Lung Alloimmunity after Bone Marrow Transplantation

描述(由申请人提供)： 迟发性肺部并发症(毛细支气管炎、闭塞性肺炎和间质性肺炎)是骨髓移植后发病率和死亡率的重要原因。它们的发展与免疫表型的转换有关。利用异基因骨髓移植后肺部疾病的小鼠模型，我们将检验调节性CD8+淋巴细胞在骨髓移植后慢性肺移植物抗宿主病发展中的作用这一假设。我们假设调节性CD8+淋巴细胞最初是同种异体免疫的细胞毒性T淋巴细胞，经过多轮抗原刺激后变得无能，形成调节特性并从功能上抑制导致慢性病的TH1反应。具体目标包括：1)在小鼠模型中确定肺嵌合在骨髓移植后在肺内产生同种免疫反应的影响，2)确定是否可以操纵CD8+调节细胞来减少小鼠GVHD和迟发性肺部疾病，3)确定CD8+调节细胞抑制同种免疫反应的机制，以及4)前瞻性地研究非清髓性移植后的一组患者。 本提案描述了一项为期5年的培训计划，旨在发展移植免疫学基础科学研究的学术生涯，因为移植免疫学与骨髓移植的肺部并发症有关。这位首席研究员已经完成了肺部/重症监护奖学金培训计划，在那里她学习了人类受试者的基本肺部免疫学。这项提案概述了在肺移植免疫学专家大卫·威尔克斯博士的指导下，对这些基本技术进行扩展并将其扩展到小鼠模型的培训。造血干细胞移植方面的培训将由细胞贩运和小鼠骨髓移植方面的专家Mary Dinauer博士和Edward Srour博士提供。

DESCRIPTION (provided by applicant): Late onset pulmonary complications (bronchiolitis obliterans and interstitial pneumonia) are a significant cause of morbidity and mortality after bone marrow transplantation. Their development correlates with a switch" in immune phenotype. Using a murine model of lung disease following allogeneic bone marrow 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 non-myeloablative transplantation. This proposal describes 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. David Wilkes, 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.