TRANSGENIC MOUSE MODEL FOR TOLERANCE IN THE EYE

理解自身免疫性疾病过程中的一个中心问题 T细胞对自身抗原的耐受性是如何形成和维持的。 胸腺通过一个过程获得对自身抗原的耐受性。 称为负选择，在同种异体MHC或外来抗原中 仅在胸腺外组织中表达提供了相当大的 深入了解外周耐受诱导的机制，但仍 许多问题仍然存在。我们已经开发了一种新的转基因模型 表达同种异体MCH抗原或干扰素-γ的耐受性 在眼睛的晶状体中，一个免疫特权部位。镜头 是眼部的代表，是进一步研究外周组织的良好模型 容忍有几个原因。它缺乏血管和淋巴管。 排水因此，这个场地可能具有关于容忍度的独特属性 归纳法。眼睛也是几种自身免疫疾病的显著靶点。 包括人类白细胞抗原B27在内的疾病与雷特综合征有关。为了学习 诱导对晶状体中表达的抗原的耐受性，转基因小鼠 已经产生了表达MHC I类(H-2D)或干扰素伽马 在表达下，似乎是耐受性研究的有前途的模型。 这些模型将进行免疫组织化学研究。实验还将 确定晶状体中表达的H-2D抗原是否相关 使用β2-微球蛋白。正在发生的炎症性变化 这些小鼠将在不同的年龄接受仔细的组织学评估。 还建议进行实验，以测试这些变化是否 通过免疫调节。对于I类转基因小鼠，我们将 评估两种动物对allo-I类转基因的耐受程度 体外和体内系统。对于INF-Gamma转基因小鼠，我们将 确定特异性T细胞对眼部抗原的敏感度是否 以及眼睛中干扰素-γ的表达是否改变了 眼睛的免疫抑制特性。最后，我们建议制作一个 第三种在α-A调控下表达I-E抗原的模型 晶体蛋白启动子。在这些小鼠中，Vbeta17a(I-E)的克隆缺失 反应性)T细胞将通过单抗染色和 流式细胞术。这些研究将提供重要的新信息 诱导对组织限制性抗原耐受的机制，以及 为自身免疫性葡萄膜炎提供新的小鼠模型。

A central question in the understanding of autoimmune disease processes is how T cell tolerance is developed and maintained to self antigens. Tolerance to self-antigens is acquired in the thymus through a process termed negative selection, and in the allogeneic MHC or foreign antigens are expressed only in extrathymic tissues have provided considerable insight into the mechanisms of peripheral tolerance induction, but still many questions remain. We have developed a new transgenic model for tolerance in which an allogeneic mcH antigen or IFn-gamma is expressed in the lens of the eyes, an immunologically privileged site. The lens of the eye represents and excellent model for further study of peripheral tolerance for several reasons. It lacks vascularization and lymphatic drainage Thus, this site may have unique properties concerning tolerance induction. The eye is also a prominent target in several autoimmune diseases including HLA-B27 linked Reiter's syndrome. In order to study tolerance induction to antigens expressed in the lens, transgenic mice have been produced expressing MHC class I (H-2D) or interferon gamma under expression and appear to be promising models for tolerance studies. These models will be immunohistochemistry. Experiments will also determine whether the H-2D antigen expressed in the lens is associated with Beta 2-microglobulin. The inflammatory changes taking place in these mice will be carefully evaluated histologically at different ages. Experiments are also proposed to test whether these changes are immunologically mediated. For the class I transgenic mice, we will assess the degree of tolerance to the allo class I transgenic in both in vitro and in vivo systems. For the INF-gamma transgenic mice, we will determine whether specific T cell sensitization to ocular antigens is occurring and whether IFN-gamma expression in the eye modifies the immunosuppressive nature of the eye. Finally, we propose to produce a third model by expressing I-E antigens under the control of the alpha-A crystallin promoter. In these mice, clonal deletion of Vbeta17a (I-E reactive) T cells will be assessed by monoclonal antibody staining and flow cytometry. These studies will provide important new information on the mechanisms of tolerance induction to tissue restricted antigens, and provide new mouse models for autoimmune uveitis.