CD28/B7 Costimulation Blockade-Resistant Graft Rejection

描述(由申请人提供)： 未能阻止慢性排斥反应的发生，继续削弱了移植的长期益处。实验数据表明，诱导耐受是预防慢性排斥反应和减少药物毒性的重要手段，阻断CD28/B7和/或CD154/CD40可显著延长同种异体移植物的存活时间，在某些情况下可导致永久植入。然而，共刺激抑制抵抗同种异体移植物排斥反应仍可发生。这种应用是基于最近发现的CD28和B7同源物，它们的配体在外周组织中广泛表达，并可能调节效应器T和B细胞的反应。我们将利用小鼠心脏和胰岛移植排斥反应模型研究ICOS/B7RP-1和PD-1/PD-L1/PD-L2在宿主同种异体反应中的作用，从而可以考虑主要血运重建的移植物与非血运重建的移植物的排斥反应，以及在更严格的、维持生命的同种异体胰岛移植物系统中验证异位心脏移植物的数据。目的1确定ICOS/B7RP-1共刺激通路在体内调节同种异体移植受者T细胞和B细胞反应的机制，从而靶向这种相互作用可以减少慢性排斥反应，促进耐受诱导。我们将剖析ICOS和B7RP-1在野生型以及CD28和CD154非依赖性反应中对T和B细胞反应的贡献。我们预计这些研究将为ICOS/B7RP-1在持续的宿主同种异体反应中的重要性以及如何以这一途径为靶点如何最好地促进同种异体移植耐受提供关键的机制见解。目的2假设组织特异性免疫反应受PD-1/PD-L1/PD-L2通路的调节，我们建议分析该通路的操作在多大程度上可以促进同种异体移植物的长期存活。我们的初步数据显示，通过结扎PD-1刺激负信号可以抑制宿主同种异体反应，包括那些潜在的共刺激阻断抵抗同种异体移植排斥反应。我们将扩大这些研究，剖析PD-1与其配体的相互作用如何促进同种异体移植受者的治疗效果。这项工作的成功将为在非人类灵长类动物中进行测试提供理论基础，并可能最终通过促进移植耐受和降低慢性排斥反应的发生率来改善接受器官移植或接受胰岛同种异体移植的患者的管理和长期结果。

DESCRIPTION (provided by applicant): Failure to stem the incidence of chronic rejection continues to diminish the long-term benefits of transplantation. Experimental data suggest the importance of tolerance induction as a means to prevent chronic rejection and minimize drug toxicity, and blockade of CD28/B7 and/or CD154/CD40 can markedly prolong allograft survival, in some cases leading to permanent engraftment. However, costimulation blockade-resistant allograft rejection can still occur. This application is based around recently recognized CD28 and B7 homologs whose ligands are broadly expressed in peripheral tissues, and which likely regulate effector T and B cell responses. We will study the roles of ICOS/B7RP-1 and PD-1/PD-L1/PD-L2 in host alloresponses using murine models of cardiac and islet allograft rejection, thereby allowing consideration of rejection in primarily revascularized vs. non-revascularized grafts, as well as validation of heterotopic cardiac graft data in the more stringent, life-supporting islet allograft system. Aim 1 will determine the mechanisms by which the ICOS/B7RP-1 costimulatory pathway can regulate T and B cells responses in allograft recipients in vivo, such that targeting of this interaction can diminish chronic rejection and promote tolerance induction. We will dissect the contributions of ICOS and B7RP-1 to T and B cell responses in wild-type as well as CD28- and CD154-independent responses. We anticipate these studies will provide key mechanistic insights into the importance of ICOS/B7RP-1 in ongoing host alloresponses, and how targeting of this pathway can best promote allograft tolerance. Aim 2 hypothesizes that tissue-specific immune responses are regulated by the PD-1/PD-L1/PD-L2 pathway, and we propose to analyze the extent to which manipulation of this pathway can facilitate long-term allograft survival. Our preliminary data show that stimulation of a negative signal through ligation of PD-1 can dampen host alloresponses, including those underlying costimulation blockade-resistant allograft rejection. We will expand these studies to dissect how interactions of PD-1 with its ligands can be promoted to achieve therapeutic effects in allograft recipients. Success in this work would provide a rationale for testing in non-human primates, and may ultimately improve the management and long-term results seen in patients undergoing organ transplantation or receiving islet allografts by promoting graft tolerance and decreasing the incidence of chronic rejection.