The past thirty years have witnessed the progressive acceptance of transplantation as the treatment of choice for end-stage organ failure. Nevertheless, the rate at which the practice has been embraced has greatly exceeded advances in the treatment of allograft rejection by the recipient’s immune system. While tissue typing has significantly improved survival rates, the impossibility of matching donor and recipient for the plethora of so-called minor histocompatibility (mH) antigens necessitates the use of immunosuppression with its attendant risks and long-term side-effects. The recent identification of several mH antigens in mouse and man as polymorphic proteins presented to T cells as peptide fragments bound to products of the major histocompatibility complex (MHC) has, however, offered new opportunities to intervene in the ensuing immune response. In particular, the demonstration that subtle changes in the amino acid sequence of peptides may profoundly alter both the nature and magnitude of the T cell response they elicit, suggests that such altered peptide ligands (APL) may be harnessed as potent therapeutic agents to ameliorate rejection. Here we review evidence that APL may effectively sabotage the alloreactive response and discuss new findings which suggest that they may help shift the balance from immunity to tolerance by polarising responding T cells towards a regulatory phenotype. Such a strategy may prove an effective way of tapping into a naturally-occurring form of self-tolerance, known to play an important role in preventing erroneous autoimmune responses.
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