The promiscuous IL-2/IL-15 receptor: a target for immunotherapy of HTLV-I-associated disorders.
Human T-cell lymphotrophic virus I (HTLV-I)-encoded tax plays a role in the early phases of HTLV-I-induced disease by deregulating the expression of the genes that encode interleukin-2 (IL-2) and the multisubunit (IL-2R alpha, IL-2R beta, and IL-2R gamma) IL-2 receptor (IL-2R). However, later in the course of the disease adult T-cell leukemia (ATL), cells no longer produce IL-2 yet continue to express the IL-2R. During studies to define the pathogenic mechanisms that underlie this IL-2-independent proliferation, we defined a cytokine designated IL-T/IL-15 that stimulates T-cell proliferation and requires the expression of IL-2R beta and IL-2R gamma for its action. To exploit the fact that IL-2Rs are present on abnormal T cells in patients with tropical parasitic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) and ATL but not on normal resting cells, different forms of IL-2R-directed therapy have been initiated. Unmodified humanized anti-Tac is being used to treat patient with TSP/HAM. To enhance its effector function for the treatment of ATL anti-Tac was armed with alpha- and beta-emitting radionuclides. In a clinical trial with 90Y-anti-Tac at the doses used (5, 10, and 15 mCi), 9 of the 18 patients with ATL underwent a partial or sustained complete remission. Thus the clinical application of IL-2R-directed therapy using a humanized monoclonal antibody or that antibody armed with radionuclides provides a new perspective for the treatment of autoimmune disorders such as TSP/HAM and certain neoplastic diseases including ATL.
Waldmann
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Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D016207:Cytokines / Q000276:immunology; D016356:Gene Products, tax / Q000276:immunology; D015368:Human T-lymphotropic virus 1; D006801:Humans; D007167:Immunotherapy; D000922:Immunotoxins / Q000627:therapeutic use; D015458:Leukemia, T-Cell / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology*; D009363:Neoplasm Proteins / Q000276:immunology; D015493:Paraparesis, Tropical Spastic / Q000628:therapy*; D015375:Receptors, Interleukin-2 / Q000187:drug effects*
D000912:Antibodies, Neoplasm; D016207:Cytokines; D016356:Gene Products, tax; D000922:Immunotoxins; D009363:Neoplasm Proteins; D015375:Receptors, Interleukin-2; C055533:adult T cell leukemia-derived factor