CD80-Transfected acute myeloid leukemia cells induce primary allogeneic T-cell responses directed at patient specific minor histocompatibility antigens and leukemia-associated antigens.

Abstract

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.

• Authors: T Mutis, E Schrama, C J Melief, E Goulmy
• Journal: Blood (Blood) Vol. 92 Issue 5 Pg. 1677-84 (Sep 01 1998) ISSN: 0006-4971 [Print] United States
• PMID: 9716596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 1998 by The American Society of Hematology.

Chemical References

• Antigens, Neoplasm
• B7-1 Antigen
• Histocompatibility Antigens Class I
• Tumor Necrosis Factor-alpha
• Interleukin-4
• Interferon-gamma
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Antigens, Neoplasm (immunology)
• B-Lymphocytes (immunology)
• B7-1 Antigen (genetics, immunology)
• Bone Marrow Transplantation
• Cell Line, Transformed
• Granulocyte-Macrophage Colony-Stimulating Factor (pharmacology)
• Herpesvirus 4, Human
• Histocompatibility Antigens Class I (analysis)
• Humans
• Interferon-gamma (metabolism)
• Interleukin-4 (pharmacology)
• Leukemia, Myeloid, Acute (immunology, metabolism)
• Lymphocyte Activation
• Lymphocyte Culture Test, Mixed
• T-Lymphocytes (immunology)
• Transfection
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (pharmacology)