PEPTIDE EPITOPES PRESENTED IN AUTOIMMUNE DIABETES

这一申请医生科学家奖提出了严格的， 广泛的抗原呈递和蛋白质化学培训， 实验免疫学职业生涯的基础。 启动这种 职业生涯，在杰克博士的指导下， L.斯特罗明格将结合相关的研究生水平的教学工作， 参加系列研讨会。 斯特罗明格博士将作为第一阶段的赞助人 一项研究计划，调查表位呈递在自身免疫性 糖尿病 I型糖尿病是胰腺的器官特异性自身免疫性疾病。 组织相容性复合体（MHC）II类基因的某些等位基因， 人类HLA-DR 4和HLA-DQ 8与糖尿病相关。 稳获 起始自身抗原是谷氨酸脱羧酶（GAD 65）。 表位 来源于GAD 65的T细胞在免疫的最早阶段被T细胞识别。 自身免疫 这种现象可能会导致自身免疫反应。 的 假设HLA等位基因通过以下方式定义免疫攻击特异性： GAD 65的特异性表位的呈递。 以调查此问题 能够呈递天然加工的GAD 65的永生化B细胞将 发展。 永生化B细胞将用于鉴定和 表征与IDDM相关的潜在自身反应性T细胞表位。 一旦定义了自然加工表位的库，一系列 合成肽将用于探测HLA的各种特征， 抗原结合裂缝和T细胞受体活化。 这些结果 应突出显示的长度，序列和锚残基的差异 GAD 65衍生的表位可能在糖尿病发生中很重要。 博士约瑟夫Avruch，糖尿病科主任在MGH，将担任阶段 II临床申办者。 第二阶段的主旨（有待第二阶段的结果）是： I）将是a）进一步表征重要的表位及其T细胞抗原决定簇。 与眼的相互作用，以开发特异性拮抗剂，和，B） 进一步研究加工抗原的重要途径。 的 候选人计划使用该系统作为抗原的通用模型 加工和展示。

This application for a Physician Scientist Award proposes rigorous and extensive training in antigen presentation and protein chemistry as the foundation for a career in experimental immunology. To initiate such a career, an intensive laboratory experience under the direction of Dr. Jack L. Strominger will be coupled pertinent graduate level didactic work and seminar series attendance. Dr. Strominger will serve as phase I sponsor of a research proposal to investigate epitope presentation in autoimmune diabetes. Type I diabetes is an organ-specific autoimmune disease of the pancreas. Certain alleles of the histocompatibility complex (MHC) class II genes in humans, HLA-DR4 and HLA-DQ8, correlate with diabetes. The presumptive initiating autoantigen is glutamic acid decarboxylase (GAD 65). Epitopes derived from GAD 65 are recognized by T-cells in the earliest stage of autoimmunity. This phenomena may then drive the autoimmune response. The hypothesis is that HLA alleles define the specificity of immune attack by presentation of specific epitopes of GAD 65. To investigate this problem immortalized B cells capable of presenting naturally processed GAD 65 will be developed. The immortalized B cells will be used to identify and characterize potential autoreactive T cell epitopes in relation to IDDM. Once the repertoire of naturally processed epitopes are defined, a series of synthetic peptides will be used to probe various characteristics of HLA antigen binding clefts and T-cell receptor activation. These results should highlight differences in length, sequence, and anchor residues of presented GAD 65-derived epitopes that may be important in diabetogenesis. Dr. Joseph Avruch, Chief of the Diabetes Unit at MGH, will serve as phase II clinical sponsor. The thrust of phase II (pending results from phase I) will be to a) further characterize important epitopes and their T-cell interaction with an eye towards developing specific antagonists and, b) investigate further the pathways important in processing antigen. The candidate plans to use this system as a generalized model for antigen processing and presentation.