ALLOREACTIVITY AND CYTOMEGALOVIRUS ASSOCIATED PNEUMONIA

同种异体反应性和巨细胞病毒相关性肺炎

• 批准号: 3812353
• 负责人: STEPHEN J FORMAN
• 金额: --
• 依托单位: CITY OF HOPE NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3812353
• 关键词: Betaherpesvirinae; antibody formation; antiidiotype antibody; antiviral agents; antiviral antibody; bone marrow transplantation; disease /disorder model; graft versus host disease; histocompatibility antigens; homologous transplantation; laboratory mouse; lung alveolus; major histocompatibility complex; membrane activity; monoclonal antibody; surface antigens; viral pneumonia; virus antigen; virus cytopathogenic effect; virus infection mechanism

Human cytomegalovirus (HCMV) is the most important pathogen that limits the success of allogeneic BMT. The infection is associated with an often fatal pneumonitis (IP) particularly in the setting of acute GVHD. The pathophysiology of HCMV associated pneumonitis is not fully understood. This project is designed to answer questions in four areas to extend our understanding of the pathogenesis of this important complication of BMT. Experiments will be performed to determine if HCMV can induce antigenic alterations on cells that make them an enhanced target for subsequent immunologic injury. Experiments have been performed that suggest that HCMV antigen can induce surface antigen changes on lymphocytes, possibly related to enhanced expression of class II antigens. These studies will be extended from this model system to cell lines in order to explore the mechanisms for this HCMV related alteration. The immunologic response of the lung to HCMV will be examined by studying the mononuclear cells obtained by broncho-alveolar lavage in patients who had received allogeneic BMT grafts. These studies (cell surface markers, MHC antigen expression, cytotoxicity) will be correlated with the virologic data from the specimen and the clinical outcome. This will give new information concerning the development of interstitial pneumonia associated with HCMV. Previous work in a GVHD-CMV model analogous to human IP supports the hypothesis that the pathophysiology of murine CMV pneumonitis is immunologically mediated. Studies will be performed to examine the effect of MCMV-infection on the expression of class I and class II MHC antigens on pulmonary tissue and to determine the effect of passive transfer of monoclonal antibodies to class I and class II MHC antigens on MCMV infection, GVHD, and pneumonitis. The administration of murine monoclonal antibody to humans is limited due to host immune responses to species specific antigens. This project will also attempt to convert a murine anti-DR antibody with striking affinity for human class II antigens into a human/murine hybrid antibody. Exon switching technology will be utilized and the recombinant antibody will be compared in activity to the original murine antibody. This converted antibody may be more therapeutically useful in patients with immunologically mediated disorders.

人类巨细胞病毒（HCMV）是最重要的病原体 这限制了同种异体BMT的成功。 感染是 与经常致命的肺炎（IP）有关 急性GVHD的设置。 HCMV相关的病理生理学 肺炎尚不完全了解。 该项目旨在 在四个领域回答问题，以扩展我们对 BMT的这种重要并发症的发病机理。 将进行实验以确定HCMV是否可以诱导 细胞的抗原改变使它们成为增强的靶标 随后的免疫损伤。 实验已经过去了 表明HCMV抗原可以诱导表面 淋巴细胞的抗原变化，可能与增强 II类抗原的表达。 这些研究将扩展 从这个模型系统到单元线，以探索 此HCMV相关改变的机制。 将检查肺对HCMV的免疫反应 通过研究通过支气管 - 肺泡获得的单核细胞 接受过同种异体BMT移植的患者的灌洗。 这些 研究（细胞表面标记，MHC抗原表达， 细胞毒性）将与来自 标本和临床结果。 这将给予新的 有关间质肺炎发展的信息 与HCMV相关。 以类似于人类IP类似的GVHD-CMV模型中的先前工作 支持鼠CMV的病理生理学的假设 肺炎是免疫学介导的。 研究将是 进行了检查MCMV感染对 I类和II类MHC抗原在肺部的表达 组织并确定被动转移的影响 I类和II类MHC抗原的单克隆抗体 MCMV感染，GVHD和肺炎。 给人类的鼠单克隆抗体给药是 由于宿主对物种特定抗原的免疫反应而限制。 该项目还将尝试转换鼠抗DR 对人类II类抗原具有惊人亲和力的抗体 人/鼠杂化抗体。 外显子切换技术将是 利用和重组抗体将在 原始鼠抗体的活性。 这种转换的抗体 对于患者 免疫学介导的疾病。