New HIV/AIDS vaccines employing inflammatory dendritic cells

描述（由申请人提供）：我们开发了一种创新的方法来解决艾滋病毒/艾滋病疫苗问题。科学家们一直致力于将疫苗与佐剂一起靶向体内树突状细胞（DCs）。然而，目前的策略具有显著的潜在局限性：疫苗仅靶向处于稳定状态的经典DC（cDC）。我们假设，炎症性树突状细胞，动员大量和迅速感染期间，是重要的，不仅在先天性防御，但在呈递抗原的适应性免疫对入侵的病原体，包括艾滋病毒。随着几种单克隆抗体的开发，我们发现了一种新的表达小鼠CD 209 a或DC-SIGN C型凝集素受体的炎性单核细胞衍生的DC（MoDC）亚群。这些炎性DC在脂多糖（LPS）以TLR 4依赖性方式处理后以及在注射含LPS的细菌后12小时内在淋巴结中积累。新的炎性MoDC与cDC一样有效或更有效，甚至对于抗原的交叉呈递。在此，我们提出利用炎性MoDC来改进HIV疫苗，在小鼠中的R21可行性研究中具有两个特定目标：（1）确定炎性MoDC在体内呈递模型卵清蛋白蛋白的最佳条件;（2）通过用选择的佐剂将HIV Gag p24和Env gp 120靶向CD 209 a+炎性MoDC，开发具有改善的免疫力的炎性MoDC靶向HIV疫苗路线（S）在完成R21里程碑后，我们建议，对于R33阶段，（3）比较然后联合收割机新的靶向MoDC和当前靶向cDC的HIV疫苗，用于开发临床策略以最大化DC在抗HIV体液和T细胞免疫中的作用;（4）使用抗HIV抗体制备靶向人/猴MoDC的HIV疫苗，人CD 209 mAb，并评价它们在人CD 209小鼠中引发组合的B和T细胞免疫的能力;（5）确定CD 209 a+的生物学特性炎症和微生物感染期间粘膜组织中的MoDC，用于开发粘膜靶向疫苗策略。这种利用炎性MoDC的新疫苗方法可能有效地保护免受广谱感染因子的侵害。 公共卫生相关性：该提案将首次研究炎症树突细胞，作为HIV疫苗开发的重点。炎性树突状细胞是重要的免疫调节细胞，在感染过程中特异性动员。成功利用炎性树突状细胞也会影响开发针对其他感染和癌症的疫苗。

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.