Immunomodulation for Heart Allograft Tolerance

描述（由申请人提供）： 使用当前可用的免疫抑制方法，心脏移植受者经历慢性排斥、肾功能不全、感染和恶性肿瘤的高发生率。如果能够实现耐受性（永久接受而无慢性免疫抑制），这些发病率和死亡率的重要原因中的每一个都可以减轻。该RFA承认，诱导对心脏同种异体移植物的耐受似乎需要与其他器官不同的方法。该提案将探索新的方法来调节对供体和心脏特异性抗原的主动免疫应答，基于对CD 40/CD 40 L和CD 28/B7共刺激通路的抑制，作为促进对心脏同种异体移植物的外周耐受的方法。 在食蟹猴心脏移植模型中，我们发现CD 154或CsA治疗的强化早期阻断可靠地减弱灵长类动物心脏同种异体移植物的急性排斥反应。然而，即使是高剂量持续抗CD 154单药治疗也不能预防心脏同种异体移植物血管病（CAV），其可靠地发生在抗供体同种抗体（AlloAb）产生之前，并通过诱导型共刺激因子（ICOS）的心内表达增加，ICOS是CD 28结扎后表达的共刺激途径成分。基于这些观察结果，我们假设AlloAb诱导和CAV主要由共刺激依赖性适应性（获得性）免疫驱动，在CD 154阻断的背景下，由CD 28和ICOS驱动。我们预测，更有效地控制致病性共刺激通路的激活将防止AlloAb和CAV。将在目标1中使用选择性阻断CD 28信号传导但允许B7和CTLA 4之间的致耐受性相互作用的非活化scFv抗CD 28分子测试该预测。将在三种有望诱导啮齿动物耐受性的方法的背景下对这种新试剂进行评价：CsA; CD 154阻断;和强化诱导T细胞耗竭。目标2将扩展我们先前的CD 154阻断工作，另外靶向我们先前的工作（和其他人的工作）鉴定为灵长类动物中同种抗体制备不可或缺的三种途径，CCR 5，CD 20和ICOS。通过监测免疫供体抗原和心脏特异性抗原，心肌肌球蛋白，在这两个目标的背景下，提出的实验将扩展我们的理解的作用，共刺激的致病性和致耐受性免疫的心脏同种异体移植在临床前NHP模型。关键试剂的可用性是通过一个供应商来保证的。

DESCRIPTION (provided by applicant): Using currently available immunosuppressive approaches, heart transplant recipients experience high incidence of chronic rejection, renal insufficiency, infection, and malignancy. If tolerance could be achieved (permanent acceptance without chronic immunosuppression), each of these important causes of morbidity and mortality could be alleviated. This RFA acknowledges that inducing tolerance to a heart allograft appears to require different approaches than may apply for other organs. This proposal will explore new approaches to modulate an active immune response to donor and heart-specific antigens, based on inhibition of the CD40/CD40L and CD28/B7 costimulation pathways, as an approach to promote peripheral tolerance to a cardiac allograft. In a cynomolgus monkey heart transplant model we find that intensive early blockade of CD 154 or CsA treatment reliably attenuates acute rejection of primate cardiac allografts. However even high-dose ongoing anti-CD154 monotherapy does not prevent cardiac allograft vasculopathy (CAV), which is reliably preceded by production of antidonor alloantibodies (AlloAb), and by increased intracardiac expression of inducible costimulator (ICOS), a costimulation pathway constituent that is expressed following CD28 ligation. Based on these observations, we hypothesize that AlloAb induction and CAV are driven primarily by costimulation-dependent adaptive (acquired) immunity that, in the context of CD154 blockade, is driven by CD28 and ICOS. We predict that more effective control of pathogenic costimulation pathway activation will prevent AlloAb and CAV. This prediction will be tested in Aim 1 using a non-activating scFv anti-CD28 molecule that selectively blocks CD28 signaling, but allows tolerogenic interaction between B7 and CTLA4. This new reagent will be evaluated in the context of three approaches that show promise to induce tolerance in rodents: CsA; CD 154 blockade; and intensive induction T-cell depletion. Aim 2 will extend our prior work with CD 154 blockade, additionally targeting three pathways, CCR5, CD20, and ICOS, that our prior work (and that of others) identifies as integral to alloantibody elaboration in primates. By monitoring immunity to donor antigens and a heart-specific antigen, cardiac myosin, in the context of these two Aims, the experiments proposed will extend our understanding of the role of costimulation in pathogenic and tolerogenic immunity to a heart allograft in a preclinical NHP model. Availability of key reagents is assured through a subcontract.