ROLE & EFFECT OF GAMMA INTERFERON IN THE AIDS SYNDROME

此应用程序的长期目标是定义角色 以及可溶性T细胞产物γ干扰素（IFN-γ）的作用。 γ），在艾滋病免疫缺陷，易患艾滋病 致命性机会性感染的患者（01）。 我们的研究 表明IFN-γ是一种关键的T4+细胞衍生的 在抗原刺激细胞的过程中产生的淋巴因子- 介导的免疫反应，这是成功的关键 单核细胞吞噬细胞的激活， 抗菌活性 此外，我们已经确定，T4+ 来自艾滋病患者的01细胞不能分泌抗原诱导的 IFN-γ，一种使他们容易受到 来控制机会致病菌 与此同时，我们还 然而，研究表明，艾滋病外周血单核细胞， 单核细胞源性巨噬细胞和组织（肺泡）巨噬细胞 在体外对外源性IFN-γ的激活完全应答， 在最近的一项体内试验中，显示艾滋病单核细胞 静脉注射重组（r）IFN-γ， 活化和增强的抗菌能力。 在一个持续的 艾滋病高危人群纵向前瞻性研究 这是在我们完善的免疫系统中进行的 缺陷研究单位（IDRU），我们还报告说， 分泌抗原刺激的IFN-γ的能力是一种准确的 预测进展为艾滋病和发展为01的风险。 在本申请的更新中，我们建议将我们的工作 使用两个基本的具体目标：（1）继续和扩大我们的IDRU 风险患者的纵向研究，和（2）确定两个 对照试验，如果免疫治疗的联合方案 IFN-γ联合抗病毒治疗（AZT）优于AZT单药治疗（上级） 在艾滋病患者的治疗中有着优先01. 虽然AZT （叠氮胸苷）似乎是目前的抗艾滋病毒剂， 并显著降低了艾滋病的短期死亡率， 30%接受AZT治疗的患者仍有新的或 01例复发，25-40%发生重度（3级） 血液学毒性 因此，我们设计了我们的试验， 确定在AZT的基础上加入rIFN-γ治疗是否能 协同作用，以（1）显著减少新的 或复发01和（2）允许减少AZT剂量， 毒性，同时保持临床疗效。 的预测 到1991年，该国将有30万艾滋病病例， 已知的死亡率和发病率，将伴随01在这些 患者清楚地合理化了新的和 必要的实验性治疗方法。

The long-term objective of this application is to define the role and effect of the soluble T cell product, gamma interferon (IFN- gamma), in the AIDS immune defect which predisposes AIDS patients to fatal opportunistic infections (01). Our studies have demonstrated that IFN-gamma is a key T4+ cell-derived lymphokine generated during the antigen-stimulated cell- mediated immune response which is critical for successful activation of mononclear phagocytes to exert enhanced antimicrobial activity. In addition, we have established that T4+ cells from AIDS patients with 01 fail to secrete antigen-induced IFN-gamma, a state which renders them vulnerable to and unable to control opportunistic pathogens. In parallel, we have also demonstrated, however, that the AIDS peripheral blood monocyte, monocyte-derived macrophage, and tissue (alveolar) macrophage is fully responsive to activation by exogenous IFN-gamma in vitro, and in a recent in vivo trial, showed that AIDS monocytes respond to intravenous recombinant (r) IFN-gamma with clear evidence of activation and enhanced antimicrobial capacity. In an on-going longitudinal prospective study of patients at high risk for AIDS which is being conducted in our well-established Immune Deficiency Research Unit (IDRU), we have also reported that the capacity to secrete antigen-stimulated IFN-gamma is an accurate predictor of the risk of progressing to AIDS and developing an 01. In the renewal of this application, we propose to extend our work using two basic specific aims: (1) continue and expand our IDRU longitudinal study of at-risk patients, and (2) determine in two controlled trials, if a combination regimen of immunotherapy (IFN-gamma) plus antiviral therapy (AZT) is superior to AZT alone in the treatment of AIDS patients with a prior 01. Although AZT (azidothymidine) appears to be the current anti-HIV agent of choice and has strikingly reduced short-term mortality in AIDS, 30% of AZT-treated patients were still subject to new or recurrent 01 and 25-40% experienced severe (grade 3) hematologic toxicity. Thus, we have designed our trials to determine if the addition of rIFN-gamma therapy to AZT can act synergistically to (1) significantly decrease the occurrence of new or recurrent 01 and (2) permit a reduction in AZT dose to diminish toxicity while preserving clinical efficacy. The prediction that there will be 300,000 cases of AIDS by 1991 in the country and the known mortality and morbidity which will accompany 01 in these patients clearly rationalize the critical need for new and necessarily experimental therapeutic approaches.