CD80-TRANSFECTED ACUTE MYELOID-LEUKEMIA CELLS INDUCE PRIMARY ALLOGENEIC T-CELL RESPONSES DIRECTED AT PATIENT-SPECIFIC MINOR HISTOCOMPATIBILITY ANTIGENS AND LEUKEMIA-ASSOCIATED ANTIGENS

Despite sufficient levels of HLA class I and class II expression, acut e myeloid leukemia (AML) cells usually fail to induce a significant T- cell response in vitro. Therefore, we investigated whether in vitro mo difications could enhance the T-cell stimulatory properties of AML cel ls. AML cells were either cultured with granulocyte-macrophage colony- stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-alpha), or transfected with the CD80 (B7.1) gene and used as stimulator cells for primed and unprimed allogeneic T cells. Cytokine treatment increased HLA class I and II expression, but did no t induce CD80 on AML cells. Cytokine-treated AML cells efficiently pre sented nominal and allo-antigens to primed T-cell clones, induced stro ng T-cell proliferation in HLA mismatched mixed lymphocyte reactions ( MLR), but failed to induce primary T-cell responses from an HLA identi cal bone marrow donor in MLR. In contrast, CD80-transfected AML cells induced T-cell proliferation of HLA-identical bone marrow donor periph eral blood mononuclear cell (PBMC) in primary MLR, allowing the genera tion of leukemia reactive CD4(+) T-cell lines and clones. The majority of the generated oligoclonal (25 of 35) T-cell cultures showed patien t specific reactivity that did not discriminate between patient's leuk emic cells and Epstein-Barr virus (EBV)-transformed B cells (EBV-LCL). The remaining 10 oligoclonal T-cell cultures recognized only leukemic cells. One of these tatter leukemia reactive oligoclonal T cells was cloned. The majority of the clones (25 of 29) reacted against both leu kemic cells and patient's EBV-LCL. A minority of the T-cell clones wit h the CD4 phenotype (four of 29) showed strong HLA-DP restricted react ivity against leukemic cells, but not against patient's EBV-LCL or aga inst HLA-matched nonleukemic cells, indicating that their target antig ens are preferentially expressed by leukemic cells. In conclusion, our study shows that the in vitro allogeneic T-cell response induced by C D80-transfected AML cells is mainly directed against patient's specifi c minor histocompatibility antigens, while antigens preferentially exp ressed by leukemic cells can also trigger T-cell responses. (C) 1998 b y The American Society of Hematology.