CD40 Ligand: Therapy for Opportunistic Pathogens and HIV

描述(由申请人提供)：不确定抗逆转录病毒药物是否 完全恢复HIV+患者的免疫能力。免疫疗法一直是 提出作为实现这一目标的一种方式。IL-2和IL-12是正在使用的细胞因子 或为此目的进行评估。然而，这些细胞因子的能力 在HIV+患者中恢复细胞免疫(CMI)仍未解决。因此， 有必要探索其他方法来进一步提高免疫力 HIV阳性患者的重建。CD40-CD40配体(CD40L)在T细胞中起着至关重要的作用 细胞-抗原提呈细胞(APC)相互作用。它能促进IL-12/干扰素-γ 分泌，诱导APC激活，调节CD8+T细胞分化。 功能性CD40L缺失会导致人类免疫缺陷，其特征是 对机会性病原体感染的易感性增加。CD40L是 与艾滋病毒感染有关。CD40L对CD_4~+T细胞的诱导存在缺陷 HIV阳性患者。外源性CD40L对抗HIV和CMI有深远影响 HIV阳性患者的机会性病原体。CD40L保护CD4+T细胞免受HIV感染 感染并能抑制树突状细胞中的艾滋病毒复制。CD40L抑制 巨噬细胞中条件致病菌的生长。因此，CD40L的增强 信号转导是HIV+患者免疫治疗的一个有吸引力的候选方案。在……里面 具体目标1，我们将确定CD40L损伤的机制 条件致病菌在人巨噬细胞中的复制。我们将决定 如果CD40L也刺激HIV+巨噬细胞的抗微生物活性 病人。我们将调查HIV+患者的T细胞是否存在缺陷 它们刺激巨噬细胞抗微生物活性的能力，如果这 CD40L可增强其活性。最后，我们将研究CD40L是否增强了 CD8+T细胞抑制HIV复制的能力。在具体目标2中，我们 将确定体内注射外源性CD40L是否对T细胞缺陷 老鼠增加了对机会性病原体的抵抗力。这些机制可以 调节这一效应的机制将被阐明。这项工作将提供至关重要的 评估CD40L信号调制的信息作为一种方法 针对HIV+患者的免疫治疗。

DESCRIPTION (Provided by the applicant): It is uncertain if anti-retrovirals fully restore immune competence in HIV+ patients. Immunotherapy has been proposed as a way to achieve this goal. IL-2 and IL-12 are cytokines being used or evaluated for this purpose. However, the ability of these cytokines to restore cell mediated immunity (CMI) in HIV+ patients remains unsettled. Thus, there is a need to explore additional approaches to further improve immune reconstitution in HIV+ patients. CD40-CD40 ligand (CD40L) is crucial for T cell-antigen presenting cell (APC) interaction. It promotes IL-12/IFN-gamma secretion, induces APC activation and regulates CD8+ T cell differentiation. Absence of functional CD40L causes immunodeficiency in humans characterized by increased susceptibility to infections with opportunistic pathogens. CD40L is relevant to HIV infection. CD40L induction is defective on CD4+ T cells from HIV+ patients. Exogenous CD40L has profound effects on CMI against HIV and opportunistic pathogens in HIV+ patients. CD40L protects CD4+ T cells from HIV infection and can inhibit HIV replication in dendritic cells. CD40L inhibits growth of opportunistic pathogens in macrophages. Thus, enhancement of CD40L signaling is an attractive candidate for immunotherapy in HIV+ patients. In Specific Aim 1, we will identify the mechanisms by which CD40L impairs replication of opportunistic pathogens in human macrophages. We will determine if CD40L also stimulates anti-microbial activity of macrophages from HIV+ patients. We will investigate if T cells from HIV+ patients are defective in their capacity to stimulate macrophage anti-microbial activity and if this activity can be enhanced by CD40L. Finally, we will examine if CD40L enhances the capacity of CD8+ T cells to inhibit HIV replication. In Specific Aim 2, we will ascertain if in vivo administration of exogenous CD40L to T cell-deficient mice increases resistance to an opportunistic pathogen. The mechanisms that mediate this effect will be elucidated. This work will provide crucial information for the evaluation of modulation of CD40L signaling as an approach to immunotherapy in HIV+ individuals.