主要组织相容复合物份子（MHC）II类分子是包括1型糖尿病在内的多种自身免疫性疾病的基本易感位点。和NOD小鼠I-A^g7分子，其作为相关致糖尿病性等位基因的生物结构数据资料，现在已经可以使用，使结构引导的抗原向T细胞提呈的研究得以开展。人HLA-DQ8分子和自发性自身免疫性糖尿病模型的NOD小鼠中的1I-A^g7分子，通过在胸腺和外周组织中调节特异性胰岛肽的呈递，带来罹患糖尿病的风险。在NOD小鼠中，胰岛素B链肽是由9~23个氨基酸残基构成的基本自身抗原的靶点，有突变胰岛素B:9–23 (B:16Y–B:16A)的鼠不得糖尿病。自身抗原胰岛素B:9–23被NOD鼠的MHC II类分子I-A^g7提呈给CD4+ T细胞。
差异性结构域，如p1、p4、p6和p9，可容纳多肽侧链沿MCH II类分子上抗原结合槽分布。应用硅分子对接程序筛选一个大型的类药性化学库，以确定小分子上可以和I-A^g7上抗原结合槽结合的特异性结构域，从而达到影响自身抗原胰岛素B肽链向T细胞的提呈。此研究表明：以结构域为靶点，在同源靶多肽的存在下，应用小鼠及人类细胞小分子，均能增强或抑制特异性TCR信号。这种复合物对TCR应答的影响是具有结构域依赖性的，结构域1和6复合物抑制应答，结构域9增强向多肽的应答。在纳摩尔级浓度水平，抑制性分子封闭了胰岛素B链肽、内源性胰岛素和胰岛刺激T细胞的应答。草甘二膦，结构域9复合物，在10 nM的低浓度水平，可增强胰岛素多肽向T细胞的提呈，上调IL-10的分泌，预防NOD小鼠患糖尿病。这些研究展示出一种新的识别小分子的方法，这些小分子能够刺激或抑制T淋巴细胞反应，有着潜在的治疗1型糖尿病的前景。

 Structure-Based Selection of Small Molecules To Alter Allele-Specific MHC Class II Antigen Presentation
 Class II major histocompatibility molecules are the primary susceptibility locus for many autoimmune disorders, including type 1 diabetes. Human DQ8 and I-Ag7, in the NOD mouse model of spontaneous autoimmune diabetes, confers diabetes risk by modulating presentation of specific islet peptides in the thymus and periphery. We used an in silico molecular docking program to screen a large “druglike” chemical library to define small molecules capable of occupying specific structural pockets along the I-Ag7 binding groove, with the objective of influencing presentation to T cells of the autoantigen insulin B chain peptide consisting of amino acids 9–23. In this study we show, using both murine and human cells, that small molecules can enhance or inhibit specific TCR signaling in the presence of cognate target peptides, based upon the structural pocket targeted. The influence of compounds on the TCR response was pocket dependent, with pocket 1 and 6 compounds inhibiting responses and molecules directed at pocket 9 enhancing responses to peptide. At nanomolar concentrations, the inhibitory molecules block the insulin B chain peptide consisting of amino acids 9–23, endogenous insulin, and islet-stimulated T cell responses. Glyphosine, a pocket 9 compound,enhances insulin peptide presentation to T cells at concentrations as low as 10 nM, upregulates IL-10 secretion, and prevents diabetes in NOD mice. These studies present a novel method for identifying small molecules capable of both stimulating and inhibiting T cell responses, with potentially therapeutic applications.

链接: http://www.jimmunol.org/content/187/11/5921