Thymic Tolerance in Pediatric Heart Transplantation

目前儿科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、排斥监测的高成本和侵入性，以及我们现有的免疫抑制剂无法预防慢性排斥反应(移植后冠状动脉血管病变)。如果能够实现特定于供者的“移植耐受”(移植医学的圣杯)，这些限制可能会被消除。供者特异性耐受可以被定义为受者的免疫系统对供者抗原无反应，并将永久接受同种异体移植物，而不需要长期的抗排斥治疗，但仍保持对非供者抗原的正常免疫反应。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，人们花费了巨大的努力来了解移植耐受是如何实现的，在小动物身上的实验现在已经扩展到了亚人类灵长类动物。然而，很少有研究转移到临床领域，也没有一项研究在儿童胸部移植中进行。由于儿科移植在中年存活的可能性很小，我们认为现在是时候谨慎地将最有希望的诱导耐受的实验室技术推广到临床了。在儿科心脏移植中使用“胸腺”方法诱导耐受的理由有以下几个方面：i)。这个 2)胸腺对儿童早期T细胞成熟的重要性；越来越多的实验文献显示，通过向受体胸腺接种供体特异性抗原，成功地诱导了供体特异性耐受；以及iii)。心脏移植时胸骨正中切开时胸腺的良好显露。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、安全的和潜在有效的。因此，我们提出了一项前瞻性、盲法、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，与没有接受供者特异性胸腺内骨髓接种的当代对照组相比，胸腺耐受的诱导将是安全的，并将减少急性排斥事件和免疫抑制药物的长期需求。我们还假设，改善的结果将与供者特异性低反应的体外证据有关。

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.