REJECTION AND TOLERANCE OF RESPIRATORY TRACT ALLOGRAFTS

肺移植通常是一种有效的治疗方法， 顽固性心肺功能障碍 尽管最近的技术进步， 然而，同种异体移植排斥仍然是发病的常见原因， 和死亡率之间的关系。 候选人 award在这些患者的护理和管理方面具有临床经验 现在正在寻求必要的专业知识， 排斥现象的研究。 本文所述的项目将 研究呼吸道同种异体反应性的机制， 肺移植新方法的可行性 排斥反应此外，这些实验是制定利用 这个实验室和机构的独特专业知识。T细胞 抗原受体（TCR）基因表达在移植物浸润 人肺淋巴细胞（GIL）和外周血淋巴细胞（PBL 同种异体移植受者的广泛特征是敏感的 和定量RNase测定法。 这些数据 表明慢性肺排斥患者T细胞库 通常高度偏倚，在某些情况下，异常TCR VP是由于 寡克隆（或单克隆）增殖和/或隔离。 的 研究结果表明，慢性排斥反应的严重肺损伤是 由有限数量的T细胞克隆介导， 可识别的细胞表面标记物，其可被新的 治疗对选定患者的纵向研究还将 确定T细胞克隆型的扩增或收缩是否 改变临床状况的有用指标（即，排斥或 感染）。 我们还成功地在小鼠模型中诱导了同种异体耐受， 胸腺内注射供者的呼吸道移植 抗原呈递细胞正在进行的调查将探讨各种机制 并确定这种同种异体耐受的持续时间。最后我们将开始一个 一系列研究开发重组基因治疗方法， 将最终导致同种异体（供体） 主要组织相容性复合体（MHC）抗原。 影响的能力 受体胸腺中供体MHC的表达，特别是在 静脉内给药，可以使广泛使用的 通过微创方法诱导成人同种异体耐受。

Pulmonary transplantation is often an effective therapy for otherwise intractable cardiopulmonary disorders. Despite recent technical advances, however, allograft rejection continues to be a frequent cause of morbidity and mortality among lung transplant recipients. The candidate for this award has clinical experience in the care and management of these patients and is now seeking the necessary expertise to continue fundamental investigations of rejection phenomena. The projects described herein will investigate mechanisms of respiratory tract alloreactivity and explore the feasibilities of new modalities to obviate or ameliorate lung transplant rejection. Furthermore, these experiments are formulated to capitalize on the unique expertise available in this laboratory and institution. T cell antigen receptor (TCR) gene expression among graft-infiltrating lymphocytes (GIL) and peripheral blood lymphocytes (PBL) of human lung allograft recipients have been extensively characterized by a sensitive and quantitative RNase assay developed in this laboratory. These data show that T cell repertoires of patients with chronic lung rejection are often highly biased and, in some, the abnormal TCR VP are due to oligoclonal (or monoclonal) proliferations and/or sequestrations. The findings suggest that the severe lung injury of chronic rejection is mediated by a limited number of T cell clones with unique, and readily identifiable, cell surface markers that could be exploited by novel therapies. Longitudinal studies of selected patients will additionally establish whether expansions or contractions of T cell clonotypes are useful indicators of changing clinical conditions (i.e., rejection or infection). We have also successfully induced allotolerance in a murine model of respiratory tract transplantation using intrathymic injections of donor antigen-presenting cells. Ongoing investigations will explore mechanisms and establish the duration of this allotolerance. Finally we will begin a series of studies to develop recombinant gene therapy methodologies that will ultimately result in intrathymic expression of allogeneic (donor) major histocompatibility complex (MHC) antigens. The ability to effect expression of donor MHC in the thymuses of recipients, particularly after intravenous administration, could enable widespread utilization of allotolerance induction in adult humans by minimally invasive means.