CD8 T Cell Reactivity to IGRP as an Autoimmunity Marker in Type 1 Diabetes

描述（由申请人提供）：1型糖尿病（T1 D）是一种自身免疫性疾病，其特征在于T细胞介导的胰岛β细胞破坏。对非肥胖糖尿病（NOD）小鼠模型的研究表明，β细胞毒性CD 8 + T细胞是导致T1 D的β细胞破坏的重要参与者。CD 8 + T细胞也被怀疑是患者中β细胞消除的贡献者。我们确定了一种来自胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白（IGRP）的肽，作为NOD小鼠中致病性CD 8 + T细胞流行群体的靶点。鉴于NOD小鼠和人类T1 D之间的相似性，我们假设IGRP反应性CD 8 + T细胞将是T1 D患者中β细胞根除的重要贡献者，因为它们在NOD小鼠中。为了开始将我们的发现转化给患者，我们使用了人I类MHC分子HLA-A*0201转基因的NOD小鼠来鉴定T1 D自发发展过程中T细胞靶向的HLA-A*0201结合的HRP肽。使用来自未免疫的HLA转基因小鼠的胰岛浸润T细胞鉴定的反应性是自发发生的和疾病相关的。因此，这些肽代表了作为人类T1 D患者中T细胞靶标的探索的优秀候选物。虽然HLA-A*0201是常见的I类MHC分子，但在其他人I类分子的背景下识别的IGRP肽的阐明将允许在可以受益于基于肽的预测、诊断和治疗策略的开发的那些方面更广泛地覆盖群体。为此，我们已经产生了表达HLA-A*1101、HLA-B*0702或HLA-Cw*0304的三种新的NOD菌株。这些HLA分子代表三种不同的HLA超型，而HLA-A*0201代表第四种。当所有四种超型都被靶向时，群体的覆盖率可以约为90%。我们将从HLA转基因小鼠中分离胰岛浸润性T细胞，并确定在不同HLA分子背景下识别的IGRP肽。然后，我们将测试相同的肽将被T1 D患者的T细胞识别的假设。鉴于在标准和HLA-A*0201转基因NOD小鼠中，IGRP作为自身免疫应答的靶点的重要性，我们假设对IGRP的CD 8 + T细胞应答也将作为人类β细胞特异性自身免疫活性的标志物。监测这些T细胞反应可以评估干预治疗的免疫学影响，并允许比目前可能的更早检测自身免疫活性。外行语言的相关性：拟议的工作可能会导致新的测试，以确定个人在发展T1 D的风险。还可以开发测试来监测正在接受治疗的患者的破坏性T细胞活性，以便医生能够知道治疗是否有效。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Studies of the nonobese diabetic (NOD) mouse model of the disease have shown that beta cell-cytotoxic CD8+ T cells are essential participants in the beta cell destruction that leads to T1D. CD8+ T cells are also suspected contributors to beta cell elimination in patients. We identified a peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) as the target of a prevalent population of pathogenic CD8+ T cells in NOD mice. In light of the similarities between T1D in NOD mice and humans, we hypothesize that IGRP-reactive CD8+ T cells will be important contributors to beta cell eradication in T1D patients as they are in NOD mice. To begin to translate our findings to patients, we used NOD mice transgenic for the human class I MHC molecule HLA-A*0201 to identify HLA-A*0201-binding IGRP peptides targeted by T cells during the spontaneous development of T1D. Reactivities identified using islet-infiltrating T cells from unimmunized HLA-transgenic mice are both spontaneously occurring and disease-relevant. Thus, these peptides represent excellent candidates for exploration as targets of T cells in human T1D patients. While HLA-A*0201 is a common class I MHC molecule, elucidation of the IGRP peptides recognized in the context of other human class I molecules would allow wider coverage of the population in terms of those that could benefit from the development of peptide- based predictive, diagnostic, and therapeutic strategies. To this end, we have generated three new NOD strains expressing HLA-A*1101, HLA-B*0702, or HLA-Cw*0304. These HLA molecules are representative of three different HLA supertypes, while HLA-A*0201 is representative of yet a fourth. Coverage of the population can be approximately 90% when all four supertypes are targeted. We will isolate islet-infiltrating T cells from the HLA-transgenic mice and determine the IGRP peptides recognized in the context of the different HLA molecules. We will then test the hypothesis that the same peptides will be recognized by T cells from T1D patients. Given the importance of IGRP as a target of the autoimmune response in both standard and HLA-A*0201-transgenic NOD mice, we hypothesize that CD8+ T cell responses to IGRP will also serve as markers for beta cell-specific autoimmune activity in humans. Monitoring of these T cell responses may permit assessment of the immunological impact of intervention therapies and allow earlier detection of autoimmune activity than is currently possible. Relevance in lay language: The proposed work may lead to new tests to identify individuals at risk of developing T1D. Tests may also be developed to monitor destructive T cell activity in patients undergoing treatment, so that doctors will be able to know if the treatments are working.