Immunomodulation for Heart Allograft Tolerance

心脏同种异体移植耐受的免疫调节

基本信息

批准号：
7002147
负责人：
Richard N Pierson
金额：
$ 62.14万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7002147
关键词：
CD40 molecule Macaca fascicularis antiantibody enzyme linked immunosorbent assay flow cytometry heart transplantation humoral immunity immune tolerance /unresponsiveness immunomodulators immunopathology immunosuppressive immunotherapy isoantibody nonhuman therapy evaluation polymerase chain reaction transplant rejection transplantation immunology

项目摘要

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.

描述（由申请人提供）：使用目前可用的免疫抑制方法，心脏移植受者慢性排斥、肾功能不全、感染和恶性肿瘤的发生率很高。如果能够实现耐受性（在没有长期免疫抑制的情况下永久接受），那么这些发病率和死亡率的重要原因都可以得到缓解。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。该提案将探索基于 CD40/CD40L 和 CD28/B7 共刺激途径的抑制来调节对供体和心脏特异性抗原的主动免疫反应的新方法，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，我们发现早期强化 CD 154 或 CsA 治疗阻断可以可靠地减轻灵长类同种异体心脏移植物的急性排斥反应。然而，即使是高剂量持续抗 CD154 单一疗法也不能预防心脏同种异体移植血管病 (CAV)，在发生这种病之前，可靠的是抗供体同种抗体 (AlloAb) 的产生，以及可诱导共刺激物 (ICOS) 心内表达的增加，ICOS 是一种共刺激途径成分， CD28 连接后表达。基于这些观察，我们假设 AlloAb 诱导和 CAV 主要是由共刺激依赖性适应性（获得性）免疫驱动的，在 CD154 阻断的背景下，这种免疫是由 CD28 和 ICOS 驱动的。我们预测，更有效地控制致病性共刺激途径激活将预防 AlloAb 和 CAV。这一预测将在目标 1 中使用非激活 scFv 抗 CD28 分子进行测试，该分子选择性阻断 CD28 信号传导，但允许 B7 和 CTLA4 之间发生耐受性相互作用。这种新试剂将在三种有望诱导啮齿类动物耐受的方法中进行评估：CsA； CD 154封锁；和强化诱导 T 细胞耗竭。目标 2 将扩展我们之前的 CD 154 阻断工作，另外针对三个途径：CCR5、CD20 和 ICOS，我们之前的工作（以及其他人的工作）将其确定为灵长类动物同种抗体精制的组成部分。通过监测对供体抗原和心脏特异性抗原心肌肌球蛋白的免疫，在这两个目标的背景下，所提出的实验将扩展我们对临床前 NHP 模型中心脏同种异体移植物的致病性和耐受性免疫中共刺激作用的理解。通过分包合同确保关键试剂的可用性。