Autoantigens for Diabetogenic CD4 T Cells

描述(申请人提供)：关于1型糖尿病(T1D)的研究，该领域的一个主要空白是缺乏诱导抗原特异性耐受的试剂。识别在这种疾病中驱动致病T细胞的β细胞自身抗原一直是研究人员的首要任务，因为了解这些蛋白质可以极大地帮助我们理解糖尿病是如何发展的，包括在疾病不同阶段产生的抗原的相对重要性。为了确定一组长期建立的高度糖尿病、NOD来源的T细胞克隆的抗原，我们使用生化分离程序和蛋白质组学分析从胰岛β细胞中分离蛋白质。这项工作导致了最近在T1D中发现了一种新的自身抗原--分泌颗粒蛋白--嗜铬粒蛋白A。该项目的基本假设是，这组促糖尿病克隆的抗原配体来自一组密切相关的蛋白质，并通过共同的机制产生。为了验证这一假设，我们设计了一个项目，其中我们的目标是识别糖尿病T细胞的抗原，定义它们产生的机制，并表征它们与疾病的生物学相关性。我们的目标是：(1)分离胰岛反应性、致糖尿病的CD4T细胞克隆的2-细胞抗原；(2)确定抗原肽的一级结构，包括修饰；(3)确定来自ChgA的多肽WE14是否可用作耐受原，以预防或延缓T1D。扩大我们对作为T细胞肽抗原来源的蛋白质的了解将使我们更好地了解它们在T1D中的意义，并将为在T细胞水平上进行特定的治疗干预提供基础。这些蛋白质及其多肽配体将提供有关自身免疫机制的信息，可用于诱导抗原特异性耐受或作为药物干预的靶点，还可能有助于开发早期诊断和监测疾病进展的方法。 公共卫生相关性：扩大我们对作为自身反应性T细胞抗原的蛋白质的了解，将使我们更好地了解它们在T1D中的意义，并将为T细胞水平的特定治疗干预提供基础。被确认为T细胞自身抗原的蛋白质将提供关于自身免疫机制的信息，可以作为药物干预的靶点，也可能有助于开发早期诊断和监测疾病进展的方法。此外，了解自身抗原靶标的生物学功能本身可能为了解2-细胞在健康和疾病中的功能提供新的见解。

DESCRIPTION (provided by applicant): With respect to research on type 1 diabetes (T1D), a major gap in the field has been the lack of reagents for the induction of antigen-specific tolerance. Identification of the beta-cell autoantigens that drive the pathogenic T cells in this disease has been a top priority for researchers since knowledge of these proteins could add considerably to our understanding of how diabetes develops, including the relative importance of antigens arising at different stages of disease. To identify antigens for a long- established panel of highly diabetogenic, NOD-derived T cell clones, we have used biochemical separation procedures and proteomic analysis to isolate proteins from islet beta-cells. This work has led to the recent discovery of a new autoantigen in T1D, the secretory granule protein, chromogranin A. The underlying hypothesis of this project is that the antigenic ligands for this panel of diabetogenic clones are derived from a set of closely related proteins and are generated through a common mechanism. To test this hypothesis, we have designed a project in which our goals are to identify antigens for diabetogenic T cells, define the mechanisms by which they arise, and characterize their biological relevance to disease. Our aims are to: (1) isolate the 2-cell antigens for islet- reactive, diabetogenic CD4 T cell clones, (2) determine the primary structure, including modifications, of antigenic peptides, and (3) determine whether WE14, a peptide from ChgA, can be used as a tolerogen to prevent or delay T1D. Expanding our knowledge of the proteins that are the sources of T cell peptide antigens will allow us to better understand their significance in T1D, and will provide the basis for specific therapeutic intervention at the level of the T cell. These proteins, and the peptide ligands from them, will provide information about autoimmune mechanisms, can be used for induction of antigen-specific tolerance or serve as targets for drug intervention, and may also assist in developing methods for early diagnosis and monitoring disease progression. PUBLIC HEALTH RELEVANCE: Expanding our knowledge of the proteins that are antigens for autoreactive T cells will allow us to better understand their significance in T1D and will provide the basis for specific therapeutic intervention at the level of the T cell. Proteins identified to be T cell autoantigens will provide information about autoimmune mechanisms, can serve as targets for drug intervention, and may also assist in developing methods for early diagnosis and monitoring disease progression. In addition, knowledge of the biological function of the autoantigenic targets may itself provide new insight into 2-cell function in health and disease.