Enhancing Mucosal Cellular Imm Resp by Co-Delivery of Plasmid IL-15 w/DNA Vaccine

描述（由申请方提供）：HIV-1疫苗诱导CD 8细胞免疫应答非常重要。在粘膜部位存在诱导的免疫应答也是重要的。粘膜部位是HIV-1的进入途径，也是重要的病毒复制部位。因此，粘膜的细胞免疫应答对于保护和清除这些易感部位的病毒将是重要的。IL-15是参与CD 8效应细胞和记忆细胞的稳态增殖和维持的关键分子。在非人灵长类动物模型中，我们发现IL-15在体外抗原刺激时增强抗原特异性CD 8和CD 4淋巴细胞增殖。相关的是，我们还鉴定了IL-15引发粘膜免疫应答。最后也是最值得注意的是，我们在猕猴模型中发现，接受与质粒IL-15共递送的SHIV DNA疫苗的动物显著抑制了SHIV 89.6p病毒复制。我们推测IL-15可增加外周血CD 8淋巴细胞的潜在增殖能力。我们进一步假设，这种抗原特异性免疫应答反映在粘膜中。这项资助的目的是确定CD 8粘膜免疫应答的性质，并进一步描述IL-15与DNA疫苗共同递送诱导的外周应答。我们有四个具体目标来实现我们的目标。AIM 1和AIM 2将开发并随后应用定量RT-PCR系统来评价一组可以定义外周和粘膜抗原特异性CD 8淋巴细胞生物活性的基因。AIM 3将研究通过在有和没有质粒IL-15共递送的情况下接种诱导的外周和粘膜CD 8淋巴细胞的增殖能力。AIM 4将研究SIV攻毒后对照和接种动物的外周和粘膜细胞免疫应答。

DESCRIPTION (provided by applicant): It is important that an HIV-1 vaccine induce a CD8 cellular immune response. It is also central that an induced immune response be present at mucosal sites. The mucosal sites are entry routes for HIV-1 as well as a site of significant viral replication. Therefore, a cellular immune response at the mucosa will be important to protect and clear virus from these susceptible sites. IL-15 is a key molecule involved in the homeostatic proliferation and maintenance of CD8 effector and memory cells. In a non-human primate model we found IL-15 enhanced the antigen specific CD8 and CD4 lymphocyte proliferation upon in vitro antigen stimulation. Of relevance we also identified that IL-15 primed for a mucosal immune response. Finally and most notable we have found in the macaque model that the animals that received SHIV DNA vaccines co-delivered with plasmid IL-15 suppressed SHIV89.6p viral replication significantly. We hypothesize that the IL-15 increased the potential proliferative capacity of CD8 lymphocytes both in periphery. We further hypothesize that this antigen specific immune response is mirrored in the mucosa. The goals of this grant are to determine the nature of the CD8 mucosal immune response and further delineate the peripheral response that is induced by co-delivering IL-15 with a DNA vaccine. We have four specific aims to accomplish our goal. AIM1 and AIM 2 will develop and subsequently apply a quantitative RT-PCR system to evaluate a set of genes that can define the biological activity of peripheral and mucosal antigen specific CD8 lymphocytes. AIM3 will investigate the proliferative capacity of the peripheral and mucosal CD8 lymphocytes induced by vaccination with and without co-delivery of plasmid IL-15. AIM4 will investigate the peripheral and mucosal cellular immune responses in control and vaccinated animals following SIV challenge.