Tolerance Strategies in Non-Human Primate Cardiac Allograft Recipients

非人灵长类同种异体心脏移植受者的耐受策略

• 批准号: 8523175
• 负责人: Joren C Madsen
• 金额: $ 84.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523175
• 关键词: Anti-Inflammatory Agents; Antithymoglobulin; B-Lymphocytes; CD58 gene; Dose; Drug usage; Equilibrium; Event; Family suidae; Goals; Heart; Heart Transplantation; Immune; Immune response; Immune system; Immunosuppression; Infection; Inflammation; Inflammatory Response; Injury; Instruction; 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; The Sun; 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 sun/ival, 2) preserve normal graft function, and 3) prevent cardiac allograft vasculopathy (CAV) without long term immunosuppression. Recent studies have demonstrated that the cotrahsplantation 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 screpancy, 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 cyiniomolgus 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. RELEVANCE (See instructions): Heart transplant recipients do not survive long enough because the drugs used to prevent the immune system from attacking the organs are not completely effective and they make transplant recipients more susceptible to infections and cancer. We will find new ways to transplant organs without drugs using tolerance which makes the organs immunologically invisible to the recipient.

我们的中心假设是诱导强大，可重复和耐用的心脏同种异体移植物的耐受性 会导致长期移植太阳/IVAR，2）保留正常的移植功能，3）预防心脏同种异体移植物 无长期免疫抑制的血管病（CAV）。最近的研究表明 血管化供体胸腺的CotrahSplantation诱导MHC不同心脏的快速和稳定的耐受性 在微型猪中。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。解释这一点 放映，我们假设非人类灵长类动物百里香移植物更容易受到早期的影响 免疫损伤和炎症比猪胸腺移植物，这种早期损害可防止 胸腺胸腺移植物完全贡献了耐受性的诱导。我们进一步 假设cernomolgus受体中早期胸腺损伤的三个最有可能的原因是：1）早期 高剂量ATG治疗对有益的宿主Treg的消耗，2）有害的稳态扩张 通过高剂量ATG治疗的记忆症状，3）与手术程序相关的炎症 我们的目标是制定一种创新和综合的策略来阻止这些事件中的每一个，尽早保存 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）确定是否扩展宿主调节性T细胞 体内将废除早期胸腺损失，2）确定耗尽或抑制记忆T细胞是否会阻止 早期胸腺排斥和3）确定降低促炎反应是否会减少早期 胸腺损伤并促进心脏的胸腔胸腔同种异体移植者的耐受性。 相关性（请参阅说明）： 心脏移植接受者的生存时间不够长，因为用于预防免疫的药物 攻击器官的系统并不完全有效，它们使移植受者更多 容易感染和癌症。我们将找到新的方法来移植器官，而无需使用药物 耐受性，使器官在免疫学上看不见受体。