Influence of HLA phenotypes on the inhibition of in vitro alloreactivity by cyclosporine

Interindividual variations in the immunosuppressive effect of Cyclosporine have been observed in clinical organ transplantation. Searching for an in vitro correlate we investigated a possible relation between inhibition of alloresponsiveness by CsA and the HLA phenotypes of the responder or stimulator in mixed lymphocyte reactions. Peripheral blood mononuclear cells from 28 healthy volunteers were used as responder or stimulator cells (gamma-irradiated) and the inhibitory effect of graded amounts of CsA was determined in 130 criss-cross combinations. Sensitivity of alloresponsiveness to the drug was expressed as the dose causing 50% inhibition (ED50) and was read from the inhibition curves generated after four-parameter logistic curve fitting. ED50 ranged from 0.35 ng/ml to 33.4 ng/ml and correlated only weakly with the magnitude of the response (r = 0.12). In MLC with HLA DR4-positive responder cells, ED50 was significantly lower (Pc = 0.0035, Kruskal Wallis) when compared with MLC with responder cells of other DR haplotypes. For HLA DR5-positive responder cells ED50 was significantly higher (Pc = 0.042) when compared with DR5-negative responder cells. No significant correlation between ED50 and any particular haplotype of the stimulator cells could be observed. Sensitivity to CSA did not differ in MLC with 1 or 2 mismatches in the HLA-DR locus. In summary, we found that sensitivity of in vitro alloreactivity was different for particular HLA DR phenotypes, which may have important implications for the immunosuppressive therapy of transplanted patients with cyclosporine.