Suppression of Allograft Rejection by A Novel Protein ESAT-6

描述（由申请人提供）：除非接受者终生服用免疫抑制药物，否则移植的组织或器官总是会被排斥。然而，传统的免疫抑制药物会引起严重的副作用，包括病毒感染和恶性肿瘤。在没有持续的全局免疫抑制的情况下，实现长期的同种异体移植物存活或耐受是移植的一个非常理想的目标。ESAT-6是一种6kda的蛋白，最初在结核分枝杆菌的短期培养滤液中被鉴定为T细胞Ag。大量证据表明，它是促进结核分枝杆菌生长和发病的毒力因子。特别是，ESAT-6已被证明可以抑制T细胞增殖。我们的初步研究首次证明了ESAT-6促进胰岛移植物长期存活并抑制移植物浸润的T细胞增殖。因此，ESAT-6可以作为一种新的药物，在没有持续使用全局免疫抑制剂的情况下诱导长期的同种异体移植物存活或耐受。基于这些发现，我们将进一步研究ESAT-6抑制同种异体移植排斥反应的机制，有两个具体目的：(1)研究ESAT-6在体内和体外抑制同种异体免疫反应的机制。我们将研究ESAT-6对辅助性T细胞分化为Th1/Th17/Th2细胞和T细胞发育为调节性T （Treg）和记忆性T （Tmem）细胞的影响，因为在同种异体免疫反应的背景下，将它们的平衡转向Th2或Treg调节对同种异体移植物的长期存活至关重要；(2)研究ESAT-6是否在没有或存在短暂和轻度免疫抑制的情况下也能促进糖尿病NOD小鼠胰岛异体移植的长期存活。本提案的目标是探索新的策略，在缺乏或存在短暂和轻度免疫抑制的情况下，使用一种最初由结核分枝杆菌产生的新蛋白来促进其生长，以诱导长期的同种异体移植物存活或耐受。本研究将探讨两组基本的免疫平衡：Th1/Th17/Th2和Treg/Tmem，它们都是决定同种异体移植物命运的关键。因此，该项目对通过胰岛移植治疗1型糖尿病以及通过实体器官移植治疗其他终末期器官疾病具有重要的临床意义。

DESCRIPTION (provided by applicant): Transplanted tissues or organs are always rejected by recipients unless they take immunosuppressive drugs for the rest of their lives. However, traditional immunosuppressive drugs cause serious side-effects including viral infection and malignancy. Achieving long-term allograft survival or tolerance in the absence of continuous global immunosuppression is a highly desirable goal in transplantation. ESAT-6 is a protein of 6 kDa that was originally identified as a T cell Ag in the short-term culture filtrate of M. tuberculosis. Substantial evidence has shown that it is a virulence factor that promotes the growth and pathogenesis of M. tuberculosis. In particular, ESAT-6 has been shown to suppress T cell proliferation. Our preliminary studies for the first time have demonstrated that ESAT-6 promotes the induction of long-term islet allograft survival and suppresses graft-infiltrating T cell proliferation. Therefore, ESAT-6 could be utilized as a novel agent to induce long- term allograft survival or tolerance in the absence of continuous treatment with a globally immunosuppressive agent. Based on these findings, we propose to further study the mechanisms underlying the suppression of allograft rejection by ESAT-6 with two specific aims: (1) To investigate the mechanisms by which ESAT-6 suppresses alloimmune responses in vivo and in vitro. We will investigate the impact of ESAT-6 on T helper cell differentiation into Th1/Th17/Th2 cells and on T cell development into regulatory T (Treg) and memory T (Tmem) cells in the context of alloimmune responses, as tipping their balance toward either Th2 or Treg regulation is critical for long-term allograft survival; and (2) To study whether ESAT-6 also promotes long-term islet allograft survival in diabetic NOD mice in the absence or presence of brief and mild immunosuppression. The goal of this proposal is to explore new strategies to induce long-term allograft survival or tolerance in the absence or presence of brief and mild immunosuppression using a novel protein that is originally produced by Mycobacteria tuberculosis to enhance their growth. This study will look into two basic sets of immunologic balance: Th1/Th17/Th2 and Treg/Tmem, both of which are critical for determining an allograft fate. Therefore this project has important clinical implications for the cure of type 1 diabetes by islet transplantation and perhaps other end-stage organ diseases via solid organ transplantation.