Role of HLA molecules in the induction of alloimmune responses: clinical significance in the cyclosporine era

Abstract

HLA molecules are peptide-presenting molecules for T cells. T-cell receptors (TCR) recognize antigen-derived peptides bound to HLA molecules in cell membranes, namely, peptide-HLA (pHLA) complexes. An allograft will be recognized as foreign by recipient T cells via two slightly different mechanisms--direct and indirect allorecognition. In direct allorecognition, recipient T cells directly recognize foreign pHLA complexes on donor cells, in particular on donor dendritic cells (DC). In indirect allorecognition, recipient T cells recognize foreign peptides from the graft presented by self-HLA molecules on recipient DC. Cyclosporine (CsA) inhibits some activation signals in T cells as the result of allorecognition. Notwithstanding the strong immunosuppressive effects of CsA, reducing the degree of allorecognition through HLA matching is still of clinical significance. Data from our own transplant center and results from others demonstrate that the introduction of CsA as a main immunosuppressive drug does not nullify the significant beneficial effects of HLA matching on the frequency and strength of rejection episodes as well as on graft survival after allotransplantation. In cadaveric donor transplantation we observe significant effects of matching just for a limited number of (broad) HLA-DR molecules. We conclude that one should take advantage both of the strong immunosuppressive effects of CsA and other modern immunosuppressants as well as the beneficial effects of optimal HLA matching in clinical transplantation.