Regulation of T cell Differentiation

T 细胞分化的调节

• 批准号: 7964436
• 负责人: Warren Strober
• 金额: $ 66.48万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964436
• 关键词: Affect; Antibodies; Antigen-Antibody Complex; Ants; Area; Arthritis; Attenuated; B-Lymphocytes; Cell Differentiation process; Cells; Chronic; Clinical; Clinical Research; Colitis; Collagen; Collagen Arthritis; Crohn' s disease; Data; Disease; Goals; Goat; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interferons; Interleukin-1; Interleukin-12; Interleukin-17; Interleukin-6; Joints; Laboratories; Matrix Metalloproteinases; Measures; Mediating; Modeling; Mucosal Immune Responses; Mucositis; Mus; Pathway interactions; Patients; Peptide Hydrolases; Play; Production; Rattus; Regulation; Reporting; Resistance; Role; Severity of illness; Stream; T-Lymphocyte; TNF gene; Time; Tissues; Ulcerative Colitis; autocrine; clinical effect; cytokine; effective therapy; efficacy testing; in vivo; interest; interleukin-23; mRNA Expression; macrophage; mouse model; neutralizing monoclonal antibodies; response

In the present study, we tested the efficacy of neutralizing mAbs reacting with IL-12/IL-23p40 and thus active against both IL-12p70 and IL-23, as well as anti IL-23p19 and TNFR-Fc in two mouse arthritis models, one a putative Th17-mediated disease, CIA, and the other an antibody/immune complex-mediated disease, CAIA. Somewhat to our surprise, the results demonstrated that antibody neutralization of either p40 or p19 had quite an opposite effect on these two arthritis mouse models. In the CIA model, both anti-p40 and p19 antibody as well as TNFR-Fc down-regulated the increase in Th1-related cytokines (IFN?, IL-12 (p40, p35)) and Th17-related cytokines (IL-17A, IL-17F, IL-23 (p40, p19)) as well as down-stream proinflammatory cytokines (IL-6, TNF-? and IL-1?) and proteinases accompanying the inflammation in paw tissues and ameliorated the arthritis. Of interest, the anti-p40 antibody had the most profound clinical effect, but the only difference between its effect on cytokine production and that of anti-p19 was a greater effect on p40 and p35 production. This suggests that its greater effect was due to an IL-12p70-related downstream cytokine that was not measured in this study. These studies are consistent with a previous study reporting that a goat polyclonal anti-p19 attenuates rat CIA, but this study did not contain a detailed analysis of the effect of the antibody on cytokines and did not compare the effect of anti-p19 with anti-p40 (ART 2007 Yago). In addition, these studies are consistent with a study already mentioned showing that mice bearing a p19 deletion are resistant to CIA. Thus, these studies provide additional support for the conclusion that the arthritis in CIA are primarily driven by Th17 response dependent on IL-23p19. However, since anti-p40 had a more profound clinical effect than anti-p19, it is clear that the arthritis in this model is also mediated by an IL-12p70 cytokine(s) that is not under IL-23 control. A very different result was obtained upon treatment of CAIA with the various antibodies. In this case both anti-p40 and ant-p19 was accompanied by a major intensification of disease and only the TNFR-Fc continued to have an ameliorative effect. This clinical result was reflected in the analysis of paw cytokine production which showed first that CAIA was accompanied by low levels of Th1 or Th17 cytokines mRNA expression which were not further lowered by anti-p40 and anti-p19 treatment and second that such antibody treatment was accompanied by elevations of downstream proinflammatory cytokines (IL-6 and IL-1?) as well as elevations in matrix metalloproteinases. In addition, anti-p40 and anti-p19 treatment of CAIA (but not CIA) led to increased production of one potential inductive cytokine, IL-27 (p28), raising the possibility that this cytokine was responsible for the increased disease severity. To understand the origin of the increased IL-27 production following anti-p40- or anti-p19-treated CAIA we performed in vitro studies to determine if p40 or p19 blockade affects IL-27 secretion. In particular we stimulated RAW cells (cells from the RAW264.7 macrophage line) with LPS alone or in combination with collagen antigen-antibody complexes and found that the cells produced increased amounts of IL-27 and IL-6 when cultured in the presence of neutralizing anti-p40 or anti-p19. This suggested that macrophage production of IL-12 and/or IL-23 exerts an autocrine negative regulatory effect on IL-27 production and therefore that the increased IL-27 production (as well as IL-6 production) noted in anti-p40- and anti-p19-treated CAIA could arise from blockade of the negative effect of baseline levels of IL-12 or IL-23 on joint macrophages being stimulated in vivo by antigen-antibody complexes in the presence of LPS. The fact that a similar mechanism of inflammation does not apply to antibody-treated CIA can be ascribed to the likelihood that in this model regional macrophages are not being stimulated by immune complexes or other factors that evoke high IL-27 responses and that in CIA effectively treated with anti-p40 and/or anti-p19 the inflammation does not secondarily generated anti-collagen antibodies as reported in untreated CIA. Further studies in which anti-p40 or anti-p19 treated mice with CAIA are also treated with anti-IL-27 (anti-p28) will be necessary to further establish this possible interpretation of the IL-27 data.

在本研究中，我们在两种小鼠关节炎模型中测试了中和单克隆抗体与IL-12/IL-23p40反应的功效，从而有效对抗IL-12p70和IL-23，以及抗IL-23p19和TNFR-Fc，一种是假定的th17介导的疾病CIA，另一种是抗体/免疫复合物介导的疾病CAIA。让我们有些惊讶的是，结果表明p40或p19的抗体中和对这两种关节炎小鼠模型具有完全相反的作用。