HEMORRHAGE-INDUCED SUPPRESSION OF IMMUNE RESPONSE

免疫反应的抑制似乎是造成这种损害的原因。 在出血和创伤后的宿主防御中。我们发现了一个 出血后T细胞大量功能异常。 初步研究表明，B细胞的某些功能也是 不正常。出血性血清中存在一个16000道尔顿多肽。 分离，部分测序，发现能激活抑制性T细胞。 这些被激活的抑制T细胞负责大部分，如果不是全部的话， 观察到的异常。其长期目标是阐明 出血后导致宿主防御功能受损的事件 和创伤，并评估抑制物的潜在临床用途 细胞激活因子(SCAF)，这是本建议的目标 研究(1)进一步表征出血引起的改变 在B细胞活性和抗体应答中的作用；(2)确定机制 SCAF在亚细胞和分子水平的作用；以及(3)试验 我们的假设是出血后的免疫抑制和 发展中的感染可以通过父母预防或逆转 给予抗SCAF或抗SCAF受体抗体。 具体地说，我们建议(1)确定出血对血清的影响 细菌抗原特异性抗体水平和数量， 抗原特异性脾血浆的百分率和活性 细胞；(2)测定失血对抗体应答的影响。 肺粘膜浆细胞；(3)评估可能的出血诱导 抗体应答调节机制的改变 B细胞与辅助性T细胞、抑制性T细胞的相互作用 出血后的独特型网络；(4)制备合成的和 重组SCAF、抗SCAF抗体和抗SCAF受体 抗体；(5)测定父母给药的效果 SCAF或抗SCAF受体抗体在失血性抑郁症中的作用 (6)评估抗SCAF可能的保护作用。 或抗SCAF受体抗体对实验性肺炎的影响 (7)确定SCAF在细胞内的作用机制， 通过确定其对细胞和分子水平的影响 介质的产生和释放，细胞质酶的激活， 核鸟氨酸脱羧酶诱导和多胺生物合成。 这些研究产生的结果应该会带来更好的 了解宿主对感染的防御能力受损 发生在出血和创伤之后，以及允许发展 方法学，如SCAF血液水平的测量，用于 确定出血性、创伤性或热损伤患者 感染风险特别高的人。实验验证 我们的假设是出血后免疫抑制和倾向 可以通过父母来预防和/或逆转感染 应用抗SCAF或抗SCAF受体抗体应 为危重III级创伤的临床处理提供新途径 病人。超越目前的提议，常委会主席(S)在 调节正常免疫反应和调节免疫抑制 衰老及其在器官中的潜在临床应用 移植和治疗自身免疫性疾病，如 系统性红斑狼疮(SLE)或1型糖尿病 未来调查的重要领域。

A depressed immune response appears to be responsible for the impairment in host defense following hemorrhage and trauma. We have found a multitude of functional abnormalities in post-hemorrhage T cells. Initial studies showed that certain functions of B cells are also abnormal. A 16000 Dalton polypeptide present in hemorrhagic serum was isolated, partially sequenced, and found to activate suppressor T cells. These activated suppressor T cells are responsible for most, if not all, observed abnormalities. With the long term goal of elucidating the events that lead to the impairment of host defense following hemorrhage and trauma and to assess potential clinical usefulness of the suppressor cell activating factor (SCAF), it is the objective of this proposed investigation to (1) further characterize hemorrhage-induced alterations in B cell activities and antibody response; (2) ascertain the mechanisms of action of SCAF at the subcellular and molecular levels; and (3) test our hypothesis that post-hemorrhage immunodepression and propensity for developing infection can be prevented or reversed by parental administration of anti-SCAF or anti-SCAF-receptor antibodies. Specifically, we propose to (1) determine effects of hemorrhage on serum levels of bacterial antigen specific antibodies and the number, percentages, as well as activities of antigen specific splenic plasma cells; (2) determine the effects of hemorrhage on antibody response of pulmonary mucosal plasma cells; (3) assess possible hemorrhage-induced alteration in the regulation of antibody response by determining interactions of B cells with helper T cells, suppressor T cells, and the idiotype network following hemorrhage; (4) prepare synthetic and recombinant SCAF, anti-SCAF antibodies and anti-SCAF-receptor antibodies; (5) determine effects of parental administration of anti- SCAF or anti-SCAF-receptor antibodies on hemorrhage-induced depression of immune response; (6) assess possible protective effect of anti-SCAF or anti-SCAF-receptor antibodies against experimental pneumonia in the mouse; (7) ascertain mechanisms of action of SCAF at the cellular, subcellular and molecular levels by determining its effects on the generation and release of mediators, cytoplasmic enzyme activation, nuclear ornithine decarboxylase induction, and polyamine biosynthesis. 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 as well as permit the development of methodologies, such as the measurement of SCAF blood levels, for identifying patients with hemorrhagic, traumatic, or thermal injuries who are at particularly high risk of infections. Experimental validation of our hypotheses that post-hemorrhage immunodepression and propensity for developing infections can be prevented and/or reversed by parental administration of anti-SCAF or anti-SCAF-receptor antibodies should provide new approaches for clinical management of critically III trauma patients. Looking beyond the present proposal, the role(s) of SCAF in regulating normal immune response and in mediating immune depressions in aging, as well as its potential clinical usefulness in organ transplantation and in the treatment of auto-immune disease such as systemic lupus erythematosus (SLE) or type 1 diabetes mellitus are important areas for future investigation.