New HIV/AIDS vaccines employing inflammatory dendritic cells

描述（由申请人提供）：我们对艾滋病毒/艾滋病疫苗问题制定了一项创新办法。科学家们一直致力于用佐剂靶向树突状细胞（dc）的疫苗。然而，目前的策略具有重大的潜在局限性：疫苗仅针对稳定状态下的经典dc （cdc）。我们假设炎症性dc在感染过程中大量快速动员，不仅在先天防御中很重要，而且在针对包括HIV在内的入侵病原体的适应性免疫呈递抗原方面也很重要。随着几种单克隆抗体的发展，我们发现了一种表达小鼠CD209a或DC-SIGN c型凝集素受体的炎性单核细胞源性dc （MoDCs）的新亚群。在TLR4依赖的脂多糖（LPS）处理和注射含脂多糖的细菌后，这些炎症性dc在12小时内积聚在淋巴结中。新型炎性modc与cdc一样有效或更有效，即使抗原交叉呈递也是如此。在一项R21小鼠可行性研究中，我们提出利用炎性MoDCs来改善HIV疫苗，有两个特定的目的：(1)确定炎症MoDCs在体内呈递模型卵白蛋白的最佳条件；(2)通过选择佐剂和途径，将HIV Gag p24和Env gp120靶向CD209a+炎症性modc，开发免疫能力提高的炎症性modc靶向HIV疫苗。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靶向和当前的cdc靶向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)利用抗人CD209单克隆抗体制备人/猴modc靶向HIV疫苗，并评价其在人CD209小鼠中引发B细胞和T细胞联合免疫的能力；(5)确定炎症和微生物感染期间粘膜组织中CD209a+ MoDCs的生物学特性，以开发粘膜靶向疫苗策略。这种利用炎性MoDCs的新疫苗方法可能有效地预防广谱感染因子。

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.