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

描述（由申请人提供）：HIV-1疫苗诱导CD8细胞免疫应答是很重要的。诱导免疫反应存在于粘膜部位也是很重要的。粘膜部位是HIV-1的进入途径，也是病毒复制的重要部位。因此，粘膜细胞免疫反应对于保护和清除这些易感部位的病毒非常重要。IL-15是参与CD8效应细胞和记忆细胞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在体外抗原刺激下增强了抗原特异性CD8和CD4淋巴细胞的增殖。与此相关的是，我们还发现IL-15引发了粘膜免疫反应。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共同递送的SHIV DNA疫苗的动物显著抑制了SHIV89.6p病毒的复制。我们假设IL-15增加了外周CD8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反应反映在粘膜中。这项拨款的目的是确定CD8粘膜免疫反应的性质，并进一步描绘由IL-15和DNA疫苗共同递送诱导的外周反应。我们有四个具体目标来实现我们的目标。AIM1和AIM 2将开发并随后应用定量RT-PCR系统来评估一组可以定义外周和粘膜抗原特异性CD8淋巴细胞生物活性的基因。AIM3将研究接种和不接种质粒IL-15诱导的外周和粘膜CD8淋巴细胞的增殖能力。AIM4将研究对照组和接种疫苗的动物在SIV攻击后的外周和粘膜细胞免疫反应。

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.