GAMMA INTERFERON--MYCOBACTERIUM AVIUM INFECTION IN AIDS

患有获得性免疫缺陷综合征(AIDS)的患者 史无前例数量的播散性感染由 禽内分枝杆菌条件致病菌 (麦)情结。有效地控制或根除这些兼性因素 细胞内的生物似乎在很大程度上依赖于一个完整的细胞 由抗原致敏的T淋巴细胞组成的免疫宿主反应，其 分泌产物(淋巴因子)和淋巴因子激活的组织 巨噬细胞。因此，不足为奇的是(A)MAI感染频繁 在T细胞缺陷的艾滋病患者中发生，以及(B)这些患者 通常对传统的多种药物治疗无效，而且经常 经历持续的高级别杆菌血症并广泛传播和 渐进性感染直到死亡。典型的尸检结果包括 炎症和肉芽肿性反应和内脏反应差或缺失 被MAI大量寄生的巨噬细胞--推测是大体反射 淋巴因子分泌受损和非激活的组织巨噬细胞。 我们最近证明了伽玛干扰素(干扰素-伽马)似乎 是激活人类单核细胞来源的关键T细胞淋巴因子 巨噬细胞对细胞内的抗菌活性 病原体。此外，我们还表明，来自艾滋病患者的T细胞 机会性感染完全无法分泌干扰素-γ 用特定的微生物抗原刺激。这些病人的 然而，单核细胞来源的巨噬细胞完全有能力在 体外重组人干扰素-γ具有增强的抗菌活性。 这项工作构成了这项提案的基础，我们将在该提案中确定 干扰素-γ在急性心肌梗死免疫发病机制和治疗中的作用 艾滋病的感染。我们的目标是(1)确定所需的条件 激活人巨噬细胞体外杀伤或抑制细胞内MAI 并确定了干扰素-γ在这种抗分枝杆菌活性中的作用，(2) 艾滋病合并急性心肌梗死患者T细胞不能分泌干扰素-γ 对分枝杆菌抗原的特定刺激作出反应，(3) 建立传播性MAI感染的动物模型，以确定 体内干扰素-γ在宿主细胞免疫应答中的作用 MAI和干扰素-γ治疗的疗效，以及(4)测定 干扰素-γ作为实验性替代免疫疗法治疗艾滋病的效果 有MAI感染的患者。

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.