Lung Alloimmunity after Bone Marrow Transplantation

骨髓移植后肺同种免疫

• 批准号: 7281672
• 负责人: Karen Wood
• 金额: $ 13.05万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-05 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281672
• 关键词: Ablation; Acute; Acute Graft Versus Host Disease; Address; Adoptive Transfer; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Alveolitis; Apoptosis; Autoimmune Diseases; Autoimmunity; Basic Science; Blood; Bone Marrow Transplantation; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chimerism; Chronic; Chronic Disease; Clinical; Complex; Condition; Critical Care; Cytotoxic T-Lymphocytes; Data; Databases; Development; Disease; Fellowship; Hematopoietic Stem Cell Transplantation; Histopathology; Homologous Transplantation; Human; Immune; Immune response; Immunology; Infusion procedures; Interstitial Pneumonia; Investigation; Laboratory Finding; Learning; Lung; Lung diseases; Lymphocyte; Lymphocyte Subset; Mediating; Mentorship; Modeling; Morbidity - disease rate; Mus; Numbers; Patients; Personal Satisfaction; Phenotype; Play; Pneumonia; Principal Investigator; Property; Pulmonary function tests; Research; Research Personnel; Role; Staging; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Time; Toxic effect; Training; Training Programs; Transplant Recipients; Transplantation; Treatment Protocols; Wood material; anergy; career; chemotherapy; chronic graft versus host disease; cohort; conditioning; cytokine; graft vs host disease; graft vs host reaction; human subject; in vivo; interest; irradiation; isoimmunity; mortality; mouse model; precursor cell; programs; response; trafficking

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.

描述（由申请人提供）： 迟发性肺部并发症（闭塞性细支气管炎和间质性肺炎）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。使用同种异体骨髓移植后肺部疾病的小鼠模型，我们将测试调节性CD 8+淋巴细胞介导骨髓移植后慢性肺移植物抗宿主病的发展的假设。我们假设调节性CD 8+淋巴细胞最初是同种免疫细胞毒性T淋巴细胞，在多轮抗原刺激后变得无反应性，产生调节特性并在功能上抑制TH 1反应，导致慢性疾病。具体目标包括：1）确定肺嵌合体在鼠模型中骨髓移植后在肺中产生同种免疫应答中的影响，2）确定是否可以操纵CD 8+调节细胞以实现鼠模型中GVHD和迟发性肺病的减少，3）鉴定CD 8+调节细胞抑制同种免疫应答的机制，和4）前瞻性研究非清髓性移植后的患者队列。 该提案描述了一个为期5年的培训计划，以发展移植免疫学基础科学研究的学术生涯，因为它涉及骨髓移植的肺部并发症。主要研究者已完成肺部/重症监护奖学金培训计划，在该计划中，她学习了人类受试者的基本肺部免疫学。该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，扩展这些基本技术并将其扩展到小鼠模型的培训。造血干细胞移植培训将由细胞运输和小鼠骨髓移植专家玛丽迪诺尔博士和爱德华斯鲁尔博士提供。