Lung Alloimmunity after Bone Marrow Transplantation

迟发性肺部并发症（闭塞性细支气管炎和间质性肺炎）是一个重要的 骨髓移植后发病和死亡的原因。它们的发展与 在免疫表型中称为“开关”。使用同种异体骨髓移植后肺部疾病的小鼠模型 我们将检验调节性CD 8+淋巴细胞介导移植后肿瘤发生的假设。 骨髓移植后慢性肺移植物抗宿主病我们假设监管机构 CD 8+淋巴细胞最初是同种免疫细胞毒性T淋巴细胞，并且在多轮抗原性免疫后， 刺激变得无反应性，产生调节特性并在功能上抑制TH 1反应 导致慢性疾病。具体目的包括：1）确定肺嵌合体在 在鼠模型中骨髓移植后在肺中产生同种免疫应答，2） 确定是否可以操纵CD 8+调节细胞以实现GVHD和迟发性肺损伤的减少。 3）为了鉴定CD 8+调节细胞抑制CD 8 + T细胞表达的机制， 同种免疫应答，以及4）前瞻性研究非清髓性治疗后的患者队列 移植 该建议描述了一个5年的培训计划，以发展基础科学研究的学术生涯 在移植免疫学中，它与骨髓移植的肺部并发症有关。的 主要研究者已经完成了肺/重症监护奖学金培训计划， 人类受试者的基础肺免疫学。本建议概述了培训，以扩大这些基本的 技术，并将其扩展到小鼠模型，在DavidWilkes博士的指导下， 肺移植免疫学造血干细胞移植的培训将由Dr. 玛丽·迪瑙尔和爱德华·斯鲁尔博士，细胞贩运和小鼠骨髓移植方面的专家。

Late onset pulmonary complications (bronchiolitis obliterans and interstitial pneumonia) are a significant cause of morbidity and mortality after bone marrowtransplantation. Their development correlates with a switch" in immune phenotype. Using a murine model of lung disease following allogeneic bonemarrow transplantation we will test the hypothesis that regulatory CD8+ lymphocytes mediate the development of chronic pulmonary graft versus host disease after bone marrow transplantation. We hypothesize regulatory CD8+ lymphocytes are initially alloimmune cytotoxic T lymphocytes and after multiple rounds of antigenic stimulation become anergic, develop regulatory properties and functionally suppress the TH1 response leading to chronic disease. The specific aims include: 1)To determine the impact of pulmonary chimerism in generating an alloimmune response in the lung after bone marrow transplant in a murine model, 2)To determine if CD8+ regulatory cells can be manipulated to effect a decrease in GVHD and late onset lung disease in a murine model, 3)To identify the mechanisms by which CD8+ regulatory cells suppress the alloimmune response, and 4)To prospectively study a cohort of patients after nonmyeloablative transplantation. This proposal descibes a 5 year training program to develop an academic career in basic science research in transplant immunology as it relates to pulmonary complications of bone marrow transplantation. The principal investigator has completed a pulmonary/critical care fellowship training program where she learned basic pulmonary immunology in human subjects. This proposal outlines training to expand upon these basic techniques and extend them to a murine model, under the mentorship of Dr. DavidWilkes, an expert in pulmonary transplant immunology. Training in hematopoietic stem cell transplantation will be provided by Dr. Mary Dinauer and Dr. Edward Srour, experts in cell trafficking and murine bone marrow transplantation.