AUTOIMMUNE RETINITIS--ANTIGEN PRESENTING CELLS

自身免疫性视网膜炎——抗原呈递细胞

• 批准号: 2162834
• 负责人: DALE Sannes GREGERSON
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2162834
• 关键词: B lymphocyte; CD8 molecule; T cell receptor; T lymphocyte; anergy; antigen presentation; antigen presenting cell; athymic mouse; autoantigens; autoimmune disorder; cell sorting; enzyme linked immunosorbent assay; immune tolerance /unresponsiveness; immunofluorescence technique; inflammation; laboratory rat; macrophage; monoclonal antibody; passive immunization; retinitis; thymus; thymus transplantation; tissue mosaicism; uvea disorder; western blottings; xenotransplantation

The role of Ia-positive (Ia+) cells in the pathogenesis of autoimmune diseases mediated by CD4+ T cells is uncertain. Ia+ cells are of two types, bone-marrow derived and non-bone-marrow derived. Ia expression is often dependent on induction by IFN-gamma. The functions of Ia+ antigen-presenting cells (APC) include; processing, presentation, and costimulation, the provision of signal(s) required to fully activate antigen-specific, CD4+ Th1 cells, leading to IL-2 production and proliferation. Costimulatory potential appears to be a property of bone- marrow derived cells and may distinguish between "professional" APC'S, i.e. bone-marrow (BM) derived cells such as macrophages or activated B cells; and "non-professional" APC's, i.e. non-BM-derived cells with inducible Ia such as glia or vascular endothelium. Recent results suggest that interaction of T cells with antigen in the context of Ia on cells lacking costimulatory ability leads to induction of "anergy" in T cells; i.e. long-term, antigen-specific unresponsiveness. We wish to determine: 1.) if the presence of BM-derived APC in the retina is required for the manifestation of retinal S-antigen-mediated experimental autoimmune uveoretinitis (EAU); and 2). if non-BM-derived, Ia+ cells regulate the response. The non-BM derived cells might mediate inhibition by their inability to provide costimulation, thus engaging those T cells in abortive activation programs or anergy. Alternatively, non-BM-derived Ia+ cells might be involved in initiation and amplification of the inflammation. We propose to use rat radiation/BM chimeras in conjunction with adoptive transfer of antigen-specific, pathogenic T cell lines. Further studies will be done using nude mice grafted with rat fetal thymus. These mice develop spontaneous autoimmune uveoretinitis and provide a complementary system for study of the mechanisms of peripheral antigen-presentation in that their lymphocytes are presumed to be positively selected on rat epithelium and hence rat MHC restricted. Nevertheless, the animals are immunocompetent, demonstrating antigen presentation by murine APC's in the periphery. Characterization of the disease process, especially the APC'S, is planned. The spontaneous occurrence of disease also allows a unique approach to study the mechanisms in pathogenesis.

Ia 阳性 (Ia+) 细胞在疾病发病机制中的作用 CD4+ T 细胞介导的自身免疫性疾病尚不确定。 Ia+ 细胞是 分为骨髓来源和非骨髓来源两种。亚 表达通常依赖于 IFN-γ 的诱导。 功能 Ia+ 抗原呈递细胞 (APC) 包括；处理、呈现、 和共刺激，提供完全激活所需的信号 抗原特异性 CD4+ Th1 细胞，导致 IL-2 产生并 增殖。 共刺激潜力似乎是骨的特性 骨髓来源的细胞，可以区分“专业”APC'S， 即骨髓 (BM) 衍生细胞，例如巨噬细胞或活化的 B 细胞；和“非专业”APC，即非 BM 衍生细胞 诱导型 Ia，例如神经胶质细胞或血管内皮细胞。 最近的结果 表明 T 细胞与抗原在 Ia 的背景下相互作用 缺乏共刺激能力的细胞会导致T细胞“无反应” 细胞；即长期的抗原特异性无反应。 我们希望确定：1.) BM 衍生的 APC 是否存在于 视网膜是视网膜S抗原介导的表现所必需的 experimental autoimmune uveoretinitis (EAU);和2）。如果非 BM 衍生的， Ia+ 细胞调节反应。 非骨髓来源的细胞可能介导 由于无法提供共刺激而受到抑制，从而参与 那些T细胞处于失败的激活程序或无反应状态。 或者， 非 BM 衍生的 Ia+ 细胞可能参与启动和 炎症的放大。 我们建议使用大鼠辐射/BM 嵌合体与抗原特异性的过继转移相结合， 致病性T细胞系。 进一步的研究将使用移植有大鼠胎儿的裸鼠进行 胸腺。 这些小鼠出现自发性自身免疫性葡萄膜视网膜炎 为外周机制的研究提供一个补充系统 抗原呈递，因为它们的淋巴细胞被认为是 对大鼠上皮细胞进行正向选择，因此大鼠 MHC 受到限制。 然而，这些动物具有免疫能力，表现出抗原 小鼠 APC 在外围的呈现。 的表征 疾病过程，特别是 APC'S，是有计划的。 自发的 疾病的发生也允许采用独特的方法来研究 发病机制。