ROLE & EFFECT OF GAMMA INTERFERON IN THE AIDS SYNDROME

我们已经报道了免疫(伽马)干扰素(干扰素-伽马)似乎是 诱导人类单核细胞来源的关键T细胞淋巴因子 巨噬细胞对多种细菌表现出增强的抗菌活性 包括弓形虫在内的一组细胞内病原体。我们还有 最近证实，艾滋病患者的单个核细胞 机会性感染(01)(如弓形虫病)，其1 年死亡率超过95%，均未产生干扰素-γ 临床上对先前遇到的体外刺激的反应 相关微生物抗原。这些艾滋病患者的巨噬细胞， 然而，能够对有效的抗菌剂做出正常反应 活性一旦被天然或重组(R)人适当刺激 干扰素-伽玛。基于这些结果，我们提出了两个基本的解决方案 关于日本血吸虫细胞免疫应答缺陷的几个问题 艾滋病患者：(1)干扰素-γ患者T细胞分泌受损 这一缺陷的风险准确预测了01的未来发展？和 (2)对于既往曾监测过01的艾滋病患者，可采取预防措施 使用rIFN-Gamma免疫治疗可以预防随后的01并提高存活率？ 我们的具体目标是：(1)检测人干扰素-γ的产生能力 尚未感染01的高危患者，(2)在 人干扰素-γ体外分泌受损的前瞻性纵向研究 这些患者是艾滋病相关细胞免疫的准确标志物。 倾向于01的缺陷，(3)决定细胞或 干扰素-γ产生缺陷的分子机制(S) 为了研究在01年前逆转这些机制的方法，在 高危患者，并通过(4)确定疗效来检验这些假设 艾滋病患者间歇免疫预防干扰素-γ治疗的研究 之前有01--一组死亡率大于95%的患者 在12个月内，从另一个01。因此，通过利用临床、基础、 实验室和治疗研究，这个项目将详细关注 干扰素-γ在艾滋病相关细胞免疫缺陷中的作用和作用

We have reported that immune (gamma) interferon (IFN-Gamma) appears to be the key T cell lymphokine required to induce the human monocyte-derived macrophage to display enhanced antimicrobial activity against a diverse group of intracellular pathogens including Toxoplasma gondii. We have also recently demonostrated that mononuclear cells from AIDS patients with opportunistic infections (01) (such as toxoplasmosis), patients whose 1 year mortality rate exceeds 95%, uniformly fail to generate IFN-Gamma in response to in vitro stimulation with previously-encountered, clinically relevant microbial antigens. Macrophages from these AIDS patients, however, are capable of responding normally with effective antimicrobial activity once appropriately stimulated with native or recombinant (r) human IFN-Gamma. Based on these results, we proposed to address two basic questions concerning the defect in the cell-mediated immune responses of AIDS patients: (1) Does impaired T cell secretion of IFN-Gamma patients at risk for this defect accurately predict the future development of 01? And (2) for AIDS patients who have survised a previous 01, can prophylactic immunotherapy with rIFN-Gamma prevent subsequent 01 and enhance survival? Our specific aims are to (1) examine the IFN-Gamma generating capacity of at-risk patients who have not yet acquired an 01, (2) determine in a prospective longitudinal study if impaired in vitro IFN-Gamma secretion by these patients is an accurate marker for the AIDS-related cellular immune defect which predisposes to 01, (3) determine the nature of the cellular or molecular mechanisms(s) responsible for deficient IFN-Gamma production in order to examine methods to reverse these mechanisms before 01 develop in at-risk patients, and test these hypotheses by (4) determining the efficacy of intermittent immunoprophylactic IFN-Gamma treatment in AIDS patients with a previous 01 -- a group of patients with a Greater than 95% mortality within 12 months from another 01. Thus, by utilizing clinical, basic laboratory, and therapeutic studies, this project will focus in detail on the role and effect of IFN-Gamma in the AIDS-related cellular immune defect.