IMMUNODOMINANT MINOR HISTOCOMPATIBILITY ANTIGENS EXPRESSED BY MOUSE LEUKEMIC-CELLS CAN SERVE AS EFFECTIVE TARGETS FOR T-CELL IMMUNOTHERAPY

Numerous minor histocompatibility antigens (MiHAs) show tissue-specifi c expression and can induce vigorous T cell responses. They therefore represent attractive targets for leukemia immunotherapy mediated by ad optive transfer of T cells. The main objective of this work was to det ermine whether MiHAs expressed by normal hematopoietic cells were pres ent on leukemic cells and whether they could trigger lysis by cytotoxi c T lymphocytes (CTLs). CTL assays showed that mouse leukemic cells of both lymphoid and myeloid lineages were sensitive to CTLs targeted to ward some but not all MiHAs. In four out of four strain combinations i n which we primed CTLs against immunodominant MiHAs, effecters killed leukemic blasts, whereas no cytotoxicity was observed when CTLs were t argeted toward four immunorecessive MiHAs. Testing of HPLC fractions o btained from normal and leukemic cells provided molecular evidence tha t leukemic blasts expressed only some of the MiHAs found on normal mou se hematopoietic cells. Decreased density of H-2 class I molecules at the surface of leukemic cells suggests that down-regulation of genes e ncoding either class I molecules or proteins involved in antigen proce ssing played a role in the aberrant expression of MiHAs. In vivo resis tance to the leukemic cells by various strains of mice correlated with in vitro CTL activity. These results show that leukemic cells express only some (immunodominant) MiHAs and suggest that this subset of MiHA s represent prime targets for adoptive immunotherapy.