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减少移植的长期益处。实验数据表明耐受诱导作为预防慢性排斥反应和最小化药物毒性的手段的重要性，并且阻断CD 28/B7和/或CD 154/CD 40可以显著延长同种异体移植物存活，在某些情况下导致永久植入。然而，抗共刺激阻断的同种异体移植物排斥反应仍可能发生。本申请基于最近认识到的CD 28和B7同源物，其配体在外周组织中广泛表达，并且可能调节效应T和B细胞应答。我们将研究ICOS/B7 RP-1和PD-1/PD-L1/PD-L2在宿主同种异体反应中的作用，使用心脏和胰岛同种异体移植物排斥的小鼠模型，从而考虑主要血运重建与非血运重建移植物的排斥，以及在更严格的维持生命的胰岛同种异体移植物系统中验证异位心脏移植物数据。目的1将确定ICOS/B7 RP-1共刺激通路在体内调节同种异体移植受者T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并促进耐受诱导。我们将剖析ICOS和B7 RP-1对野生型T和B细胞应答以及CD 28和CD 154非依赖性应答的贡献。我们预计这些研究将提供关键的机制的见解ICOS/B7 RP-1的重要性，在正在进行的主机allorresponses，以及如何靶向这一途径可以最好地促进同种异体移植耐受。目的2假设组织特异性免疫应答受PD-1/PD-L1/PD-L2通路调节，我们建议分析操纵该通路可促进移植物长期存活的程度。我们的初步数据表明，通过连接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性同种异体排斥反应。我们将扩展这些研究，以剖析如何促进PD-1与其配体的相互作用，以在同种异体移植受者中实现治疗效果。这项工作的成功将为在非人灵长类动物中进行测试提供理论基础，并可能通过促进移植物耐受和降低慢性排斥反应的发生率，最终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.