New HIV/AIDS vaccines employing inflammatory dendritic cells

描述(由申请人提供)：我们已经开发出一种创新的方法来解决艾滋病毒/艾滋病疫苗问题。科学家们一直在努力在体内靶向带有树突状细胞(DC)佐剂的疫苗。然而，目前的策略有一个显著的潜在限制：疫苗只针对处于稳定状态的经典DC(CDC)。我们假设，炎性DC在感染过程中大量并迅速动员，不仅在天然防御中很重要，而且在呈递抗原以对抗包括HIV在内的入侵病原体的适应性免疫中也是重要的。随着几种单抗的发展，我们发现了一种新的表达小鼠CD209a或DC-SIGN C型凝集素受体的炎性单核细胞来源的DC(MoDC)亚群。这些炎性树突状细胞在TLR4依赖的脂多糖(LPS)治疗后12小时内积聚在淋巴结中，也在注射含有LPS的细菌时积聚。新的炎症性MODC与CDDC一样有效或更有效，甚至在抗原的交叉提呈方面也是如此。在此，我们建议利用炎症性MoDC来改进HIV疫苗，在R21的可行性研究中有两个具体目标：(1)确定炎症性MoDC在体内呈递模型卵清蛋白的最佳条件；(2)通过靶向HIV Gag p24和Env gp120到CD209a炎症性MoDC的选择性佐剂(S)和路线(S)，开发针对HIV Gag p24和Env gp120的炎症性MoDC以提高免疫力。在完成R21里程碑后，我们建议在R33阶段，(3)比较并结合新的MoDC靶向和当前CDC靶向的HIV疫苗，以制定临床策略，最大限度地提高DC在抗HIV体液和T细胞免疫中的作用；(4)使用抗人CD209单抗制备人/猴子MoDC靶向HIV疫苗，并评估其在人CD209小鼠中诱导联合B和T细胞免疫的能力；以及(5)确定炎症和微生物感染期间粘膜组织中CD209a MoDC的生物学，以制定黏膜靶向疫苗策略。这种利用炎症性MoDC的新疫苗方法可能在预防广谱感染性病原体方面有效。 与公共卫生相关：这项提案将首次研究炎性树突状细胞，作为艾滋病毒疫苗开发的重点。炎性树突状细胞是重要的免疫调节细胞，在感染过程中被特异性动员。成功地利用炎性树突状细胞也对开发针对其他感染和癌症的疫苗产生了影响。

DESCRIPTION (provided by applicant): We have developed an innovative approach to the HIV/AIDS vaccine problem. Scientists have been working to target vaccines with adjuvant to dendritic cells (DCs) in vivo. Current strategies, however, have a significant potential limitation: vaccines are targeted only to classical DCs (cDCs) in the steady state. We hypothesize that inflammatory DCs, mobilized in large numbers and rapidly during infection, are important not only in innate defenses but in presenting antigens for adaptive immunity against invading pathogens including HIV. With the development of several monoclonal antibodies, we discovered a new subset of inflammatory monocyte-derived DCs (MoDCs) expressing mouse CD209a or DC-SIGN C-type lectin receptor. These inflammatory DCs accumulate in lymph nodes in 12 hrs upon lipopolysaccharide (LPS) treatment in a TLR4 dependent fashion, and also upon injection of LPS-containing bacteria. The novel inflammatory MoDCs are as effective or more effective than cDCs, even for cross presentation of antigens. Here we propose to harness inflammatory MoDCs to improve HIV vaccines with two specific aims in an R21 feasibility study in mice: (1) to identify optimal conditions for presentation of a model ovalbumin protein by inflammatory MoDCs in vivo; (2) to develop inflammatory MoDC-targeted HIV vaccines with improved immunity by targeting HIV Gag p24 and Env gp120 to CD209a+ inflammatory MoDCs with selected adjuvant(s) and route(s). Upon completing the R21 milestones, we propose, for the R33 phase, (3) to compare and then combine new MoDC-targeted and current cDC-targeted HIV vaccines for the development of a clinical strategy to maximize DCs in anti-HIV humoral and T cell immunity; (4) to prepare human/monkey MoDC-targeted HIV vaccines using the anti-human CD209 mAbs and evaluate their capacity to elicit combined B and T cell immunity in human CD209 mice; and (5) to determine the biology of CD209a+ MoDCs in mucosal tissues during inflammation and microbial infections for the development of a mucosal targeted vaccine strategy. This new vaccine approach to exploit inflammatory MoDCs might be effective in protection against broad spectrum of infectious agents. PUBLIC HEALTH RELEVANCE: This proposal will, for the first time, investigate inflammatory dendritic cells, as a focus for HIV vaccine development. Inflammatory dendritic cells are important immune regulating cells that are mobilized specifically during infection. Successful harnessing of inflammatory dendritic cells also impacts on developing vaccines against other infections and cancer.