ROLE & EFFECT OF GAMMA INTERFERON IN THE AIDS SYNDROME

我们已经报道，免疫（γ）干扰素（IFN-γ）似乎是 诱导人类单核细胞源性 巨噬细胞显示增强的抗多种 包括刚地弓形虫在内的一组细胞内病原体。 我们还 最近证明，来自艾滋病患者的单核细胞， 机会性感染（01）（如弓形虫病），1 年死亡率超过95%，均匀不能产生IFN-γ， 对先前临床上遇到的体外刺激的反应 相关微生物抗原。 从这些艾滋病患者体内提取的巨噬细胞， 然而，能够对有效抗菌剂正常应答 活性，一旦用天然或重组（r）人 IFN-γ。 基于这些结果，我们提出解决两个基本问题， 关于细胞介导的免疫应答缺陷的问题 艾滋病患者：（1）IFN-γ患者的T细胞分泌受损， 风险这一缺陷准确预测未来的发展01？和 (2)对于艾滋病患者谁生存的前01，可以预防 用rIFN-γ免疫疗法预防随后的O 1并提高存活率？ 我们的具体目标是（1）检查IFN-γ产生能力， 尚未获得01的高危患者，（2）确定 前瞻性纵向研究，如果体外IFN-γ分泌受损， 这些患者是艾滋病相关细胞免疫的准确标志物， 缺陷易患01，（3）确定细胞的性质或 导致IFN-γ产生不足的分子机制 为了研究在01年开发之前逆转这些机制的方法， 风险患者，并通过（4）确定疗效来检验这些假设 间歇性免疫预防性IFN-γ治疗艾滋病患者 01年死亡率超过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，该项目将详细关注 IFN-γ在艾滋病相关细胞免疫缺陷中的作用及影响。

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.