CD4-Independent Vaccinations for Pulmonary Infections

肺部感染的 CD4 独立疫苗

• 批准号: 6781597
• 负责人: JAY K KOLLS
• 金额: $ 33.59万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781597
• 关键词: CD40 molecule; HIV infections; Pneumocystis carinii; Pneumocystis pneumonia; bacterial pneumonia; cellular immunity; clinical research; dendritic cells; genetically modified animals; helper T lymphocyte; immune response; interleukin 12; interleukin 4; laboratory mouse; leukocyte activation /transformation; respiratory infections; tuberculosis; vector vaccine

Pneumocystis carinii (PC) pneumonia and other infections such as TB and bacterial pneumonia remains a serious complication of HIV infection and other immunocompromised states. There is a well-known inverse relationship between CD4+ lymphocyte count and the risk of both PC infection and bacterial pneumonia but deficiency of CD4+ T cells does not hold all of the answers to mechanisms of host defense against these infections. Therefore, we have been seeking to better understand how CD4+ T cell independent (CD4IND) host defense mechanisms might defend against AIDS-related infections. Specifically we have recently shown that bone-marrow derived dendritic cells (DCs), can be genetically engineered to express CD40L (using an E1-deleted adenovirus, AdCD4OL), resulting in significant DC activation and maturation. These activated mature DCs, when pulsed with PC or bacterial antigens, and injected into mice, produce protective antigen specific IgG that is independent of CD4+ T cells. In the context of PC, this strategy was protective both in primary vaccinated CD4+ T cell deficient mice and in CD4+ T cell deficient mice receiving adoptive transfer of immune serum or immune CD4-depleted splenocytes, suggesting that B celts are critical for protection against PC after DC vaccination. However, this strategy suffers from issues of scalability and cost of producing patient-specific DC's. Thus to make this approach applicable to the global population of AIDS patients, we propose that in vivo DC modification needs to be developed. Preliminary data from our laboratory shows that co-injection of CD40L with a model antigen ovalbumin (OVA) permits in vivo DC transduction, and the generation of CD4IND antigen-specific immune responses.These results lead us to hypothesize that DCs, activated by CD40 signaling in vivo, can result in antigen specific immune responses and effective vaccination in the absence of CD4+ T-cells. Specific Aim 1. If our hypothesis is correct then co-administration of CD40L with prime-boost vaccination will result in a CD4IND humoral and CD8+ T cell response in vivo. Specific Aim 2. Our hypothesis also predicts that this strategy requires endogenous IL-12 and results in durable vaccine responses in both CD4+ T-cell deficient mice and CD40L knockout mice. Specific Aim 3. Test the hypothesis that CD4IND pathogen specific immunes responses (against P. carinii and TB) can be generated in vivo using CD40L prime-boost vaccination.

卡氏肺囊虫（PC）肺炎和其他感染如结核和细菌性肺炎仍然是HIV感染和其他免疫功能低下状态的严重并发症。众所周知，CD4+淋巴细胞计数与PC感染和细菌性肺炎的风险呈负相关，但CD4+ T细胞缺乏并不能解释宿主防御这些感染的所有机制。因此，我们一直在寻求更好地了解CD4+ T细胞独立（CD4IND）宿主防御机制如何防御艾滋病相关感染。具体来说，我们最近已经表明，骨髓来源的树突状细胞（DCs）可以通过基因工程表达CD40L（使用e1缺失的腺病毒AdCD4OL），导致显著的DC激活和成熟。这些