T-cell growth factor pathways and immune modulation

描述（由申请人提供）：与衰老和晚期糖尿病以及严重自身免疫性和炎症性疾病相关的器官衰竭代表严重的医学问题。尽管取得了重大进展，但实现有效的免疫抑制和长期移植物存活仍然是一个严重的障碍，其与这些第一代和第二代免疫抑制剂（包括环孢素A和FK 506）相关的极端副作用和毒性使其复杂化。因此，有必要探索T细胞活化和扩增的新分子方面，以便设计安全有效的治疗策略。尽管环孢菌素靶向T细胞受体激活，但现在有几条证据证明，对由白细胞介素-2（IL 2）家族细胞因子驱动的T细胞活性后期阶段进行严格研究是合理的，因为该T细胞活性是免疫抑制的新分子靶点。在这个应用中，我们提出了广泛的和令人信服的初步数据表明，药理学抑制IL 2诱导的Stat 5磷酸化是非常有效的对同种异体移植排斥反应的动物模型。本申请的目的是研究调节Stat 5a/B激活的效应子途径及其靶向基因。待检验的主要假设是活性Stat 5转录因子对于T细胞介导的免疫性是关键的，并且除了Jak 3酪氨酸激酶之外，尚未鉴定的Stat 5丝氨酸激酶对于介导T细胞应答也是重要的。为了实现该提议的目的，我们将追求三个具体目标：1）确定早期和晚期T细胞表面受体调节Stat 5a/B活化的作用，2）功能性表征和鉴定80 kDa脯氨酸指导的Stat 5丝氨酸激酶;和3）使用全基因组技术捕获Stats应答元件来鉴定人T细胞中的Stat 5靶基因。这项工作是重要的，并可能显着推进该领域提供直接的分子理论基础和临床前证据的新的免疫抑制策略，可以取代或补充目前的治疗方法

DESCRIPTION (provided by applicant): Organ failure associated with aging and advanced diabetes mellitus as well as severe autoimmune and inflammatory diseases represents severe medical problems. Despite major progress, achieving effective immunosuppression and long-term graft survival remains a serious obstacle that is complicated by their extreme side effects and toxicities associated with these first and second generation immunosuppressants including cyclosporine A and FK506. It is therefore essential to explore novel molecular aspects of T-cell activation and expansion so that safe and effective therapeutic strategies can be designed. Whereas cyclosporine targets T-cell receptor activation, several lines of evidence now justify a critical investigation of the later phase of T cell activity that is driven by interleukin-2 (IL2) family cytokines as new molecular targets for immune suppression. In this application, we present extensive and compelling preliminary data suggesting that pharmacological inhibition of IL2-induced Stat5 phosphorylation is remarkably effective against allograft rejection in animal models. The objective of this application is to investigate the effector pathways that regulate Stat5a/b activation and the genes they target. The principal hypothesis to be tested is that active Stat5 transcription factors are critical for T cell mediated immunity, and that in addition to the Jak3 tyrosine kinase, a yet-to-be identified Stat5 serine kinase is also important for mediating T cell responses. To accomplish the objective of this proposal, we will pursue three specific aims to 1) Determine the role that early and late phase T-cell surface receptors regulate Stat5a/b activation, 2) Functionally characterize and identify the 80 kDa proline-directed Stat5 serine kinase; and 3) Identify Stat5 target genes in human T cells using a genome-wide technology for trapping Stats response elements. This work is important, and may significantly advance the field by providing direct molecular rationale and preclinical evidence for a new immunosuppressive strategy that could replace or complement current treatments