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)是一种重要的 骨髓移植后并发症和死亡率的原因分析。它们的发育与 改变免疫表型。使用同种异体骨髓后肺部疾病的小鼠模型 我们将检验调节性CD8+淋巴细胞参与移植物抗肿瘤发展的假说。 骨髓移植后慢性肺移植物抗宿主病。我们假设监管机构 CD8+淋巴细胞最初是同种异体免疫的细胞毒性T淋巴细胞，经过多轮抗原性 刺激变得无能，发展调节特性，并从功能上抑制TH1反应 导致慢性病。具体目标包括：1)确定肺嵌合体对 在小鼠骨髓移植模型中在肺内产生同种异体免疫反应，2) 确定是否可以操纵CD8+调节细胞来减少移植物抗宿主病和迟发性肺 小鼠模型中的疾病，3)确定CD8+调节细胞抑制 同种异体免疫反应，以及4)前瞻性研究非清髓性治疗后的一组患者 移植。 这项建议描述了一项为期5年的培训计划，以发展基础科学研究的学术生涯 移植免疫学，因为它与骨髓移植的肺部并发症有关。这个 首席调查员完成了肺/重症监护奖学金培训计划，在那里她学到了 人体肺脏免疫学基础研究。该提案概述了在这些基础上扩展的培训 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。造血干细胞移植方面的培训将由Dr。 Mary Dinauer和Edward Srour博士是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.