THE ROLE OF MHC-ASSOCIATED SELF-PEPTIDES IN TRANSPLANTATION AND IMMUNOSURVEILLANCE

The antigen-binding site of most major histocompatibility complex (MHC) class I and II antigens is occupied by self-peptides that are derived from the proteolysis of endogenous proteins following instructions provided by the molecules of the MHC themselves. Together with MHC proteins, self-peptides define our immunological self and shape the repertoire of both T cells that recognize ''nonself,'' and NK cells that may recognize ''no self.'' Endogenous proteins of all cell compartments (nucleus, cytosol, organelles, surface membrane) can yield self peptides whose expression may be either ubiquitous or lineage-specific. Their expression allows the binary recognition mechanism of T and NK cells to check the integrity of the cell genome. A better understanding of the molecular bases of the distinction between self and nonself permits us to anticipate the possibility of modifying their expression and/or their recognition in order to: (i) make the nonself acceptable as self, thereby establishing specific transplantation tolerance, (ii) reestablish tolerance of the self lost in autoimmune diseases, and (iii) induce the rejection as nonself of neoplastic cells. These objectives are particularly pertinent to the area of bone marrow transplantation, where the ultimate goal is aimed at modulating host cell allorecognition in such a way as to both potentiate the graft-versus-leukemia reaction and prevent GVHD. (C) 1994 Academic Press, Inc.