Application of Mixed Chimerism to Lung Transplantation

在过去的二十年里，新型免疫抑制剂的发展极大地提高了同种异体肺移植受者的移植后早期存活率。然而，由于慢性排斥、感染和恶性肿瘤--所有这些都归因于慢性免疫抑制，长期存活率并没有显著改善。尽管已知或假设有许多抗原非依赖性因素可调节慢性排斥反应的发生，但同种异体免疫仍是排斥反应的必要条件。诱导移植耐受不仅可以避免全身免疫抑制的需要，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可靠的方法之一是在受者体内创造嵌合状态。通过嫁接供体或衍生 在宿主的造血细胞中，受体通过中枢对供体组织产生耐受。 机械装置。供者和受者同时稳定地植入供者和受者的造血元素(这种状态被称为混合嵌合体)不仅允许移植耐受状态，而且还防止了在完全嵌合的受者中可以看到的某些免疫学方面的缺陷。我们的中心假设是，混合嵌合体的诱导将在肺移植受者中诱导一种耐受状态，这将1)导致移植物长期存活，2)预防闭塞性毛细支气管炎，3)消除与慢性免疫抑制相关的感染和恶性肿瘤的增加风险。我们的推论是，基于新出现的啮齿动物数据，记忆T细胞对建立这种细胞构成了主要威胁 混杂的嵌合体。我们将研究三种不同的混合嵌合预适应方案，分别针对1)活体供体肺移植的受者，2)身体同种异体肺移植的受者和3)已经接受慢性免疫抑制治疗的移植受者。我们将与Benichou项目合作，研究记忆T细胞在混合嵌合体诱导耐受中的作用。在与马德森项目和病理核心组织的合作下，我们将识别和验证能够准确反映 同种异体肺移植受者的耐受状态。

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.