteria of severe AA, the latter had very severe isolated neutropenia, and was diagnosed with an immune-mediated agranulocytosis. Since no patient had a HLA-matched related donor for BMT, all the patients received intensive IST according to different institutional regimens; eculizumab was not discontinued to minimize the risk of rebound intravascular hemolysis and thrombotic complications. Three patients (2 AA and 1 agranulocytosis) received standard IST with horse-antithymocyte globulin (h-ATG, 40 mg/kg for 4 consecutive days) combined cyclosporine A (CsA). The 3 other AA patients received alemtuzumab (3-10-30-30 mg subcutaneously in 4 consecutive days) and CsA within the prospective trial NCT00895739; one of these patients a few months later also received a second IST course with rabbit-ATG (3.5 mg/kg for 5 consecutive days) and CsA. All the patients completed the scheduled treatment without any side effect, including infusion-related reactions. Lymphocyte depletion was observed in all patients irrespective of sustained therapeutic complement blockade, with lymphocyte count dropping <100/μL in all cases and lasting for several days (or even months in the case of alemtuzumab). All patients remained on eculizumab treatment, even if one AA patient required an increase of the dose up to 1200 mg because of pharmacokinetic breakthrough; in 2 patients 50% hemolytic complement (CH50) was systematically monitored during the treatment course, without showing any significant change from status at pre-IST treatment. All the patients were available for response assessment at 6 months; globally, 3 out of 6 showed a hematological response. The agranulocytosis patient achieved a partial response (PR) requiring G-CSF chronic treatment. Among the 5 AA patients, we observed 2 CR (1 with h-ATG and 1 with alemtuzumab) and 1 PR (after alemtuzumab); this latter was converted into a CR after a second IST course with r-ATG. One of the CR relapsed at 3 years showing clonal evolution toward a myelodysplastic syndrome, and finally died. All the other patients are alive, keeping their hematological response; of the 3 non-responders, 1 was rescued with an unrelated transplantation, and 2 remain on eculizumab treatment (one has developed thromboembolic complications). This is the first systematic description of the management of severe BMF in PNH patients on anti-complement treatment; we first observed that this rare challenging condition may pertain to about 5% of PNH patients. Then we demonstrated that intensive IST, based on either polyclonal or monoclonal anti-lymphocyte antibodies can be safely delivered even in concomitance of eculizumab. Pharmacological lymphocyte depletion was achieved irrespective of terminal complement inhibition. Clinical efficacy was in the expected range as in broader AA populations, with an overall reponse rate of 50%. Based on these data, intensive IST delivered on top of eculizumab should be considered in PNH patients who develop severe AA during eculizumab treatment lacking a low-risk bone marrow transplant procedure. Disclosures Peffault de Latour: Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Risitano:Alnylam: Research Funding; Novartis: Research Funding; Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Rapharma: Research Funding.
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Martinez-Prat, L., M. A. Aure, C. Bentow, D. Lucia, M. Lopez-Hoyos, and M. Mahler. "OP0118 DECIPHERING THE ANTI-PROTEIN-ARGININE DEIMINASE (PAD) RESPONSE IDENTIFIES PAD1 AND PAD6 AS NOVEL AUTOANTIGENS IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 78–79. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2853.
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Background:Protein-arginine deiminase (PAD) 4 enzymes play a central role in the pathogenesis of rheumatoid arthritis (RA) and represents an antigenic target. Among the five known family members (PAD1, PAD2, PAD3, PAD4 and PAD6), only PAD2, PAD3 and PAD4 have been described to have autoantigenic properties. Furtheremore, very little is known on the the isotype usage of these autoantibodies. Understanding the molecular basis of the anti-PAD antibody reponse has the potential to open novel approaches for precision medicine in RA.Objectives:The objectives of this study were to screen for the presence of antibodies to the five PAD family members and to evaluate the isotype usage of the anti-PAD4 response in RA.Methods:First, we developed a panel for the detection of anti-PAD IgG based on a particle-based multi-analyte technology (PMAT), that utilized paramagnetic particles coupled with the different human recombinant PAD proteins (PAD1, PAD2, PAD3, PAD4 and PAD6) and anti-human IgG conjugate. This panel was used to test sera from RA patients (n=33) and non-RA controls (n=36). The controls were comprised of apparently healthy individuals (n=10), and patients with infectious diseases (n=10), systemic lupus erythematosus (n=7), systemic sclerosis (n=9) and Sjogren’s syndrome (n=1). Next, the PAD4-coupled beads were tested with anti-human IgM, IgA and IgG conjugates on an extended cohort of RA patients (n=62) and the same non-RA controls.Results:All five anti-PAD IgG (Figure 1) demonstrated the ability to discriminate between RA patients and controls. At greater than 90% specificity, anti-PAD4 IgG, followed by anti-PAD3 IgG, showed the best diagnostic performance. Significantly higher levels of the five antibodies were observed in RAvs.controls (p-values of 0.0041, <0.0001, 0.0014, 0.0039, and 0.0140 for anti-PAD1, 2, 3, 4 and 6, respectively). Significant correlation was observed between all the antibodies, with the highest between anti-PAD1 and anti-PAD4 (Spearman´srho=0.87,p<0.0001) and the lowest between anti-PAD4 and anti-PAD2 (Spearman’srho=0.38,p=0.0015) and anti-PAD4 and anti-PAD6 (Spearman’srho=0.38,p=0.0011). While principal component analysis (PCA) (Figure 2) showed an association between all anti-PAD antibodies, there was further discrimination that displayed closer association between anti-PAD1, 3 and 4 on one hand, and between anti-PAD2 and 6. For the extended testing of anti-PAD4 with IgG, IgA and IgM, all three isotypes were identified in the sera of RA patients. Higher levels of the three isotypes were observed in RA patients with erosive disease when compared with the patients without erosion, but this association was only significant for anti-PAD4 IgA (p=0.0086).Figure 1.Receiver operating characteristics (ROC) analysis of the discrimination between rheumatoid arthritis (RA) and controls of IgG to protein-arginine deiminase (PAD) 1, PAD2, PAD3, PAD4 and PAD6. The area under the curve (AUC) values are shown in brackets for each biomarker.Abbreviations:TPF: true positive fraction; FPF: false positive fractionFigure 2.Two dimensional principal component analysis (PCA) plot of the anti-PAD levels in RA patients (n=33) and controls (n=36). Anti-PAD1, 3 and 4 have the main contribution to PC1, which explains 51.7% of the variance, and anti-PAD2 and 6 to PC2, that represents 20.8% of it.Abbreviations:PC: principal componentConclusion:Our study is the first to describe PAD1 and PAD6 as novel antigenic targets in RA and to demostrate that the anti-PAD4 B-cell immune response uses all three isotypes (IgG, IgA and IgM). The strong and significant association between anti-PAD4 IgA and joint erosion is of particular clinical relevance.Disclosure of Interests:Laura Martinez-Prat Employee of: I am an employee of Inova Diagnostics, an in vitro diagnostics company., Mary Ann Aure Employee of: I am an employee of Inova Diagnostics, an in vitro diagnostics company., Chelsea Bentow Employee of: I am an employee of Inova Diagnostics, an in vitro diagnostics company., David Lucia Employee of: I am an employee of Inova Diagnostics, an in vitro diagnostics company., Marcos Lopez-Hoyos Consultant of: Inova Diagnostics, an in vitro diagnostics company., Michael Mahler Employee of: I am an employee of Inova Diagnostics, an in vitro diagnostics company.
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SAUCIER, L., M. JULIEN, F. CHEÓUR, R. LETARTE, and J. GOULET. "Effect of Feeding Lactic Acid Bacteria and Fermented Milk on Specific and Nonspecific Immune Reponses of Mice Infected With Klebsiella pneumoniae AD-1." Journal of Food Protection 55, no. 8 (August 1, 1992): 595–600. http://dx.doi.org/10.4315/0362-028x-55.8.595.
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The diets of six groups of weaned mice were supplemented with ultra high temperature (UHT) milk containing a washed suspension of lactic acid bacteria (mixture of 8 strains) or with UHT milk fermented by the same strains and heat-treated or not. Control groups received physiological saline or UHT milk only. The mice were infected intranasally by Klebsiella pneumoniae AD-1 on the 13th d of feeding. The effect on the immune system (specific and nonspecific) before and after infection was evaluated by measuring the phagocytosis of alveolar macrophages (using zymosan particles) and by measuring of total immunoglobulin G and A levels in serum and in pulmonary fluid (using the enzyme-linked immunosorbent assay method). Postinfection survival was 0.7 d longer for mice receiving fermented milk than for the saline control group. The percent phagocytosis did not vary significantly, while serum immunoglobulin G levels differed between mice fed fermented milk and those fed bacterial suspensions in unfermented milk. Fermentation appears to be essential for the beneficial effects on the immune system and survival time; this effect no longer occurs after pasteurization of fermented milk.
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Salerno, Dominic M., Barbara Hoffman, and Dan A. Liebermann. "Gadd45 Null Mice and Neutrophils/Macrophages Derived From the Bone Marrow of These Mice Exhibit Impaired Innate-Immune/Inflammatory Reponses." Blood 114, no. 22 (November 20, 2009): 1350. http://dx.doi.org/10.1182/blood.v114.22.1350.1350.
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Abstract Abstract 1350 Poster Board I-372 Stress sensor Gadd45 proteins modulate p38-NF-Kb and JNK signaling, which play major roles in leukocyte activation and innate immunity. We have previously documentedthat under conditions of hematological stress, notably acute stimulation with cytokines or inflammation, both gadd45a-deficient and gadd45b-deficient mice exhibited impaired inflammatory responses as indicated by lower percentages of Gr-1-positive cells in the BM and lower numbers of myeloid cells in peritoneal exudates (Gupta et. al Oncogene 25:5539-46, 2006). Recent evidence has implicated Gadd45 proteins in dendritic cell functions that influence effector Th1 responses to inflammation. However, whether gadd45 genes play a role in modulating the myeloid compartment, notably macrophage & granulocyte functions in response to inflammatory stress, remains largely unexplored. To this end, we have employed in vitro & in vivo models of inflammation using BM derived neutrophils and macrophages from WT, gadd45a and gadd45b null mice. The data obtained indicate that chemotaxis and transmigration to various chemo-attractants, including LPS and fMLP, as well as oxidative burst and phagocytic functions were impaired for both neutrophils and macrophages from mice lacking either gadd45a or gadd45b. Furthermore, upon stimulation with LPS, cytokine secretion, notably, but not exclusively IL-12 and TNFa, was significantly reduced in neutrophils and macrophages of gadd45a-/- and gadd455b-/- mice. Western Blot analysis of BM derived neutrophils lacking gadd45a and stimulated with LPS (500ng/mL) exhibited defects in p38 phosphorylation as compared to controls, suggesting a possible mechanism by which the innate response is impaired. P38 phosphorylation in gadd45b null granulocytes stimulated with LPS appeared comparable to what was observed in wt controls. This suggests that gadd45a and gadd45b utilize different signaling pathways to regulate innate-mmune/inflammtory responses. Interestingly, gadd45a, gadd45b & gadd45g null mice injected intraperitoneally with sublethal (25mg/kg body weight) doses of LPS were significantly more susceptible to septic shock compared to wt mice, as indicated by significantly increased morbidity through 5 days post LPS administration. Moreover, 18 hrs. post-injection, the spleens of KO mice were shown to have numerous apoptotic foci in the white pulp, confirmed to be tingible body macrophages ingesting dying cells by IH and IF for macrophage markers. These in vitro and in vivo data suggest a novel role for gadd45 family members in myeloid innate immune responses. Further elucidation of the signaling pathways involved is in progress and is expected to elucidate the molecular basis for the role Gadd45 proteins play in macrophage and granulocyte innate immune functions. Disclosures No relevant conflicts of interest to declare.
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&NA;. "GENERATION OF A NEW RABBIT ANTI-HUMAN LEUKOCYTE POLYCLONAL ANTIBODY AND ITS POTENTIAL THERAPEUTIC APPLICATION IN PREVENTING ALLO-IMMUNE REPONSES." Transplantation 82, Suppl 2 (July 2006): 138. http://dx.doi.org/10.1097/00007890-200607152-00215.
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Heyman, M. "Evaluation of the impact of food technology on the allergenicity of cow’s milk proteins." Proceedings of the Nutrition Society 58, no. 3 (August 1999): 587–92. http://dx.doi.org/10.1017/s0029665199000774.
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The quantitative evaluation of the allergenicity of food proteins and the clinical tolerance towards antigens are problems the food industry and the clinicians have to face. The allergenicity of a protein depends on multiple factors, including the stability to digestion and the interaction with the intestinal environment. In addition to the possible reduction in allergenicity by technological treatments such as heat and enzymic hydrolysis, the complex interactions existing between the antigens, the intestinal epithelium and the underlying immune system, as well as the individual susceptibility to the sensitizing epitopes, have to be taken into account. Indeed, the intestinal cells are able to take up and process proteins, and possibly to present them directly to mucosal lymphocytes. On the other hand, pathophysiological conditions can modify the interactions between food antigens and the immune system. A large number of methods has been developed to assess the residual antigenicity of food proteins, based on the various immune responses leading to intestinal or extradigestive pathologies. Thus, the difficulty in measuring the residual allergenicity of hypoallergenic formulas is partly due to the physiology of the gastrointestinal tract, since an intricate network of interactions between enterocytes and immune cells governs the development of the immune response to food antigens. RésuméL’évaluation de l’allergénicité des aliments et leur bonne tolérance clinique est une question touchant à la fois les industriels de l’agro-alimentaire et les cliniciens. L’allergénicité d’une protéine dépend de multiples facteurs parmi lesquels la résistance à la digestion, les interactions avec le tractus digestif et les facteurs environnementaux. L’allergénicité d’un produit alimentaire peut être modifiée non seulement par les traitements technologiques industriels, mais aussi par le tractus gastrointestinal. La susceptibilité individuelle aux epitopes peptidiques formés est également un facteur primordial. En effet, les interactions complexes existant entre les antigènes, l’épithelium intestinal et le système immunitaire muqueux peuvent conduirent à des réponses immunitaires différentes selon les individus. De nombreuses méthodes existent pour mesurer l’antigénicité résiduelle des aliments, basées sur la nature des différentes réactions immunitaires anormales conduisant à une pathologie intestinale ou extradigestive. La difficulté de mesurer l’allergénicité résiduelle de formules hypoallergéniques repose donc sur les relations complexes entre les antigènes alimentaires, l’épithelium intestinal et le système immunitaire muqueux.
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Bertinetti, Cristina M., and Hendrik Veelken. "Characterization of Cellular Immune Responses to a Recombinant Idiotype Vaccine by ELISPOT and Identification of MHC Class I-Restricted T Cell Epitopes by Peptide Mapping." Blood 104, no. 11 (November 16, 2004): 1409. http://dx.doi.org/10.1182/blood.v104.11.1409.1409.
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Abstract Induction of tumor-specific immune responses by idiotype vaccination is a promising strategy for biological therapy of indolent B cell lymphomas. In a previous report, we have described immune responses in a subset of patients participating in a phase I clinical trial primarily designed to demonstrate safety and efficacy of a recombinant idiotype vaccine (Veelken et al., ASH abstract #3342, 2003). In this trial, B-NHL patients who had relapsed after standard chemotherapy received repetitive intradermal vaccinations with recombinant idiotype Fab fragment derived from their tumor mixed with lipid-based adjuvant and concurrent subcutaneous GM-CSF at the same site. We now present the final analysis of cellular immune responses in this cohort. Peripheral blood lymphocytes (PBL) were obtained prior to and on various time points during and after vaccinations. Cryopreserved PBL were stimulated twice by autologous dendritic cells (DC) exposed to the autologous Fab protein for cross-presentation as MHC class I-bound peptides. INFγ-secreting cells were subsequently quantified by ELISPOT with Fab-presenting DC. Alternatively, freshly thawed PBL were directly assayed with recombinant Fab by ELISPOT without prestimulation. An increase in the frequency of Fab-responding PBL was detected in 7 of 15 evaluable patients with the prestimulation assay and in 4 of 10 patients by direct quantitation, resulting in a combined cellular response rate of 53% (9 of 17). A cellular immune response showed a trend for correlation with extended progression-free survival (p=0.08). T cell responses were predominantly idiotype-specific since lesser or no increases in IFNγ-secreting cells were detected against light chain- and VH family-matched control Fabs. Interestingly, a much higher base-line reactivity was observed against the control Fabs in comparison to the patient’s lymphoma Fab in four patients, pointing to the possibility of tumor-specific anergy in lymphoma patients that can at least be partially corrected by active immunization. In an effort to identify the MHC class I-presented idiotype-derived peptides, potential binding motifs were defined by reverse immunology with the SYFPEITHI algorithm (www.syfpeithi.de). Ten candidate peptides from the variable and constant region of an immune responder’s idiotype heavy chain were synthesized and evaluated with post-vaccination PBL by ELISPOT without prestimulation. A peptide derived from the CDR2 region showed a significantly higher response compared to an unrelated peptide control (p=0.0013). Additional peptides derived from the FWR1, CDR1, and CDR2 also showed a significant stimulation, but only in comparison to a no peptide control. ELISPOT offers a valuable tool to monitor cellular immune reponses and demonstrates successful induction of tumor immunity in pretreated, tumor bearing and immunosuppressed B cell lymphoma patients. Supported by Deutsche Krebshilfe
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Calmettes, Marion, Thibaut Girardot, and Thomas Rimmelé. "Épuration extra-corporelle et immunomodulation dans le sepsis." Médecine Intensive Réanimation 29, no. 2 (July 24, 2020): 75–85. http://dx.doi.org/10.37051/mir-00009.
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Le choc septique est fréquent et représente la première cause de mortalité en réanimation. Malgré des recommandations internationales mises à jour régulièrement (Surviving Sepsis Campaign) et les progrès de la réanimation, la mortalité reste très élevée (jusqu’à 40%), en partie du fait des conséquences d’une réponse immuno-inflammatoire de l’hôte « dérégulée ». Le rationnel physiopathologique des techniques extra-corporelles d’immunomodulation dans le choc septique repose sur un meilleur contrôle de cette réponse de l’hôte. De nombreuses techniques sont proposées, certaines combinant l’élimination des cytokines et/ou des endotoxines avec l’épuration extra-rénale. La littérature scientifique est relativement abondante à ce sujet. Les grands essais cliniques multicentriques récents ne confirment pas les résultats expérimentaux et précliniques prometteurs. La recherche expérimentale et clinique doit se poursuivre dans ce domaine. Nous proposons dans cet article une revue de la littérature des différentes techniques extracorporelles d’immunomodulation dans le choc septique.
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El-Kassas, Seham, Safaa E. Abdo, Karima El-Naggar, Walied Abdo, Abeer A. K. Kirrella, and Toufic O. Nashar. "Ameliorative effect of dietary supplementation of copper oxide nanoparticles on inflammatory and immune reponses in commercial broiler under normal and heat-stress housing conditions." Journal of Thermal Biology 78 (December 2018): 235–46. http://dx.doi.org/10.1016/j.jtherbio.2018.10.009.
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Williams, Yvette J., Suzanne M. Rea, Sam Popovski, Carolyn L. Pimm, Andrew J. Williams, Andrew F. Toovey, Lucy C. Skillman, and André-Denis G. Wright. "Reponses of sheep to a vaccination of entodinial or mixed rumen protozoal antigens to reduce rumen protozoal numbers." British Journal of Nutrition 99, no. 1 (August 15, 2007): 100–109. http://dx.doi.org/10.1017/s0007114507801553.
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Two rumen protozoa vaccine formulations containing either whole fixed Entodinium or mixed rumen protozoa cells were tested on Merino sheep with the aim of decreasing the number and/or activity of protozoa in the rumen. Negative control (no antigen) and positive control (Tetrahymena corlissi antigens) treatments were also included in the experiment. Blood and saliva were sampled to measure the specific immune response. Protozoal numbers in the rumen were monitored by microscopic counts. Vaccination with protozoal formulations resulted in the presence of specific IgG in plasma and saliva, but saliva titres were low. Titres after secondary vaccination were higher (P < 0·05) than after primary vaccination. There was a moderate (r2 0·556) relationship (P < 0·05) between plasma and saliva titres for the rumen protozoal vaccine formulations. Rumen protozoa were not decreased (P>0·05) by the vaccination and there was also no difference (P>0·05) between treatments in rumen fluid ammonia-N concentration or wool growth. In vitro studies investigated the binding ability of the antibodies and estimated the amount of antibody required to reduce cell numbers in the rumen. The studies showed that the antibodies did bind to and reduced protozoa numbers, but the amount of antibody generated by vaccination was not enough to produce results in an in vivo system. It is suggested that the vaccine could be improved if specific protozoal antigens are determined and isolated and that improved understanding of the actions of protozoa antibodies in rumen fluid and the relationships between levels of antibodies and numbers of protozoa in the rumen is needed.
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Davis, Andrew A., Young Kwang Chae, Sarita Agte, Alan Pan, Nisha Anjali Mohindra, Victoria Meucci Villaflor, and Francis J. Giles. "Association of tumor mutational burden with smoking and mutation status in non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 24. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.24.
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24 Background: Reponses to immunotherapy have been observed in multiple solid tumors including non-small cell lung cancer (NSCLC). Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies remains critical. Tumor mutational burden (TMB) may indicate genomic instability and potential neoantigen binding sites to activated effector T cells. Methods: We retrospectively examined tumor mutational burden (TMB) using next-generation sequencing (Foundation Medicine) for 83 patients with NSCLC in our institution. TMB included both coding and non-coding regions, but excluded potentially functional mutations. We correlated TMB (mutations per megabase) with smoking history, number of potentially functional mutations, variants of unknown significance, and the driver mutations EGFR, ALK, and KRAS. TMB high versus low was stratified based on 15 mutations per megabase pair. Results: Our findings demonstrated that TMB was significantly associated with current/former smoking status (p = 0.01, Table 1). TMB was also significantly associated with number of potentially functional mutations, number of variants of unknown significance (VUS), and total reported mutations (p < 0.01). The absence of mutations in EGFR, ALK, or KRAS tended to be associated with higher TMB as well (p = 0.07). Conclusions: TMB was associated with smoking status, as well as potentially functional mutations, VUS, and total number of reported mutations. Our results indicate that number of coding region mutations predict genomic instability in non-coding regions. Future studies are needed to correlate this measure with other immune biomarkers and patient outcome in NSCLC. [Table: see text]
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Tanguay, Daniel. "Le problème de la clôture politique selon Daniel Jacques." Dialogue 40, no. 1 (2001): 147–66. http://dx.doi.org/10.1017/s001221730004909x.
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L'attachement aux coutumes locales tient à tous les sentiments désintéressés, nobles et pieux. Quelle politique deplorable que celle qui en fait de la rébellion! Qu'arrive-t-il? Que dans tous les États où l'on détruit ainsi toute vie partielle, un petit État se forme au centre: dans la capitale s'agglomèrent tous les intérêts: là vont s'agiter toutes les ambitions: le reste est immobile. Les individus, perdus dans un isolement contre nature, étrangers au lieu de leur naissance, sans contact avec le passé, ne vivant que dans un présent rapide, et jetés comme des atomes sur une plaine immense et nivelée, se détachent d'une patrie qu'ils n'aperçoivent nulle part, et dont l'ensemble leur devient indifférent, parce que leur affection ne peut se reposer sur aucune de ses parties.
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Strauss, Julius, Fadi S. Braiteh, Emiliano Calvo, Maria De Miguel, Andres Cervantes, William Jeffery Edenfield, Tianhong Li, et al. "Evaluation of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in cervical cancer: Data from phase 1 and phase 2 studies." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 5509. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5509.
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5509 Background: The accelerated FDA approval of pembrolizumab validated the efficacy of anti–PD-(L)1 therapy for pts with recurrent/metastatic cervical cancer; however, the objective response rate (ORR) with pembrolizumab was 14.3% in pts with PD-L1 expressing tumors. HPV infection is implicated in > 95% of cervical cancers and is linked to upregulation of TGF-β signaling. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. We report pooled safety and efficacy in pts with immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer treated with bintrafusp alfa in phase 1 (INTR@PID 001; NCT02517398) and phase 2 (study 012; NCT03427411) studies. Methods: Pts with pretreated, immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer received bintrafusp alfa 0.3-30 mg/kg (phase 1 dose escalation) or 1200 mg Q2W (phase 1 expansion/phase 2) until progressive disease, unacceptable toxicity, or withdrawal. Treatment past progression was allowed. Primary endpoints were safety for the dose-escalation part of the phase 1 study and best overall response per RECIST 1.1 for the expansion part of phase 1 and phase 2 studies. Secondary endpoints for the expansion part of the phase 1 and 2 studies included safety. Results: As of May 15, 2020 (phase 1) and December 22, 2020 (phase 2), 39 pts had received bintrafusp alfa for a median duration of 2.8 months (range, 0.5-19.3). The median follow-up to data cutoff was 35.0 months and 24.1 months for the phase 1 and phase 2 studies, respectively. All pts had received prior anticancer therapy; 16 pts (41.0%) had received ≥3 prior anticancer regimens. There were 2 complete responses and 9 partial responses (PRs; ORR per RECIST 1.1, 28.2%). Median duration of response was 11.7 months (range, 1.4-41.2), and 5 pts (45.5%) had ongoing responses (duration 1.5-41.2 months). An additional delayed PR was observed (duration 23.7 months). Reponses occurred irrespective of tumor histology or prior bevacizumab or radiation treatment. Median overall survival (mOS) was 13.4 months (95% CI, 5.5 to not reached); 24-month OS rate was 33.2%. Any-grade treatment-related adverse events (TRAEs) occurred in 33 pts (84.6%). Grade 3 TRAEs occurred in 8 pts (20.5%; anemia, colitis, gastroparesis, upper gastrointestinal hemorrhage, keratoacanthoma, cystitis noninfective, hematuria, pneumonitis, rash macular [n = 1 each]); 1 patient (2.6%) had a grade 4 TRAE (asymptomatic hypokalemia related to the above grade 3 gastroparesis). No treatment-related deaths occurred. Conclusions: Bintrafusp alfa had a manageable safety profile and demonstrated clinical activity in pts with heavily pretreated, immune checkpoint inhibitor–naive recurrent/metastatic cervical cancer. Clinical trial information: NCT02517398 , NCT03427411.
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RAVINET, N., C. CHARTIER, H. HOSTE, M. MAHIEU, A. DUVAUCHELLE-WACHE, A. MERLIN, N. BAREILLE, P. JACQUIET, and A. CHAUVIN. "Enjeux et outils du traitement raisonné contre les strongles gastro-intestinaux chez les bovins et les petits ruminants." INRA Productions Animales 30, no. 1 (June 14, 2018): 57–76. http://dx.doi.org/10.20870/productions-animales.2017.30.1.2233.
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Chez les ruminants élevés au pâturage, les strongles gastro-intestinaux (SGI) peuvent induire des pertes de production, voire des atteintes cliniques chez les animaux non immuns. Le contrôle de l’infestation repose essentiellement sur les traitements anthelminthiques (AH) administrés fréquemment sans évaluation préalable de la réalité du risque parasitaire. Cette synthèse vise tout d’abord à exposer les principaux risques associés à ce recours insuffisamment raisonné aux AH : apparition de populations de parasites résistants aux AH, écotoxicité pour la microfaune prairiale dégradant les fèces, et installation retardée de l’immunité anti-strongles (notamment chez les bovins). Les stratégies de traitement ciblé-sélectif devraient permettre de maîtriser ces risques tout en prévenant les atteintes cliniques et sécurisant les performances des animaux. Il s’agit de rationaliser les traitements AH en ciblant les troupeaux ou les lots et les périodes à risque, et en sélectionnant les individus les plus parasités ou « souffrant » le plus du parasitisme. Cette synthèse vise donc ensuite à décrire les outils et les indicateurs étudiés pour mettre en œuvre de telles stratégies chez les ruminants. Il s’agit d’indicateurs zootechniques (gain moyen quotidien, parité, niveau de production…), cliniques (FAMACHA©, index de diarrhée…), parasitologiques (coproscopie, niveau d’anticorps anti-SGI…), ou d’indicateurs de conduite (modalité de pâturage), et aussi d’outils informatiques (modélisation du recyclage parasitaire). Leur fiabilité et leur opérationnalité sont variables. La mise en place de telles stratégies nécessitera de dépasser les freins à l’acceptation de ces nouvelles pratiques tant au niveau des éleveurs que des vétérinaires prescripteurs. Cet usage raisonné des AH assurerait une meilleure durabilité du contrôle de l’infestation par les SGI.
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Friedman, S. M., A. Al-Den, and D. Porplycia. "P051: Management of subcutaneous abscesses in the emergency department." CJEM 20, S1 (May 2018): S74—S75. http://dx.doi.org/10.1017/cem.2018.249.
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Introduction: We sought to characterize the management of uncomplicated subcutaneous abscesses (SA) by Canadian emergency physicians (EPs). Methods: Cross-sectional study of CAEP membership. Subjects were emailed an invitation to an online survey, and two biweekly reminders. Wilcoxon rank sum test was used for association with age, and Chi Square and Fischers exact test were used for binary variables. Results: Response rate was 21.2 % (392 Reponses / 1850 surveyed). Duration of practice ranged from 30.2 % practising <= 5 years, to 25.7% practising >= 20 years. Teaching setting was described in 89.1% of responses. Irrigation with saline is performed by 57.1 % of EPs, tap water 2.1 %, or disinfectant 2.1% of EPs, with 39.1% not doing any irrigation. Approximately half (49.2%) typically do not pack or close wounds, while 40.6 % employ ribbon or gauze packing, and 1.6 % primary closure. Antibiotics are generally not prescribed by 16.8%. EPs prescribe antibiotics when suspecting surrounding cellulitis (84.2%), immunocompromised host (51.6%), MRSA (28.9%), or recurrence within 30 days (27.5 %). Cultures are taken almost always by 28.2%, half the time or less by 33.9%, never by 11.6%, and if MRSA is suspected by 33.9%. Follow-up instructions are with FP (56.7%), ED at 24 hours (5.91 %) or 48 hours (17.74 %), or not required (24.7%). Most EPs (90.9%) report having no standardized protocol for abscess management in their ED. EPs with fewer years in practice are more likely to make cruciate incisions (p=0.009), to generally not irrigate incisions (p=0.02), to culture if MRSA is suspected (p=0.02), and to prescribe antibiotics when suspecting MRSA (p=0.02) immune-compromised host (p=0.03), and in case of spontaneous treatment failure or recurrence (p=0.0004). EPs with more years in practice are more likely to pack with ribbon gauze (p=0.06), and to almost always swab for C&S (p=0.04) Conclusion: Practice variability and deviations from practice guidelines (i.e. IDSA, Choosing Wisely Canada) are noted. A knowledge translation exercise based on the guidelines for Canadian EPs would be useful.
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Dorfel, Daniela, Barbara Beck, Christiane Geiger, Felix Lichtenegger, Lysann Lindner, Martina Merk, Dolores Schendel, and Marion Subklewe. "The TLR7/8 Ligand R848 Is Superior In Generation of Monocyte Derived Dendritic Cells From AML Patients for the Induction of Potent T and NK Cell Immune Responses." Blood 116, no. 21 (November 19, 2010): 2195. http://dx.doi.org/10.1182/blood.v116.21.2195.2195.
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Abstract Abstract 2195 Introduction: Therapeutic vaccination with dendritic cells (DC) is currently considered as an investigational therapy in acute myeloid leukemia (AML) for eradication of minimal residual disease (MRD). Dendritic cells derived from autologous peripheral blood monocytes have been tested as cellular adjuvants for therapeutic vaccination of malignancies and proven feasibility and safety, but overall clinical response rates remain very low. The vast majority of DCs used for clinical trials were differentiated with a standard maturation cocktail composed of the cytokines TNF-a, IL-1b, IL-6 and PGE2 leading to DCs unable to secrete biologically active IL-12. This cytokine is fervently desired because of its leading role in promoting T helper 1 cell polarization and therefore fostering the appropriate adaptive immune responses needed to combat minimal residual disease. Cocktails containing synthetic Toll-like receptors (TLR) agonists emerged as an attractive alternative for the induction of DC maturation with T helper type 1 polarizing capacity. Our present investigation was designed to study the feasability of a clinical grade DC 3-day mDC generation protocol from nonleukemic monocytes of intensively pretreated AML patients with novel maturation cocktails containing different TLR-agonists in vitro and assessment of their potency to induce adaptive and innate immune responses. Material & Methods: Monocytes isolated from peripheral blood of AML patients in CR and healthy donors were differentiated into immature DC with GM-CSF and IL-4. After 48 hours DC were additionally cultured with TNF-a, IL1-b, INF-g, PGE2 and corresponding to the defined cocktail with the TLR7/8 agonists R848 (R) or CL075 (C) with or without the TLR3 agonist poly(I:C) (P) for 24 hours. mDCs were analyzed for expression of maturation surface markers, costimulatory profile, IL-12(p70)/IL-10 ratio, migratory capacity, NK cell activation and polarization of T cells. Results: No significant difference in absolute monocyte counts and percentage of DC recovery between healthy controls and AML patients in CR was found using different maturation cocktails (C, CP, R, and RP). Phenotype analysis of surface marker expression revealed no substantial differences between the different DC generation protocols used in healthy donors and AML patients in CR. The costimulatory profile assesed by the expression of two members of the B7 family, CD80 (B7.1) and CD274 (B7-H1 or PD-L1), was in healthy donors superior to AML patients, but these differences were not statistically significant. Variations were noted in the capacity of DCs derived from different donors to produce IL-12(p70) and IL-10, but importantly no significant differences between AML patients in CR and healthy controls could be observed. Interestingly, both healthy donor and AML derived DCs secrete a significantly higher proportion of IL-12(p70) with R848 containing cocktails compared to CL075. Treatment with the CP cocktails even leads to a inverse Il12/IL-10 ratio in AML patients. The high CCR7 expression was paralleled by a strong migratory capacity as well as positive chemotactic reponses to CCL19 chemokine signals. DCs matured with these novel cocktails induced potent alloresponses and strongly activated NK cells measured by upregulation of CD69 expression and IFN-g secretion. No differences beetween R848 and CL075 could be observed. Conclusion: Here we report for the first time a clinically applicable, time- and resource saving 3-day TLR-agonist containing maturation protocol for the generation of IL-12(p70) secreting DCs from AML patients in remission validated with healthy controls which allowed efficient generation, easy harvesting, stable maturation and substantial recoveries of mature DCs. Comparison of different TLR7/8 agonists showed superiority of R848 in IL-12(p70) production to CL075. We believe that these studies point the way to improved DCs that will induce better and long lasting immune responses in the vaccination against acute myelo Disclosures: No relevant conflicts of interest to declare.
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Schutz, Natalia, Jorge Arbelbide, Walter Skordo, Susana Viñuales, Elsa Nucifora, and Dorotea Beatriz Fantl. "Rituximab Treatment for Autoinmune Hemolitic Diseases,." Blood 118, no. 21 (November 18, 2011): 3168. http://dx.doi.org/10.1182/blood.v118.21.3168.3168.
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Abstract Abstract 3168 INTRODUCTION: Steroids are the first line treatment for Autoimmune Hemolytic Anemia (AHA) and Immune Thrombocytopenic Purpura (ITP). Second line treatments for patients with partial reponses or steroid dependence are controversial and have changed during the last decades. Several authors have proposed the use of Rituximab in these patients although published data are still sparse. OBJECTIVES: We reviewed the medical records of all the patients treated in our hospital with Rituximab in order to evaluate the response rate and security of this treatment. MATHERIALS AND METHODS: We included in the study all the patients older than 18 years with diagnoses of Immune Thrombocytopenia or Autoimmune Hemolytic Anemia treated with Rituximab. Patients with oncologic diseases that required specific chemotherapy apart from AHA or ITP were excluded. Rituximab was administered at a dose of 375mg/m3 weekly for 4 weeks. In patients with AHA we assessed the response according to the following criteria: complete response a hemoglobin level higher than 12 g/dl without hemolysis (normal bilirubin, LDH and haptoglobin) and partial response at least 2g/dl increase from the basal hemoglobin level with improvement in the hemolysis parameters. In patients with ITP we defined complete response as >100.000 platelets/mm3 and partial response >50.000 platelets/mm3. In both cases patients should be tapering steroids (less than 10mg/day of prednisone) and without transfusions. RESULTS: We performed 55 treatments with Rituximab in 37 pts., 19 AHA (12 cold hemolytic anemia) and 18 ITP. The median age was 60 years (26 – 86) and 31 pts. were female. Five patients had other autoimmune diseases (lupus, sjogren, autoimmune hepatitis), and six patients had an underlying onco-hematologyc disease (CLL, indolent lymphoma). All patients had been treated with steroids before and most of them had also received azathioprine, cyclophosphamide or gamaglobuline. The median of previous treatments was 3. Eight patients had undergone also splenectomy. The reason for the treatment was steroid dependence in 16 patients, partial response 6 patients and no response to previous treatment in 15 patients. The overall response rate was 79% for AHA and 94% for ITP, with 8pts (42%) and 13pts (72%) achieving a complete response and 7pts (37%) and 4pts (22%) achieving a partial response respectively. The median time to the complete response was 14 days for ITP and 28 days for AHA. The treatment was well tolerated with only one infusion related serious adverse event and one pulmonary thromboembolism during the period of treatment. Fourteen patients relapsed (8 AHA and 6 PTI). The response rate to Rituximab at relapsed for those patients that received a second or even third course of treatment were similar to the observed before. The median time of follow up was 50 months with and event free survival at 1 year of 34% (median 11,9 months) for AHA vs. 60% for PTI (median 38 months) (p 0,23). The overall survival at 5 years was 39% (median 53 months) vs. 86% (median not reached) (p 0,18) respectively. Seven patients with AHA and 2pts with ITP died, mostly of infectious complications. CONCLUSIONS: Rituximab is an effective treatment for ITP and AHA patients with no response to previous treatments or corticoid dependence. There were few serious adverse effects related to the treatment with Rituximab itself. The mortality rate was higher in patients with AHA although it wasn`t statistically significant. The main cause of death was related to infectious complications but most of the patients had a long history of immunosuppression treatment. Patients who relapsed and were treated again with rituximab had very good response rate. Disclosures: No relevant conflicts of interest to declare.
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Rapoport, Aaron P., Stephan A. Grupp, Edward A. Stadtmauer, Robert H. Vonderheide, Bruce L. Levine, Hongbin Fang, Kelly Yager, Anne Chew, Elizabeth Veloso, and Carl H. June. "Rapid T Cell Recovery and Possible Auto-GVHD Following Adoptive Transfer of Ex-Vivo Costimulated Autologous T Cells at Day +2 Post-Transplant." Blood 110, no. 11 (November 16, 2007): 769. http://dx.doi.org/10.1182/blood.v110.11.769.769.
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Abstract Retrospective studies suggest that rapid lymphocyte recovery following autologous stem cell transplants (SCT) may be associated with better outcomes. Previously we showed that adoptive transfer of in-vivo vaccine-primed and ex-vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at about day 14 post-transplant increased CD4 and CD8 T cell counts at day 42 post-transplant and induced pneumococcal conjugate vaccine-directed T and B-cell responses [Rapoport et al, Nature Medicine, 2005]. In 2 current studies, we are further investigating the impact of ex-vivo costimulated autologous T cells on vaccine responses after SCT. In the first study, we are investigating whether a similar strategy of pre- and post-transplant immunizations along with an early infusion of vaccine-primed ex-T can induce responses to a putative tumor vaccine composed of 4 HLA-A2-restricted peptides derived from survivin and hTERT in pts undergoing SCT for myeloma. In the second (randomized) trial, the impact of early ex-T on immune recovery and vaccine reponses is being tested in pediatric neuroblastoma pts. Compared to the previous study, two methodologic changes were made: The target number of T cells infused was raised 5-fold to 5 x 1010 (109/kg) T cells were infused on day + 2 to take greater advantage of homeostatic expansion mechanisms. Patients were monitored for delayed hematopoietic recovery because of this switch to early ex-T and the fact that survivin and hTERT are also expressed in hematopoietic stem cells. At the time of submission, 16 adult and 30 pediatric patients have been enrolled on these trials of whom 11 and 21, respectively, are evaluable for post-transplant hematopoietic and T-cell recovery. On the myeloma trial, the mean # of T cells infused was 3.95 x 1010 with 96% viability and a CD4/CD8 ratio of 1.8:1. At day 14 post-transplant, the median CD4 count was 1951/mcl (range 651–7668) and the median CD8 count was 4117/mcl (range 1499–39,354). The median # days to achieve an absolute neutrophil count (ANC) > 500 was 12 (range 11–14) and the median # days to achieve a PLT count >20,000/mcl was 13 days (range 0–28). Similarly, in the pediatric cohort, median CD4 and CD8 counts at day 30 were 1500 and 2100/mcl, respectively, compared to 22 and 14 in a group of pts who did not receive d+2 ex-T, with no impact on engraftment. 1 adult and 3 pediatric pts also developed an “engraftment syndrome” characterized by GHVD-like features with or without fever. The adult pt with day 14 CD4 and CD8 counts of 2,724 and 11,571 cells/mcl had clinical and histologic features of (autologous) gut GVHD. 3 pediatric pts developed pruritic rashes clinically and pathologically indistiguishable from GVHD within 14 d of ex-T infusion, with fever seen in 1. In the adult and 1 pediatric pt, steroid treatment led to complete resolution of symptoms. These combined data sets demonstrate that robust CD4 and CD8 T cells counts can be achieved as early as day 14 post-SCT when adults or children receive ex-T at day +2 post-SCT without exogenous IL-2 or other cytokine support. It appears that a subset of patients develop a T cell “engraftment syndrome” similar to autologous GVHD. The mechanisms responsible for this rapid immune cell recovery are currently under investigation.
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Andrijašević, Nemanja. "George Radin on Bishop Dr. Nicholai Velimirovich and the Serbian Orthodox Church in America." Nicholai Studies: International Journal for Research of Theological and Ecclesiastical Contribution of Nicholai Velimirovich I, no. 2 (July 26, 2021): 369–94. http://dx.doi.org/10.46825/icholaistudies/ns.2021.1.2.369-394.
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Abstract: George Radin (Đorđe Radin, 1896–1981) was one of the numerous Serbian emigrants in the USA in the period right before WW2. He studied at the most eminent American Universities and had become an attorney, then a lawyer and finally an expert in international law. He managed to achieve great success and expertise in the field of American foreign politics and diplomacy. In the period between the two World Wars, he met Bishop Dr. Nicholai Velimirovich who made a strong impression on him. He was the Bishop’s guide across the USA during his two visits there: in 1920 and in 1927. During his first visit to the continent, the Bishop had organized the life of the Serbian Orthodox Church (SOC), considering that at the time SOC didn’t have its residing bishop there. Radin was, according to his own testimony, one of the organizers of the Bishop’s arrival to America at the beginning of 1946. He had been of the opinion that this significant Bishop should live in one of the Protestant Churches and hold lectures at the Universities, thus serving SOC and its members. In other words, it was his conviction that the Bishop should have organized the church life in the same way he did in his previous two visits to the USA. However, the situation between the two World Wars was far more complicated. The Serbian Church had by that time appointed its ruling bishop in America and Canada — Dionisiye Milivoyevich (Dionisije Milivojević, 1898–1979), who parted ways with Bishop Nicholai soon after his arrival to the USA. Immense damage had been done to the SOC by the utter lack of cooperation between these two bishops. Bishop Nicholai found a “Solomon’s solution” for this by deciding to live and work in Saint Tikhon’s Orthodox Monastery in South Canaan, Pennsylvania. It was in this holy place that he reposed in 1956. Until the end of his life, Radin was of the opinion that a fundamental mistake had been made by the secession of the opportunity that through abiding in the Protestant communities Bishop Nicholai might do more for the SOC and the Serbs, especially through his acquaintances and contacts with the representatives of other Christian confessions, primarily Protestants. He mentioned this in his correspondence with Sliјepchevich (Đoko Slijepčević, 1908–1993). Also, Radin made all the efforts in his power to help overcome the current schism in the SOC. He wrote about his opinions, ideas and steps taken in that direction to the bishops of the Serbian Church, as well as the Patriarch German Djorich himself. Even though the Patriarch of the SOC also made efforts to help overcome the schism, at one point he told Radin that this unfortunate and extremely difficult issue is an internal matter of the SOC, and thus should be dealt with internally. In the appendix of this work, there are excerpts from the letters found in the Radin — Slijepchevich correspondence. They illustrate the enormous mutual trust and respect that these two acquaintances had for each other, having met by the mediation of Bishop Nicholai. The excerpts also present the opinions of the respectful lawyer and law expert — Radin who, in his own way, tried to contribute to the benefit of the SOC. They also convey his judgment on the importance of Bishop Nicholai as well as his discernment about the missed opportunity that the above mentioned bishop should have been presented with in order to contribute more to the SOC, its faithful people and all the Serbs in general — on the American continent, as well as in the whole world. It is clear that he remained hindered in that respect — among other factors — by the will of Bishop Dionisiye. Only a few years after the death of Bishop Nicholai, the most complicated problem of the SOC in diaspora unraveled — the schism. Radin directed all his attention and efforts towards the solution of this problem, in the ways he considered to be the most acceptable. In all this he had agreement with and support of Slijepchevich, with whom he had researched the best ways of achieving reconciliation. Fragments of his letters imply that the majority of his emigrant life he devoted to taking care of Bishop Nicholai, as well as fighting against schism and finding the possibilities of its overcoming.