Application of Mixed Chimerism to Lung Transplantation

混合嵌合体在肺移植中的应用

• 批准号: 7310376
• 负责人: James S. Allan
• 金额: $ 25.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7310376
• 关键词: Macaca fascicularis; T lymphocyte; artificial immunosuppression; biomarker; bone marrow transplantation; bronchus disorder; cancer risk; cell population study; disease /disorder prevention /control; immune tolerance /unresponsiveness; immunologic memory; immunosuppressive; immunotherapy; lung transplantation; medical complication; nonhuman therapy evaluation; opportunistic infections; postmortem; tissue mosaicism; transplantation immunology

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.

在过去的二十年中，新的免疫抑制剂的发展大大改善了肺同种异体移植者的早期移植后生存。然而，由于慢性排斥，感染和恶性肿瘤，长期生存并未显着改善，这是归因于慢性免疫抑制。尽管已知或假设许多抗原独立的因素是为了调节慢性排斥的发展，但同种免疫仍然是不可排斥的正弦。移植耐受的诱导不仅可以消除需要全身免疫抑制的需求，而且还可以防止慢性抑制的发展是诱导移植耐受性最有成熟，最强大的方法之一，这是在接受者中的嵌合状态的创造。通过雕刻Donordored 宿主中的造血细胞，接受者可以耐受供体组织通过中央 机制。在受体中（称为“混合嵌合主义”的状态）中供体和受体造血元素的同时稳定的植入不仅允许移植耐受的状态，而且还可以防止在完全奇特的受体中可以看到的免疫学库中某些缺陷。我们的中心假设是，混合嵌合物的诱导将诱导肺同种异体移植受体的耐受性，这将使1）导致长期移植生存），2）防止闭塞性支气管炎，3）消除与慢性免疫抑制相关的感染和恶性肿瘤的风险增加。基于新兴的啮齿动物数据，我们的推论假设是记忆T细胞对机构构成了重大威胁 混合嵌合。我们将研究针对1）活肺肺同种异体移植物的三种不同的混合嵌合调节方案，2）尸体肺同种异体移植物的接受者和3）已经接受了慢性免疫抑制治疗的移植受者。在Benichou的项目中，我们将研究记忆T细胞对混合嵌合诱导耐受性诱导的影响。通过Madsen和病理学核心的项目合作，我们将确定和验证生物标志物，以准确反映出存在或不存在的生物标志物 肺同种异体受体中耐用的耐受状态。