Cytotoxic effector cells against HLA antigens in strong linkage disequilibrium: identification of a strong, new CML determinant.

Three sets of cytotoxic effector cells were generated against the A1, B8, DR3 haplotype using haploidentical individuals in three different families. The three sets of effector cells generated against this haplotype showed excellent reproducibility testing, strong cytotoxicity against their specific targets, low autologous kill, and segregation with the sensitizing haplotype within the family. When tested against a panel of cells bearing all combinations of the A1, B8, DR3 antigens, a hierarchy of contribution of the individual HLA antigens as CML target determinants was seen. A new strong target cell determinant was identified by cytotoxicity with one of the effector cells not explicable in terms of the A1, B8, DR3 antigens or known HLA cross-reactivity. A family study demonstrated that this determinant clearly segregates with HLA. The success of this approach in defining new CML determinants may result from the generation of effector cells across a single haplotype in strong linkage disequilibrium or from the presentation of CML determinants in the context of self.