GAMMA INTERFERON--MYCOBACTERIUM AVIUM INFECTION IN AIDS

获得性免疫缺陷综合征（艾滋病）患者已经发展成为 由艾滋病毒引起的传播性感染的数量前所未有， 属于鸟胞内分枝杆菌的条件致病菌 (MAI)复杂. 有效控制或根除这些兼性 细胞内生物似乎在很大程度上依赖于完整的细胞 免疫宿主反应包括抗原致敏的T淋巴细胞，它们 分泌产物（淋巴因子）和淋巴因子激活的组织 巨噬细胞 因此，这并不奇怪，（a）MAI感染经常 在T细胞缺陷型AIDS患者中发展，和（B）这些患者 通常对常规的多种药物治疗无效， 经历持续的高级别菌血症并广泛传播， 进行性感染直至死亡。 典型的尸检结果包括 炎症和肉芽肿反应差或不存在，内脏 巨噬细胞严重寄生MAI-大概反映了严重 淋巴因子分泌受损和组织巨噬细胞未活化。 我们最近证明γ干扰素（IFN-γ）似乎 是激活人类单核细胞衍生的 巨噬细胞发挥抗细胞内 病原体 此外，我们已经表明，来自艾滋病患者的T细胞， 机会性感染完全不能分泌IFN-γ， 用特异性微生物抗原刺激。 这些患者的 然而，单核细胞衍生的巨噬细胞完全能够响应， 体外重组人IFN-γ具有增强的抗微生物活性。 这项工作构成了本提案的基础，我们将在其中确定 IFN-γ在MAI免疫发病机制及治疗中的作用 艾滋病感染。 我们的目标是（1）确定所需的条件 体外激活人巨噬细胞杀死或抑制细胞内MAI 并确定IFN-γ在这种抗分枝杆菌活性中的作用，（2） 证实来自MAI的AIDS患者的T细胞不能分泌IFN-γ 响应分枝杆菌抗原的特异性刺激，（3） 建立播散性MAI感染的动物模型， IFN-γ在宿主细胞免疫应答中的作用 MAI和IFN-γ治疗的疗效，以及（4）确定 IFN-γ作为实验性替代免疫疗法治疗艾滋病疗效观察 感染MAI的患者。

Patients with the acquired immune deficiency syndrome (AIDS) have developed an unprecedented number of disseminated infections caused by the opportunistic pathogens belonging to the Mycobacterium avium-intracellulare (MAI) complex. Effective control or eradication of these facultative intracellular organisms appears to depend largely on an intact cellular immune host response comprised of antigen-sensitized T lymphocytes, their secretory products (lymphokines), and lymphokine-activated tissue macrophages. Thus, it is not surprising that (a) MAI infections frequently develop in T cell deficient AIDS patients, and (b) that these patients typically fail to respond to conventional multi-drug therapy and often experience persistent high-grade bacillemia and widely disseminated and progressive infection until death. Characteristic autopsy findings include poor or absent inflammatory and granulomatous responses and visceral macrophages heavily parasitized with MAI--presumably reflecting grossly impaired lymphokine secretion and non-activated tissue macrophages. We have recently demonstrated that gamma interferon (IFN-Gamma) appears to be the key T cell lymphokine which activates the human monocyte-derived macrophage to exert antimicrobial activity against intracellular pathogens. In addition, we have shown that T cells from AIDs patients with opportunistic infections fail totally to secrete IFN-Gamma in response to stimulation with specific microbial antigen. These patients' monocyte-derived macrophages, however, are fully capable of responding in vitro to recombinant human IFN-Gamma with enhanced antimicrobial activity. This work forms the basis of this proposal in which we will determine the role and effect of IFN-Gamma in the immunopathogenesis and therapy of MAI infections in AIDS. Our aims are to (1) determine the conditions required to activate human macrophages to kill or inhibit intracellular MAI in vitro and define the role of IFN-Gamma in this antimycobacterial activity, (2) confirm that T cells from AIDs patients with MAI fail to secrete IFN-Gamma in response to specific stimulation with mycobacterial antigens, (3) develop an animal model of disseminated MAI infection with which to define in vivo both the role of IFN-Gamma in the host cellular immune response to MAI and the efficacy of treatment with IFN-Gamma, and (4) determine the effect of IFN-gamma as experimental replacement immunotherapy for AIDS patients with MAI infetions.