We proposed to study the nature and regulation of effector cells and target antigens in patients with graft-versus-host disease (GVHD). These studies will extend previous project work which demonstrated GVHD-associated populations of cytotoxic, proliferative, and specific and nonspecific suppressor cells in the peripheral blood of patients with acute and chronic GVHD, respectively. The main hypotheses to be tested in this project are as follows: A. A subpopulation of donor T cells can specifically bind and respond to recipient epidermal cells. B. Cellular cytotoxicity in cutaneous acute GVHD is mediated by cytotoxic T lymphocytes (CTL) as opposed to other CD8+ cytotoxic effector cells. These CTL recognize target antigens in the context of host HLA products, i.e., they are HLA-restricted. C. Skin cells secrete cytokines (IL1 and tissue growth factors) that stimulate lymphoid effector cell function and secretion of cytokines. These lymphoid cytokines (e.g., gamma interferon and colony stimulating factors) complete an inflammatory circuit by amplifying skin cytokine secretion and target antigen expression. Our approach will involve the culture of skin explants and skin components from pre- and post marrow transplant patient biopsies. Putative effector cells will be expanded from the latter biopsies, from patient peripheral blood, and from bone marrow. These cell populations will then be combined in vitro to analyze effector/target binding specificity and function, and to study the roles of lymphokines and tissue growth factors in these interactions.
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