AUTOREATIVE T CELLS RESISTANT TO TOLERANCE IN DIABETES

本提案的长期目标是确定和描述 导致自身免疫性I型糖尿病的T细胞通过 确定涉及的特定人群，更精确的干预 可以采用一些方法来预防疾病的发展。作为 已被确定为所有项目的中心主题， 我们已经确定了细胞凋亡和自身免疫性之间的联系， 疾病具体来说，我们从我们对糖尿病易感BB的研究中得出结论- DP大鼠自身反应性T细胞对凋亡有抵抗作用， 无反应性诱导，它们最好的特征是髓质胸腺细胞 而不是成熟的外周T细胞。我们的假设是 耐药表型与这些胸腺细胞 逃避正常的选择过程，删除自身反应性T细胞， 胸腺这种对无反应性和凋亡的抵抗是一种关键的 自身反应性“髓质胸腺细胞”亚群的特征， 自身免疫性糖尿病的发展本提案的具体目标 将重点关注糖尿病易感基因对糖尿病的遗传贡献， 自身反应性T细胞的特征， 如果能从糖尿病患者的胸腺中分离出自身反应性T细胞， 易患病和非糖尿病动物。

The long term objective of this proposal is to identify and characterize the T cells responsible for causing autoimmune type I diabetes. By identifying the specific populations involved, more precise intervention approaches can be employed to prevent the development of the disease. As has been determined to be a central theme of all projects in this proposal, we have identified a link between apoptosis and autoimmune disease. Specifically, we conclude from our studies of diabetes prone BB- DP rats that the autoreactive T cells are resistant to apoptosis and anergy induction and they are best characterized as medullary thymocytes rather than mature peripheral T cells. Our working hypothesis is that the resistant phenotype is associated with the way in which these thymocytes escape the normal selection process that deletes self reactive T cells in the thymus. This resistance to anergy and apoptosis is a critical characteristic of an autoreactive "medullary thymocyte" subset involved in the development of autoimmune diabetes. The specific aims of this proposal will focus on the genetic contribution of diabetes susceptibility genes to the characteristics ascribed to the autoreactive T cells and determining if the autoreactive T cells can be isolated from the thymus of diabetes prone and non diabetic animals.