CELLULAR MECHANISMS OF HEMORRHAGED-INDUCED SUPPRESSION

出血引起的抑制的细胞机制

• 批准号: 3295966
• 负责人: YI-HAN CHANG
• 金额: $ 16.71万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3295966
• 关键词: T lymphocyte; antigens; bactericidal immunity; helper T lymphocyte; hemorrhage; immunosuppression; interleukin 2; laboratory mouse; laboratory rat; mixed tissue /cell culture; suppressor T lymphocyte; trauma

Despite the availability of a variety of antimicrobial agents and rigorous prophylactic therapy, infections are the major cause of morbidity and mortality after traumatic injuries or burns. A depressed cell-mediated immune response appears to be primarily responsible for the impairment in host defense. We have found that unanesthetized hemorrhage in "untraumatized" animals was sufficient by itself to bring about a state of immune depression manifested by a reduced T cell proliferation in response to mitogen stimulation as well as the production of IL-2. We have found further that a serum immunosuppressive factor (SIP) with a molecular weight between 13,000 and 23,000 appears to be responsible for the alterations in lymphocyte proliferative response observed after hemorrhage. With the long term goal of elucidating the events that lead to an impairment in host defense following hemorrhage and trauma and to explore possible clinical applications of SIP, it is the objective of this proposed investigation to characterize the hemorrhage-induced alterations of immune response against specific antigens in vivo, and to test our hypotheses that (1) the hemorrhage-induced suppression of immune response is mediated by SIP and (2) SIP suppresses immune response through activation of suppressor T cells and consequently reduce the production of interleukin 2 (IL-2) by helper T cells. Specifically we propose to: (1) determine effects of hemorrhage on the development as well as the effector phase of immune response against antigens in vivo by measuring DTH, CTL, and levels of circulating antibodies in animals immunized with EL4 cells; (2) determine the subclass(s) of lymphocytes responsible for the observed alterations in immune response; (3) determine if all in vivo alterations of immune response brought about by hemorrhage can be reproduced in rats by i.v. administration of SIP alone; (4) elucidate the mechanism of action of SIP by determining its effects on mononuclear cell interactions and production of lymphokines. Results generated from these studies should lead to a better understanding of the impairment of host defense against infections that occurs following hemorrhage and trauma and provide information which may permit the development of methods to identify trauma patients who are at particularly highly risk of infection as well as suggest unique therapeutic approaches to correct such conditions.

尽管有多种抗微生物剂和 严格的预防性治疗，感染是主要原因 创伤或烧伤后的发病率和死亡率。 一 抑制细胞介导的免疫反应似乎主要是 对宿主防御的损害负责。 我们发现 在“未受创伤”的动物中， 足以导致免疫抑制状态 表现为T细胞增殖减少， 促分裂原刺激以及IL-2的产生。 我们有 进一步发现，血清免疫抑制因子（SIP）与 分子量在13，000和23，000之间似乎是 负责淋巴细胞增殖的改变， 出血后观察到反应。 长期目标是 阐明导致宿主防御受损的事件 出血和创伤后，并探讨可能的临床 SIP的应用，这是本建议的目的， 研究以表征药物诱导的变化 体内针对特定抗原的免疫应答，并测试 我们的假设是：（1）药物诱导的抑制， 免疫应答是由SIP介导的;（2）SIP抑制 通过激活抑制性T细胞的免疫应答， 从而减少白细胞介素2（IL-2）的产生， 辅助性T细胞 具体而言，我们建议：（1）确定影响 出血的发展以及效应阶段 通过测量DTH来测量体内针对抗原的免疫应答， CTL和免疫动物中的循环抗体水平 用EL 4细胞;（2）确定淋巴细胞的亚类 负责观察到的免疫应答变化;（3） 确定是否所有体内免疫应答的改变 通过i. v. （4）阐明其作用机制 通过确定其对单核细胞相互作用的影响， 和淋巴因子的产生。 从这些产生的结果 研究应有助于更好地了解 宿主对出血后感染的防御 和创伤，并提供信息， 开发方法，以确定创伤患者谁是在 感染的风险特别高， 治疗方法，以纠正这些条件。