INTERLEUKIN-12 AND AIDS PATHOGENESIS

体液和细胞之间存在着相互作用的关系 豁免权。对感染性病原体的反应涉及一个复杂的 不同细胞之间的相互作用，通常受其功能的调节 通过细胞因子网络。细胞因子在肿瘤发生、发展中的关键作用 免疫反应的调节及其多发性和多发性 重叠效应表明，产量不足或异常可能 导致临床免疫缺陷。各种深奥的免疫学 已经描述了艾滋病毒感染者的异常情况，包括 不仅是ARC或艾滋病患者，而且是无症状的受试者。这个 这一提议的中心假设是白介素12(IL-12)，一种 新的细胞因子具有强大的多态活性，发挥着重要的作用 免疫调节作用在恢复HIV抑制的免疫功能中的作用 被感染的人。HIV感染者IL-12缺乏症可能 在一定程度上导致了细胞免疫功能低下，即高IgE 综合征、多克隆B细胞活化及其可能的优势 辅助性T细胞2型(Th2)样反应。新开发的方法 检测IL-12将用来确定造血细胞的能力 来自HIV感染者的细胞产生IL-12以及其他 细胞因子，跟随不同的刺激。不同细胞株的体外培养能力 艾滋病毒毒株、病毒突变体以及细胞产品将被 在原代单核细胞和THP-1细胞中进行比较，以分析 IL-12产生减少的分子机制。T细胞 克隆将在对照捐赠者、高危个人和 HIV感染者在存在IL-12或IL-12拮抗剂的情况下，以及 我们将研究IL-12是否有利于Th1样细胞的分化 并将影响HIV中细胞因子的产生模式- 被感染的人。我们将分析IL-12恢复的能力 HIV感染者的免疫功能。我们将研究它的 在感染细胞系中调节HIV表达的作用，以及HIV- 被感染的原代细胞，我们将把这种影响与其他 已知的细胞因子可以上调感染细胞中艾滋病毒的表达。这个 这些研究的结果将提供有关以下方面的新信息： 这种新的细胞因子在艾滋病的发病机制中将大有作为 在确定其潜在的治疗作用方面。

A reciprocal relationship exists between humoral and cell mediated immunity. The response to infectious agents involves a complex interaction between different cells, often regulated in their functions by a network of cytokines. The critical roles of cytokines in the regulation of the immune response and their multiple and often overlapping effects suggest that deficient or abnormal production may results in clinical immunodeficiency. A variety of profound immunological abnormalities have been described in HIV-infected individuals, including not only patients with ARC or AIDS, but also asymptomatic subjects. The central hypothesis of this proposal is that Interleukin-12 (IL-12), a novel cytokine with potent and pleomorphic activities, play an important immunomodulatory role in restoring depressed immune functions in HIV- infected individuals. IL-12 deficiency in HIV-infected individuals may be in part responsible for the deficient cellular immunity, hyper-IgE syndrome, polyclonal B-cell activation and the possible predominance of T helper type 2 (Th2) like responses. Newly developed methods for detecting IL-12 will be used to determine the ability of hematopoietic cells from HIV-infected individuals to produce IL-12 as well as other cytokines, following different stimuli. The in-vitro ability of different HIV strains, viral mutants, as well as cellular products, will be compared in primary monocytes and THP-1 cells, in order to analyze the molecular mechanisms involved in the reduced IL-12 production. T cell clones will be generated in control donors, high risk individuals and HIV-infected patients in the presence of IL-12 or IL-12 antagonists, and we will examine whether IL-12 will favor the differentiation of Th1 like responses, and will affect the pattern of cytokine production in HIV- infected individuals. We will analyze the ability of IL-12 to restore immunological functions in HIV-infected individuals. We will examine its role in the modulation of HIV expression in infected cell lines, and HIV- infected primary cells, and we will compare this effect to that of other cytokines known to up regulate HIV expression in infected cells. The results of these studies will provide new informations about the role of this novel cytokine in the pathogenesis of AIDS, and will be of great use in defining its potential therapeutic role.