Lung Alloimmunity after Bone Marrow Transplantation

骨髓移植后肺同种免疫

• 批准号: 7488834
• 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/7488834
• 关键词: Ablation; Acute; Acute Graft Versus Host Disease; Address; Adoptive Transfer; Alloantigen; 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; 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; bone; 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

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.

迟发性肺部并发症（闭塞性细支气管炎和间质性肺炎）是一个重要的并发症。 骨髓移植后发病和死亡的原因。他们的发展与 免疫表型中的“开关”。使用同种异体骨髓后的小鼠肺部疾病模型 移植我们将检验调节性 CD8+ 淋巴细胞介导细胞发育的假设 骨髓移植后慢性肺移植物抗宿主病。我们假设监管 CD8+淋巴细胞最初是同种免疫细胞毒性T淋巴细胞，经过多轮抗原作用后 刺激变得无反应，形成调节特性并在功能上抑制 TH1 反应 导致慢性疾病。具体目标包括： 1）确定肺嵌合现象对 在小鼠模型中进行骨髓移植后，在肺部产生同种免疫反应，2)To 确定是否可以操纵 CD8+ 调节细胞来减少 GVHD 和晚发型肺病 小鼠模型中的疾病，3）确定 CD8+ 调节细胞抑制 同种免疫反应，以及 4) 前瞻性研究非清髓性治疗后的一组患者 移植。 该提案描述了一个为期 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 首席研究员完成了肺部/重症监护奖学金培训计划，她在那里学到了 人类受试者的基础肺免疫学。该提案概述了扩展这些基本内容的培训 在专家 DavidWilkes 博士的指导下，并将其扩展到小鼠模型 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 博士是细胞运输和小鼠骨髓移植方面的专家。