Thymic Tolerance in Pediatric Heart Transplantation

目前小儿心脏移植的主要局限性包括与常规非特异性免疫抑制相关的副作用、排斥反应监测的高成本和侵入性以及我们目前免疫抑制剂设备无法预防慢性排斥反应（移植后冠状动脉血管病变）。如果能够实现供体特异性的“移植耐受”（移植医学的圣杯），这些限制可能会被消除。供体特异性耐受可以定义为受体的免疫系统对供体抗原无反应性，并且将永久接受同种异体移植物而不需要长期抗排斥治疗，但保留对非供体抗原的正常免疫应答的状态。感染的风险，淋巴增生性疾病， 因此避免了恶性肿瘤和终末器官药物毒性。在过去的50年里，人们付出了巨大的努力来了解如何实现移植耐受，并且现在已经将小动物实验扩展到了非人灵长类动物。然而，很少有研究已经转移到临床竞技场，并没有在小儿胸部移植。由于儿童移植提供了很少的机会长期生存到中年生活，我们认为，这是最有前途的实验室技术耐受诱导谨慎地扩展到临床的时候了。在儿科心脏移植中采用“胸腺”方法诱导耐受的基本原理来自以下几个途径：i）。的 胸腺对于儿童早期T细胞成熟的重要性; ii）.越来越多的实验文献显示通过用供体特异性抗原接种受体胸腺成功诱导供体特异性耐受;和iii）.在心脏移植时正中胸骨切开术中获得的胸腺暴露极佳。我们机构的一项试点研究提供了初步数据，表明这种方法是可行的，安全的和潜在的有效性。因此，我们提出了一个前瞻性的，盲法的，对照的临床试验，将未经修饰的供体特异性骨髓细胞接种到受体胸腺的两个叶中， 心脏移植的时间。我们假设，胸腺耐受的诱导将是安全的，并将减少急性排斥反应事件和免疫抑制药物的长期需求相比，当代对照，不接受供体特异性胸腺内骨髓接种。我们还假设，改善的结果将与体外证据的供体特异性低反应性。

Major limitations in pediatric heart transplantation at this time include the side effects associated with conventional non-specific immunosuppression, the high costs and invasive nature of rejection surveillance and the inability to prevent chronic rejection (post-transplant coronary vasculopathy) with our current armamentarium of immunosuppressive agents. These limitations might be eliminated if donor-specific 'transplantation tolerance' (the Holy Grail of transplantation medicine) could be achieved. Donor-specific tolerance can be defined as a state in which the recipient's immune system is non-reactive to donor antigens and will permanently accept the allograft without the need for long-term anti-rejection therapy, yet retains normal immune responses to non-donor antigens. The risks of infection, lymphoproliferative disorders, malignancy and end-organ drug toxicities are thus avoided. Tremendous efforts have been expended over the last 50 years to understand how transplantation tolerance can be achieved and experiments in small animals have now been extended to subhuman primates. However, few studies have moved to the clinical arena, and none have been performed in pediatric thoracic transplantation. Since pediatric transplantation offers little chance of long-term survival into mid-adult life, we believe that it is time for the most promising laboratory techniques for tolerance induction to be cautiously extended to the clinic. Rationale for the 'thymic' approach to tolerance induction in pediatric heart transplantation comes from several avenues: i). the importance of the thymus gland for T cell maturation in early childhood; ii). a growing experimental literature showing successful induction of donor-specific tolerance by inoculation of the recipient thymus with donor-specific antigens; and iii). the excellent exposure of the thymus obtained during median sternotomy at time of heart transplantation. A pilot study at our institution provides preliminary data to suggest that this approach is feasible, safe and potentially effective. We therefore propose a prospective, blinded, controlled clinical trial of inoculation of unmodified donor-specific bone marrow cells into both lobes of the recipient thymus gland at the time of heart transplantation. We hypothesize that the induction of thymic tolerance will be safe and will reduce acute rejection events and long-term requirements for immunosuppressive medications when compared to contemporary controls that do not receive donor-specific intra-thymic bone marrow inoculation. We also hypothesize that the improved outcomes will be associated with in vitro evidence of donor-specific hyporesponsiveness.