DEVELOPMENT OF A JANUS KINASE 3 (JAK3) INHIBITOR FOR USE IN RHESUS MACAQUES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们以前的数据将CD4+中央记忆T细胞和维持这一群体的动态平衡并调节其分化为组织归巢效应记忆的机制置于艾滋病发病机制的中心。在啮齿动物模型中，记忆T细胞稳态的主要调节因子是常见的伽马链细胞因子IL-7和IL-15，我们和其他人已经证明这些细胞因子在非人类灵长类动物中具有类似的活性。这些细胞因子在SIV感染相关的上述CD4+记忆产生反应中的作用尚不清楚。这很可能是这两种细胞因子中的一种或两种在这一关键反应中发挥重要作用，从而对抗免疫缺陷的发展。另一方面，这些促增殖的细胞因子也可能通过诱导产生病毒复制的靶(底物)细胞来支持或增加SIV的致病性。了解常见的伽马链细胞因子IL-7和IL-15在SIV感染期间维持和调节T细胞群中的作用，对于更好地了解SIV感染的致病机制和利用这一调节轴获得治疗益处的潜力是必要的。IL-7和IL-15受体共享一个共同的伽马链(因此而得名“共同的伽马链细胞因子家族”)，并使用Janus Kinase 3(JAK3)作为该共同伽马链下游的细胞内信号介质。对JAK3的药物抑制将同时抑制IL-7和IL-15的活性(以及其他常见的伽玛链细胞因子，如IL-2、IL-4和IL-21，这些细胞因子具有更特殊的功能)，并使我们能够全面评估这些细胞因子在艾滋病发病机制中的整体作用。本项目的目的是评估JAK3抑制剂JANEX-1作为体内抑制猕猴IL-7和IL-15活性的工具的潜力，并为评估常见的伽马链细胞因子家族在SIV发病机制中的作用提供初步数据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our previous data place CD4+ central memory T cells and the mechanisms that maintain the homeostasis of this population and regulate its differentiation into tissue homing effector memory at the center of AIDS pathogenesis. In rodent models, the major regulators of memory T cell homeostasis are the common gamma chain cytokines IL-7 and IL-15, and we and others have demonstrated that these cytokines have analogous activities in non-human primates. The role of these cytokines in the SIV infection-associated CD4+ memory production response described above is unknown. It is very likely that either or both of these cytokines play a major part in this crucial response, and therefore counter the development of immunodeficiency. On the other hand, it is also possible that these pro-proliferative cytokines support or increase SIV pathogenicity by their ability to induce production of target (substrate) cells for viral replication. Understanding the role of common gamma chain cytokines IL-7 and IL-15 in maintaining and regulating T-cell populations during SIV infection will be necessary to better understand both pathogenic mechanisms and the potential for exploiting this regulatory axis for therapeutic benefit. IL-7 and IL-15 receptors share a common gamma chain (hence, the name "common gamma chain cytokine family"), and the use of Janus Kinase 3 (JAK3) as an intracellular signaling mediator downstream of this common gamma chain. Pharmacologic inhibition of JAK3 would inhibit the activities of both IL-7 and IL-15 (as well as other common gamma chain cytokines such as IL-2, IL-4 and IL-21, which have more specialized functions), and allow us to globally assess the overall role of these cytokines in AIDS pathogenesis. The goal of this project is to assess the potential of the JAK3 inhibitor JANEX-1 as a tool for in vivo inhibition of IL-7 and IL-15 activity in rhesus macaques, and to provide preliminary data demonstrating the utility of this reagent for assessment of the role of the common gamma chain cytokine family in SIV pathogenesis.