Achieving Tolerance to Cardiac Allografts using Vascularized Donor Thymus

使用带血管的供体胸腺实现心脏同种异体移植的耐受性

• 批准号: 9130493
• 负责人: Joren C Madsen
• 金额: $ 96.15万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130493
• 关键词: Anti-Inflammatory Agents; Antithymoglobulin; B-Lymphocytes; CD58 gene; Dose; Drug usage; Equilibrium; Event; Family suidae; Goals; Graft Survival; Heart; Heart Transplantation; Immune; Immune response; Immune system; Immunosuppression; Infection; Inflammation; Inflammatory Response; Injury; Interleukin-17; Malignant Neoplasms; Memory; Miniature Swine; Operative Surgical Procedures; Organ; Organ Transplantation; Oryctolagus cuniculus; Peripheral; Protein C Inhibitor; Regulatory T-Lymphocyte; T memory cell; T-Lymphocyte; Testing; Thymus Gland; Transplant Recipients; Transplantation; Tumor Debulking; Vascular Diseases; graft function; heart allograft; in vivo; inhibitor/antagonist; innovation; nonhuman primate; novel; prevent; small molecule; thymocyte; thymus allograft

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) without long term immunosuppression. Recent studies have demonstrated that the cotransplantation of vascularized donor thymus induces rapid and stable tolerance to MHC disparate hearts in miniature swine. The goal of this Project is to extrapolate this innovative strategy to nonhuman primates. However, preliminary attempts to co-transplant vascularized thymus and heart allografts in nonhuman primates resulted in early loss of the donor thymus followed by rejection of the heart. To explain this discrepancy, we hypothesize that nonhuman primate thymus grafts are more susceptible to early immune injury and inflammation than the porcine thymus grafts and that this early damage prevents cynomolgus thymus grafts from contributing fully to the induction of tolerance. We further hypothesize that the three most likely causes of early thymus injury in cynomolgus recipients are: 1) the early depletion of salutary host Tregs by high-dose ATG therapy, 2) the homeostatic expansion of deleterious memory T ceils by high-dose ATG therapy, and 3) the inflammation associated with the surgical procedure Our goal is develop an innovative and integrated strategy to block each of these events, preserve early thymic function and allow the transplanted thymus to participate fully in the induction of tolerance to cotransplanted cardiac allografts. Our aims are 1) determine whether expanding host regulatory T cells in vivo will abrogate early thymic loss, 2) determine whether depleting or inhibiting memory T cells will prevent early thymic rejection, and 3) determine if dampening the pro-inflammatory response will diminish early thymus injury and promote tolerance in heart en bloc thymus allograft recipients.

我们的中心假设是，诱导鲁棒，可重复和耐用的耐受性，对心脏同种异体移植的耐受性1）导致长期的移植物存活，2）保持正常的移植功能，3）防止心脏同种异体移植血管病（CAV）无长期免疫抑制。最近的研究表明，血管供体胸腺的共转移会在微型猪中诱导对MHC不同心脏的快速且稳定的耐受性。该项目的目的是将这种创新策略推送到非人类灵长类动物。然而，非人类的初步尝试进行移植的血管化胸腺和心脏同种异体移植 灵长类动物导致胸肌的早期丧失，然后拒绝心脏。为了解释这一差异，我们假设非人类灵长类动物百里香移植物比猪胸骨疗法更容易受到早期免疫损伤和炎症的影响，并且这种早期损害可阻止cynomolgus thymus thymus嫁接完全有助于耐受性的诱导。我们进一步 假设在cernomolgus接受者中最可能造成胸腺早期损伤的三个原因是：1）高用药ATG治疗对有价值的宿主Treg的早期耗尽，2）2）高剂量ATG治疗对有害记忆的稳态扩展，以及与每个事件相关的炎症，并与这些事件相关联，并建立在这些事件中，并整合了这些事件，并整合了这些事件，并整合了这些事件，并整合了这些事件胸腺功能，允许移植的胸腺充分参与耐受性 共转移心脏同种异体移植物。我们的目的是1）确定体内扩展的宿主调节T细胞是否会消除早期胸腺损失，2）确定耗尽或抑制记忆T细胞是否会防止早期胸腺抑制作用，3）确定降低促炎反应是否会减少早期胸腺胸骨的早期胸骨和耐受性降低，并促进心脏bloc thymus thymus thymus thymus prolograft Grofters。