Application of Mixed Chimerism to Lung Transplantation

混合嵌合体在肺移植中的应用

• 批准号: 7009885
• 负责人: James S. Allan
• 金额: $ 25.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009885
• 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.

过去二十年来，新型免疫抑制剂的开发极大地改善了同种异体肺移植受者的早期移植后存活率。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，长期生存率并没有显着改善。尽管已知或假设许多不依赖于抗原的因素可调节慢性排斥反应的发生，但同种免疫仍然是排斥反应的必要条件。移植耐受的诱导不仅有望消除全身免疫抑制的需要，而且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产生嵌合状态。通过移植供体来源 宿主的造血细胞中，受体通过中枢对供体组织产生耐受性 机制。供体和受体造血元件同时、稳定地植入受体体内（称为“混合嵌合状态”）不仅允许移植耐受状态，而且还可以防止在完全嵌合体中可见的免疫库中的某些缺陷收件人。我们的中心假设是，混合嵌合体的诱导将在肺同种异体移植受者中诱导一种耐受状态，这将 1) 导致长期移植物存活，2) 预防闭塞性细支气管炎，3) 消除相关感染和恶性肿瘤风险增加伴有慢性免疫抑制。我们基于新出现的啮齿类动物数据得出的推论假设是，记忆 T 细胞对组织构成重大威胁。 的混合嵌合现象。我们将研究三种不同的混合嵌合调理方案，针对 1) 活体肺同种异体移植受者、2) 尸体肺同种异体移植受者和 3) 已经接受长期免疫抑制治疗的移植受者。我们将与 Benichou 的 Project 合作，研究记忆 T 细胞对混合嵌合体耐受诱导的影响。通过与 Madsen 项目和病理学核心合作，我们将识别和验证能够准确反映是否存在某种疾病的生物标志物。 同种异体肺移植受者的持久耐受状态。