The laboratory is focused on elucidating important aspects of Langerhans cell biology, particularly those that relate to Langerhans cell differentiation, trafficking and activation. To faciliate these studies we have identified culture conditions that permit Langerhans cell-like cells to be expanded from murine fetal skin and extensively characterized them. We have determined that fetal skin-derived dendritic cells and Langerhans cells exhibit similar surface phenotypes and possess similar functional activities. The dendritic cells propagated in vitro also respond to the same inflammatory mediators (IL-1, TNF and LPS) that activate and mobilize dendritic cells in vivo. We have previously characterized the response of fetal skin-derived dendritic cells to immunostimulatory oligodeoxynucleotides (in collaboration with Dr. Jonathan Vogel) and Leishmania major. The results of these experiments indicate that both immunostimulatory oligodeoxynucleotides and Leishmania activate dendritic cells inducing them to upregulate cell surface MHC and costimulatory molecules and to produce the Th1-promoting cytokine IL-12. In ongoing studies, we are continuing to examine Leishmania-dendritic cell interactions and effects of immunostimlutory oligodeoxynucelotides. Extensive studies of dendritic cells from susceptible (BALB/c) and resistant (C57BL/6) mice did not reveal significant differences in parasite ingestion, activation, IL-12 production or in their ability to educate helper T cells in vitro. In vivo studies are in progress. A polymorphism in dendritic cell IL-1 production has been noted and we are actively exploring the potential of this cytokine to influence the development of helper T cells in vitro and in vivo. Experiments with immunostimulatory oligodeoxynucleotides indicate that these agents are potent stimulators of BALB/c skin macrophage IL-12 production and may explain why immunostimulatory oligodeoxynucleotides are efficacious in the prevention and treatment of murine cutaneous Leishmaniasis.Studies of matrix metalloprotease production and function in Langerhans cell- like dendritic cells are in progress. We have determined that murine dendritic cells can produce several matrix metalloprotease mRNAs after stimulation in vitro and in vivo. We are in the process of determining if these increases in mRNA expression are accompanied by changes in protein levels and if these enzymes are involved in Langerhans cell migration in vitro and in vivo. Studies of patterns of gene expression in Langerhans cells using cDNA macro- and microarrays and representational difference analysis are in the information accumulation phase and are encouraging. - Langerhans cells, matrix metalloproteases, dendritic cells, Leishmania, immunostimulatory oligodeoxynucleotides, - Human Tissues, Fluids, Cells, etc.
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