REGULATION OF AUTOIMMUNITY TO GAD65 IN IDDM

IDDM 中 GAD65 自身免疫的调节

• 批准号: 6105806
• 负责人: ADRIAN Clive HAYDAY
• 金额: $ 17.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105806
• 关键词: CD4 molecule; CD8 molecule; T lymphocyte; antigen receptors; autoantibody; autoantigens; disease /disorder etiology; disease /disorder model; enzyme mechanism; gene expression; genetic strain; genetically modified animals; glutamate decarboxylase; helper T lymphocyte; immunocytochemistry; insulin dependent diabetes mellitus; laboratory mouse; model design /development; pathologic process; suppressor T lymphocyte; tissue /cell culture

Type 1 diabetes or 'IDDM' is a severe autommune disease afflicting hundreds of thousands of Americans. It is characterized by an attack on the pancreas, that abrogates insulin production. While the attacking infiltrate comprises multiple cell types, T cells are critical. The precise target of the T cells may also be manifold, but among them, central importance is attached to glutamic acid decarboxylase (GAD), particularly the 65kD form, GAD65. Experimental administration of recombinant GAD to non obese diabetic (NOD) mice that are highly predisposed to IDDM, ameliorated the attack on the pancreas, and subsequent disease development. These and other results have prompted the Food and Drug Administration to review the idea of administering GAD to individuals at high risk for developing IDDM. This notwithstanding, there is currently very little understanding of autoreactivity to GAD. In particular, it remains unclear why NOD mice and (by extrapolation) humans predisposed to IDDM fail to develop tolerance to GAD naturally. The characterization of the autoreactivity to GAD65 can be facilitated by the development of novel strains of NOD mouse in which GAD65 and/or T cell antigen T cell antigen receptors to GAD65, are expressed in unusual patterns. Such mice also facilitate the study of how T cells autoreactive to GAD can be regulated by other lymphocytes, and by the microbial environment. The development of such mice is described in the proposal and the case made for their detailed study.

1型糖尿病或“IDDM”是一种严重的自身免疫性疾病， 成千上万的美国人。 它的特点是攻击 在胰腺上，它会抑制胰岛素的产生。 当攻击 浸润物包含多种细胞类型，T细胞是关键的。 的 T细胞的精确靶点也可以是多种多样的，但是在它们之中， 谷氨酸脱羧酶（GAD）是最重要的， 特别是65 kD形式，GAD 65。 实验性给药 重组GAD对非肥胖糖尿病（NOD）小鼠， 易患胰岛素依赖型糖尿病，改善胰腺的发作， 随后的疾病发展。 这些和其他结果 促使美国食品和药物管理局重新审查 将GAD用于发展为IDDM的高风险个体。 尽管如此，目前人们对 GAD的自身反应性。 特别是，目前还不清楚为什么NOD 易患胰岛素依赖型糖尿病的小鼠和（通过外推法）人类未能 对GAD自然产生耐受性。 的表征 对GAD 65的自身反应性可以通过以下发展来促进： 新的NOD小鼠品系，其中GAD 65和/或T细胞抗原T GAD 65的细胞抗原受体以不寻常的模式表达。 这些小鼠也有助于研究T细胞对GAD的自身反应性 可以受到其他淋巴细胞和微生物的调节 环境 这些小鼠的发育描述于 并提出了详细的研究建议。