Cd80-transfected acute myeloid leukemia cells induce primary allogeneic T-cell responses directed at patient specific minor histocompatibility antigens and leukemia-associated antigens

• Published in: Blood 1998-09, Vol.92 (5), p.1677-1684
• Main Authors: MUTIS, T, SCHRAMA, E, MELIEF, C. J. M, GOULMY, E
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - immunology; B-Lymphocytes - immunology; B7-1 Antigen - genetics; B7-1 Antigen - immunology; Biological and medical sciences; Bone Marrow Transplantation; Cell Line, Transformed; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematologic and hematopoietic diseases; Herpesvirus 4, Human; Histocompatibility Antigens Class I - analysis; Humans; Interferon-gamma - metabolism; Interleukin-4 - pharmacology; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Medical sciences; T-Lymphocytes - immunology; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V92.5.1677

Despite sufficient levels of HLA class I and class II expression, acute myeloid leukemia (AML) cells usually fail to induce a significant T-cell response in vitro. Therefore, we investigated whether in vitro modifications could enhance the T-cell stimulatory properties of AML cells. 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 not induce CD80 on AML cells. Cytokine-treated AML cells efficiently presented nominal and allo-antigens to primed T-cell clones, induced strong T-cell proliferation in HLA mismatched mixed lymphocyte reactions (MLR), but failed to induce primary T-cell responses from an HLA identical bone marrow donor in MLR. In contrast, CD80-transfected AML cells induced T-cell proliferation of HLA-identical bone marrow donor peripheral blood mononuclear cell (PBMC) in primary MLR, allowing the generation of leukemia reactive CD4(+) T-cell lines and clones. The majority of the generated oligoclonal (25 of 35) T-cell cultures showed patient specific reactivity that did not discriminate between patient's leukemic 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 latter leukemia reactive oligoclonal T cells was cloned. The majority of the clones (25 of 29) reacted against both leukemic cells and patient's EBV-LCL. A minority of the T-cell clones with the CD4 phenotype (four of 29) showed strong HLA-DP restricted reactivity against leukemic cells, but not against patient's EBV-LCL or against HLA-matched nonleukemic cells, indicating that their target antigens are preferentially expressed by leukemic cells. In conclusion, our study shows that the in vitro allogeneic T-cell response induced by CD80-transfected AML cells is mainly directed against patient's specific minor histocompatibility antigens, while antigens preferentially expressed by leukemic cells can also trigger T-cell responses.