PEPTIDE EPITOPES PRESENTED IN AUTOIMMUNE DIABETES

这份医生科学家奖的申请书提出了严谨和 在抗原呈递和蛋白质化学方面的广泛培训 为实验免疫学的职业生涯奠定了基础。发起这样一个 职业生涯，在杰克博士的指导下获得密集的实验室经验 L.Strominger将结合相关的研究生水平的教学工作和 参加系列研讨会。斯特罗明格博士将担任第一阶段赞助商 关于研究自身免疫表位呈递的研究建议 糖尿病。 I型糖尿病是一种胰腺器官特异性自身免疫性疾病。 人类组织相容性复合体(MHC)II类基因的某些等位基因 人类的HLADR4和HLADQ8与糖尿病相关。推定 启动自身抗原的是谷氨酸脱羧酶(GAD 65)。表位 来源于GAD 65的T细胞在早期被T细胞识别 自身免疫力。然后，这种现象可能会驱动自身免疫反应。这个 假设人类白细胞抗原等位基因通过以下方式定义免疫攻击的特异性 介绍GAD 65的特定表位。调查这个问题 永生化的B细胞能够呈现自然处理的GAD 65 被开发出来。永生化的B细胞将被用来鉴定和 鉴定潜在的自身反应性T细胞表位与IDDM的关系。 一旦定义了自然处理的表位的保留范围，一系列 将用于探索人类白细胞抗原的各种特性 抗原结合裂解和T细胞受体激活。这些结果 应该突出在长度、序列和锚定残基方面的差异 介绍了可能在糖尿病发生中重要的GAD 65衍生表位。 MGH糖尿病科主任约瑟夫·阿夫鲁赫博士将担任阶段 II临床赞助商。第二阶段的主旨(尚待阶段的结果 I)将是a)进一步表征重要的表位及其T细胞 与着眼于开发特定拮抗剂的互动，以及，b) 进一步研究在处理抗原过程中重要的途径。这个 候选人计划使用这个系统作为抗原的通用模型。 处理和演示。

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.