Our long standing interest in cutaneous dendritic cell physiology continues. Recently developed mice that are constitutively, or that can be made conditionally, Langerhans cell-deficient allow definitive studies of Langerhans cell function and development to be carried out for the first time. Using one of these strains of mice and a variety of monoclonal antibodies have allowed us to conclusively identify at least 3 distinct subsets of dendritic cells in skin and to begin to characterize lineage relationships between them. In addition, we have utilized Langerhans cell-deficient to identify an unexpected role for these cells in antibody forming responses. Immunization of transgenic mice at a time when they are Langerhans cell deficient via gene gun leads to selective attenuation of the IgG1 isotype response. Since IgG1 formation is thought to be IL-4-dependent, this suggests that Langerhans cells may be specialized to present antigen to Th2 cells. How this might occur remains to be determined. These findings are described in a paper that has been published in the Proceedings of the National Academy of Sciences since submission of the last annual report. The above studies have provided data that has resulted in development of new hypotheses regarding Langerhans cell ontogeny. We are in the process of examining the possibility that locally secreted influences that may be keratinocyte-derived may be important regulators of Langerhans cell differentiation. Both in vitro and in vivo approaches are being utilized in these studies. Another project area that has been actively pursued in the laboratory involves testing the feasibility of using T cell receptor proteins expressed by clonal T cell malignancies as tumor antigens in vaccines. DNA-based (genetic vaccination) strategies are being emphasized because of concerns regarding the practicality of patient-specific therapies. A reproducible model involving subcutaneous growth of T cell lymphomas in mice has been established in the laboratory. cDNAs encoding T cell receptor alpha and beta chains from this murine T cell lymphoma have been cloned and sequenced, and several candidate vaccines have been generated. We have determined that several candidate vaccines have activity. In the course of these studies, we identified a novel adjuvant strategy that dramatically increases the efficacy of TCR-based vaccines. We have also shown that this strategy can be generalized, both with regard to the nature of the helper antigen and to the tumor and corresponding tumor antigen. Because we anticipate that this adjuvant strategy will be generally applicable and well tolerated, incorporation into human vaccine trials may be feasible. A publication describing these findings has appeared in the journal Blood since the last annual report was submitted. Collaborative studies of dendritic cells and their products in experimental cutaneous leishmaniasis are also ongoing, and results continue to inform our understanding of dendritic cell function in this murine model of an important human disease. Recent results implicate the cytokine IL-17 and neutrophils in Leishmania pathogenesis in susceptible mice. It is anticipated that these insights will promote development of a vaccine that will attenuate the burden of this world-wide health problem. A publication describing these findings was published in the Journal of Immunology in this reporting period.
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