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 derive d from the proteolysis of endogenous proteins following instructions p rovided by the molecules of the MHC themselves. Together with MHC prot eins, self-peptides define our immunological self and shape the repert oire 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 peptide s 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 t he 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 sel f, thereby establishing specific transplantation tolerance, (ii) reest ablish tolerance of the self lost in autoimmune diseases, and (iii) in duce the rejection as nonself of neoplastic cells. These objectives ar e particularly pertinent to the area of bone marrow transplantation, w here the ultimate goal is aimed at modulating host cell allorecognitio n in such a way as to both potentiate the graft-versus-leukemia reacti on and prevent GVHD. (C) 1994 Academic Press, Inc.