Application of Mixed Chimerism to Lung Transplantation

在过去的二十年里，新的免疫抑制剂的发展极大地提高了肺移植受体移植后的早期生存率。然而，由于慢性排斥反应、感染和恶性肿瘤（均可归因于慢性免疫抑制），长期生存率并没有显著提高。虽然已知或假设许多抗原非依赖性因素可调节慢性排斥反应的发展，但同种异体免疫仍然是排斥反应的必要条件。诱导移植耐受不仅可以避免系统性免疫抑制，而且还可以防止慢性排斥反应的发生。诱导移植耐受的最成熟和最有效的方法之一是在受体中创造嵌合状态。通过移植供体来源

Over the past two decades, the development of new immunosuppressive agents has greatly improved the early post-transplant survival of lung allograft recipients. Nevertheless, long-term survival has not improved significantly, due to chronic rejection, infections, and malignancies-all attributable to chronic immunosuppression. Although many antigen-independent factors are known or hypothesized to modulate the development of chronic rejection, allo-immunity remains the sine qua non of rejection. The induction of transplantation tolerance offers the promise of not only obviating the need for systemic immunosuppression, but also preventing the development of chronic rejection One of the most established and robust methods of inducing transplantation tolerance is the creation of a chimeric state in the recipient. By engrafting donorderived hematopoietic cells in the host, the recipient is rendered tolerant to donor tissue through central mechanisms. The simultaneous, stable engraftment of both donor and recipient hematopoietic elements in a recipient (a state known as 'mixed chimerism') not only permits a state of transplantation tolerance, but also prevents certain deficiencies in the immunologic repertoire that can be seen in fully chimeric recipients. Our central hypothesis is that the induction of mixed chimerism will induce a state of tolerance in lung allograft recipients that will 1) result in long term graft survival), 2) prevent obliterative bronchiolitis, and 3) eliminate the increased risk of infection and malignancy associated with chronic immunosuppression. Our corollary hypothesis, based on emerging rodent data, is that memory T cells pose a major threat to the establishment of mixed chimerism. We will investigate three different mixed chimerism conditioning regimens aimed at 1) recipients of living-donor lung allografts, 2) recipients of cadaveric lung allografts and 3) transplanted recipients already on chronic immunosuppressive therapy. In collaboration with Project by Benichou, we will study the effects of memory T cells on tolerance induction by mixed chimerism. In collaboration with Project by Madsen and the Pathology Core, we will identify and validate biomarkers that will accurately reflect the presence or absence of a durable tolerant state in lung allograft recipients.