Immunomodulation for Heart Allograft Tolerance

心脏同种异体移植耐受的免疫调节

• 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
• 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

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，心脏移植受者经历了慢性排斥、肾功能不全、感染和恶性肿瘤的高发生率。如果可以实现耐受性(永久接受而不存在慢性免疫抑制)，这些导致发病率和死亡率的重要原因中的每一个都可以得到缓解。RFA承认，诱导同种异体心脏移植的耐受性似乎需要不同于其他器官的方法。这项建议将探索新的方法，以抑制CD40/CD40L和CD28/B7共刺激通路为基础，调节对供者和心脏特异性抗原的主动免疫反应，作为促进外周同种异体心脏移植耐受的方法。在食蟹猴心脏移植模型中，我们发现早期密集阻断CD154或CsA治疗可靠地减轻了灵长类同种心脏移植的急性排斥反应。然而，即使是正在进行的大剂量抗CD154单一治疗也不能预防心脏移植物血管病(CAV)，而CAV之前可靠的是产生抗供体同种异体抗体(AllAb)，并通过增加心内可诱导共刺激因子(ICOS)的表达来预防CAV，ICOS是CD28结扎后表达的一种共刺激通路成分。基于这些观察，我们假设，异种抗体的诱导和CAV主要由共刺激依赖的获得性(获得性)免疫驱动，在CD154阻断的背景下，由CD28和ICOS驱动。我们预测，更有效地控制致病共刺激通路的激活将预防异体抗体和CAV。这一预测将在Aim 1中使用非激活的scFv抗CD28分子进行验证，该分子选择性地阻断CD28信号，但允许B7和CTLA4之间的耐受相互作用。这种新试剂将在三种方法的背景下进行评估，这些方法显示了诱导啮齿动物耐受的前景：环孢素A；CD154阻断；以及密集诱导T细胞耗尽。AIM 2将扩展我们先前对CD154阻断的工作，另外还针对三条通路，CCR5、CD20和ICOS，我们先前的工作(以及其他人的工作)认为这是灵长类同种异体抗体形成所必需的。在这两个目标的背景下，通过监测供者抗原和心脏特异性抗原-心肌肌球蛋白的免疫，所提出的实验将扩大我们对临床前NHP模型中共刺激在心脏移植物致病和耐受免疫中的作用的理解。通过分包合同确保关键试剂的可获得性。