Optimizing Mixed-Chimerism for Heart Transplantation in Non-Human Primates

优化非人类灵长类心脏移植的混合嵌合体

• 批准号: 7736767
• 负责人: TATSUO KAWAI
• 金额: $ 73.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736767
• 关键词: Achievement; Address; Allografting; Bone Marrow Transplantation; Cessation of life; Chimera organism; Chimerism; Chronic; Clinical; Data; Goals; Graft Survival; Heart; Heart Transplantation; Hematopoietic; Human; Immunosuppression; Immunosuppressive Agents; Institutes; Kidney; Laboratories; Life; Living Donors; Maintenance; Miniature Swine; Modeling; New Agents; Organ; Organ Donor; Organ Transplantation; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Primates; Protocols documentation; Resistance; Role; Seminal; T-Lymphocyte; Testing; Therapeutic; Tissue Transplantation; Transplant Recipients; Transplantation; Transplantation Conditioning; Treatment Protocols; Vascular Diseases; base; clinical application; clinically relevant; conditioning; cytokine; design; graft function; heart allograft; improved; in vivo; innovation; kidney allograft; nonhuman primate; novel; novel strategies; prevent; success

The objective of this two-year project is to improve the outcome following heart transplantation by clarifying the mechanisms involved with the induction of donor-specific tolerance via the mixed chimerism approach. Tolerance of kidney allografts in non-human primates (NHPs) has already been achieved in our laboratories using a combination of non-myeloablative conditioning and donor bone marrow transplantation (DBMT) that results in transient mixed hematopoietic chimerism. Based upon these seminal observations, a similar protocol has been tested in human recipients of living related renal allografts and has proven successful. Dramatic as this achievement is, however, it utilizes a therapeutic protocol whose current success is limited to living donor transplantation (conditioning begins on day -6). There is an obvious need to build upon the impressive successes already achieved with living donor kidneys and optimize the mixed chimerism strategy so that it can be applied more widely to cadaveric donor organs like hearts. Recently, we have developed, in our NHP renal allograft model, a novel regimen, the "Delayed Tolerance" protocol which can extend the clinical applicability of the mixed chimerism approach. In this protocol, recipients initially undergo transplantation with conventional immunosuppression and then receive non-myeloablative conditioning and DBMT sometime later. The goal of this project is to develop the Delayed Tolerance regimen using new agents and novel strategies to induce tolerance of cardiac allografts. We will test the hypothesis that either enhancing peripheral mechanisms of tolerance by promoting Tregs or achieving more durable multilineage donor chimerism will result in long-term tolerance of cardiac allografts in NHPs. During the 2-year study we will specifically: (1) Develop a mixed chimerism protocol of Delayed Tolerance induction applicable to human heart transplant recipients, and, (2) Evaluate the role of Tregs in contributing to long-term tolerance of hearts despite the transience of the mixed chimerism induced by the Delayed Tolerance protocol. In fact, this approach could prove to be even more effective than our standard (non-delayed) protocol, since the tolerance conditioning regimen would be instituted in the absence of the proinflammatory cytokines that are invariably present during the peri-transplant period. The detailed mechanistic studies that will be performed and the analyses planned should provide relevant information for designing subsequent studies that will rationally extend the applicability of this recent clinical innovation to increasing numbers of transplant recipients.

这个为期两年的项目的目标是通过阐明通过混合嵌合方法诱导供体特异性耐受的机制来改善心脏移植后的结果。我们的实验室已通过结合非清髓性调节和供体骨髓移植 (DBMT) 实现了非人灵长类动物 (NHP) 肾同种异体移植物的耐受性，从而导致短暂的混合造血嵌合。基于这些开创性的观察结果，类似的方案已在活体相关肾同种异体移植的人类受体中进行了测试，并被证明是成功的。然而，尽管这一成就具有戏剧性，但它所采用的治疗方案目前的成功仅限于活体供体移植（调节从第-6天开始）。显然需要在活体供体肾脏已经取得的令人印象深刻的成功的基础上，优化混合嵌合策略，以便它可以更广泛地应用于心脏等尸体供体器官。最近，我们在 NHP 肾同种异体移植模型中开发了一种新的治疗方案，即“延迟耐受”方案，它可以扩展混合嵌合方法的临床适用性。在此方案中，受者最初接受常规免疫抑制移植，然后一段时间后接受非清髓性调理和 DBMT。该项目的目标是使用新药物和新策略开发延迟耐受方案，以诱导同种异体心脏移植物的耐受性。我们将检验以下假设：通过促进 Tregs 增强外周耐受机制或实现更持久的多系供体嵌合将导致 NHP 中心脏同种异体移植物的长期耐受。在为期两年的研究中，我们将具体： (1) 开发适用于人类心脏移植受者的延迟耐受诱导的混合嵌合方案，以及 (2) 评估 Tregs 在促进心脏长期耐受中的作用，尽管延迟耐受诱导的混合嵌合是短暂的协议。事实上，这种方法可能被证明比我们的标准（非延迟）方案更有效，因为耐受调节方案将在缺乏围移植期间始终存在的促炎细胞因子的情况下制定。将进行的详细机制研究和计划的分析应该为设计后续研究提供相关信息，这些研究将合理地将这一最新临床创新的适用性扩展到越来越多的移植受者。