This proposed research project involves the intensive study of the functional properties of human Langerhans cells, with special reference to functional properties related to their expression of allospecific HLA-DR antigens. Human epidermal Langerhans cells have been known to express DR alloantigens and to possess Fc and C3b receptors character istic of cells of the monocyte/macrophage lineage. However, while some experimental evidence supports assignment of specific immunological functions such as stimulation of allogeneic lymphocyts and accessory cell functions, to guinea pig Langerhans cells, such functional activities have not yet been studied in relation to human Langerhans cells. Our laboratory has now developed a procedure for significant enrichment of Langerhans cells. This procedure, will be further improved and, together with our laboratory's extensive resources and experience in studies of human histocompatibility complex, will be used to accomplish the specific objectives of this proposal. In particular, the proposed research project will involve functional assays of the DR antigens on Langerhans cells as stimulators of primary and secondary allogeneic lymphocyte proliferation and as stimulators and targets of allospecific cytotoxic effector cells. The project will also involve studies of subpopulations of Langerhans cells with different surface markers, studies of other Langerhans cell surface antigens, identified by monoclonal antisera, and functional studies of the possible role of Langerhans cells as accessory cells for T-cell responses to mitogens and antigens. The properties studies will be attributed to Langerhans cells on the basis of comparative effects of enriched and depleted cells fractions and on the basis of effects of Langerhans cell elimination and surface marker blocking. In all these studies, the role of HLA-A,B,C and/or D/DR compatibility will be evaluated in relation to Langerhans cell interactions with other cell types and to the possible role of non-HLA antigens expressed on the Langerhans cells or other epidermal cell types. A better understanding of Langerhans cell functions will contribute to the general understanding of immunological diseases of the skin and of the role these cells may play in the initiation of graft versus host disease in patients receiving therapeutic allogeneic bone marrow transplantation.
