T-cell growth factor pathways and immune modulation

描述(申请人提供)：与衰老和晚期糖尿病相关的器官衰竭，以及严重的自身免疫性和炎症性疾病是严重的医疗问题。尽管取得了重大进展，但实现有效的免疫抑制和移植物的长期存活仍然是一个严重的障碍，与这些第一代和第二代免疫抑制剂包括环孢素A和FK506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。虽然环孢素以T细胞受体激活为靶点，但现在有几条证据证明，对由白细胞介素2(IL2)家族细胞因子驱动的T细胞活性后期的关键研究是免疫抑制的新分子靶点。在这一应用中，我们提出了广泛和令人信服的初步数据，表明药物抑制IL2诱导的Stat5磷酸化在动物模型中对抗同种异体移植排斥反应非常有效。这项应用的目的是研究调节Stat5a/b激活的效应器通路及其靶向基因。需要检验的主要假设是，激活的Stat5转录因子对T细胞介导的免疫至关重要，除了JAK3酪氨酸激酶外，一种尚未确定的Stat5丝氨酸激酶对介导T细胞反应也很重要。为了实现这一建议的目标，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Stat5a/b激活的作用；2)从功能上表征和鉴定80 kDa脯氨酸指导的Stat5丝氨酸激酶；以及3)利用全基因组技术捕获Stats反应元件，识别人类T细胞中的Stat5靶基因。这项工作是重要的，并可能通过提供直接的分子基础和临床前证据为新的免疫抑制策略提供直接的分子基础和临床前证据，以取代或补充现有的治疗方法。

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