CD4-Independent Vaccinations for Pulmonary Infections

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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.