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 作为实现这一目标的一种方式。IL-2和IL-12是细胞因子， 或为此目的进行评估。然而，这些细胞因子的能力， 在HIV+患者中恢复细胞介导的免疫（CMI）仍然没有解决。因此，在本发明中， 需要探索其他方法来进一步提高免疫 在HIV+患者中进行重建。CD 40-CD 40配体（CD 40 L）是T细胞增殖的关键。 细胞-抗原呈递细胞（APC）相互作用。促进IL-12/IFN-γ 分泌，诱导APC活化并调节CD 8 + T细胞分化。 功能性CD 40 L的缺乏导致人类免疫缺陷，其特征在于 增加对机会性病原体感染的易感性。cd 40 l是 与艾滋病毒感染有关。CD 40 L诱导在来自人的CD 4 + T细胞上是有缺陷的。 艾滋病毒阳性患者。外源性CD 40 L对CMI抗HIV有显著影响， HIV+患者中的机会性病原体。CD 40 L保护CD 4 + T细胞免受HIV感染 感染，并能抑制HIV在树突状细胞中的复制。CD 40 L抑制 巨噬细胞中机会致病菌的生长。因此，CD 40 L的增强 信号传导是HIV+患者免疫治疗的有吸引力的候选者。在 具体目标1，我们将确定CD 40 L受损的机制， 条件致病菌在人巨噬细胞中的复制。我们将确定 如果CD 40 L也刺激来自HIV+的巨噬细胞的抗微生物活性， 患者我们将研究来自HIV+患者的T细胞是否有缺陷， 它们刺激巨噬细胞抗微生物活性的能力， CD 40 L可增强其活性。最后，我们将检查CD 40 L是否增强 CD 8 + T细胞抑制HIV复制的能力。在具体目标2中， 将确定外源性CD 40 L体内给药至T细胞缺陷型 小鼠增加了对机会致病菌的抵抗力。的机制 将阐明介导这种效应。这项工作将提供至关重要的 用于评价CD 40 L信号传导调节的信息 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.