Conventional major histocompatibility complex (MHC) class 1 molecules transport peptides to the cell surface and thus enable cytotoxic T-cells to detect intracellular antigen. Because of their function in T cells recognition and extensive polymorphism, conventional class 1 molecules are critical determinants in bone marrow transplantation (BMT). Recent evidence has revealed that class 1-related molecules have variously modified immune defense functions and interact with distinct T-cell subsets. We have identified novel human MHC class 1 genes, MICA and MICB, which are evolutionarily conserved and regulated by the cell-stress response. At least MICA is polymorphic and encodes a cell surface glycoprotein mainly expressed in gastrointestinal epithelium. The characteristics of MICA and putative MICB molecules strongly suggest that they are recognized by a subset of intestinal intraepithelial lymphocytes (IEL). Studies proposed under Specific Aim 1 in this project are aimed at defining the immunological function of MICA and MICB, by further investigating their expression in normal tissues and inflammatory lesions, by isolation and functional characterization of the T-cells among IEL that specifically recognize these molecules, by correlating T-cell receptor sequence diversity with MICA polymorphism, and by purification and sequence analysis of bound peptide ligands. Studies proposed under Specific Aim 2 will investigate whether polymorphic MICA is a risk factor in acute gut graft-versus-host disease (GVHD) developing after BMT, in which the often fatal destruction of intestinal epithelium results from T- cell recognition of unknown tissue-specific target determinants. It is proposed to test whether mismatching of MICA alleles correlates with increased incidence of this disease, by molecular genetic typing of well characterized panels of unrelated donor and recipient pairs. Altogether, these studies will likely reveal a novel type of MHC class 1 ligand-T-cell interaction in the poorly defined human gut mucosal immune system. Moreover, they have the potential to provide new insights into the mechanisms underlying acute gut GVHD and may thus benefit the successful outcome of future marrow grafting.
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