The Promiscuous IL-2/IL-15 Receptor: A Target for Immunotherapy of HTLV-I-Associated Disorders

Abstract

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-2Rα, IL-2Rβ, and IL-2Rγ) 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-2Rβ and IL-2Rγ 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 patients with TSP/HAM. To enhance its effector function for the treatment of ATL anti-Tac was armed with α- and β-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.