Novel Tolerance Strategies in Cardiac Allograft Recipients

心脏同种异体移植受者的新耐受策略

• 批准号: 7481044
• 负责人: Joren C Madsen
• 金额: $ 56.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7481044
• 关键词: Agonist; Animal Model; Animals; Biological Assay; Biological Markers; Chimeric Proteins; Chimerism; Clinical; Condition; Data; Development; Engineering; Family suidae; Graft Survival; Heart Transplantation; Human; Immune; Immune response; Immune system; Kidney Transplantation; Laboratories; Longevity; Macaca fascicularis; Modeling; Monkeys; Mus; Numbers; Organ; Peripheral; Proteins; Protocols documentation; Reagent; Research Personnel; Rodent; Sirolimus; Surrogate Markers; Sus scrofa; System; Testing; Transplant Recipients; Treatment Protocols; Work; base; body system; conditioning; graft function; heart allograft; improved; mutant; nonhuman primate; novel; novel strategies; prevent; success; thymus transplantation

Our central hypothesis is that induction of robust, reproducible and durable tolerance to cardiac allografts will 1) result in long-term graft survival, 2) preserve normal graft function, and 3) prevent cardiac allograft vasculopathy (CAV). However, we cannot base the development of clinical tolerance strategies aimed at heart transplant recipients on studies in other organs and we should not assume that every protocol that promotes long-term survival will protect the graft from development of progressive CAV. Instead, the most effective tolerance strategies from rodent studies must be specifically tested in large animal models of heart transplantation. The cynomolgus monkey heart transplant model provides an ideal system for both tasks because of the similarity of their immune system to that of humans, the large number of reagents available for mechanistic assays, and the well-characterized development of CAV in these animals. We will test the ability of novel tolerance induction strategies to induce tolerance to cardiac allografts and prevent CAV, and assess biomarkers of the tolerant state. Our aims are to, 1) determine whether a regimen that uses agonist-type IL-2/Fc and mutant antagonist-type IL-15/Fc fusion proteins with sirolimus can induce tolerance to cardiac allografts, 2) determine whether combining the agonist IL-2/antagonist IL-15/sirolimus regimen with vascularized donor thymus transplantation or a mixed chimerism conditioning regimen will improve the longevity of tolerance and prevent CAV and 3) devise a set of biomarkers which will reflect the establishment and/or loss of tolerance.

我们的中心假设是，诱导对同种异体心脏移植物的稳健、可重复和持久的耐受性将1）导致移植物长期存活，2）保持正常的移植物功能，以及3）预防同种异体心脏移植物血管病变（CAV）。然而，我们不能将针对心脏移植受者的临床耐受策略的制定建立在其他器官研究的基础上，我们也不应该假设每一个促进长期生存的方案都会保护移植物免受进行性 CAV 的发展。相反，啮齿动物研究中最有效的耐受策略必须在大型动物心脏移植模型中进行专门测试。食蟹猴心脏移植模型为这两项任务提供了理想的系统 因为它们的免疫系统与人类相似，有大量可用于机械检测的试剂，以及这些动物中 CAV 的发育特征。我们将测试新型耐受诱导策略诱导对心脏同种异体移植耐受和预防 CAV 的能力，并评估耐受状态的生物标志物。我们的目标是，1) 确定使用激动剂型 IL-2/Fc 和突变拮抗剂型 IL-15/Fc 融合蛋白与西罗莫司的治疗方案是否可以诱导对心脏同种异体移植物的耐受性，2) 确定是否将激动剂 IL-2/Fc 与突变拮抗剂型 IL-15/Fc 融合蛋白联合使用-2/拮抗剂 IL-15/西罗莫司方案与血管化供体胸腺移植或混合嵌合调理方案将改善 延长耐受性并预防 CAV，并且 3) 设计一套反映耐受性建立和/或丧失的生物标志物。