Dr. Waldmanns studies have focused on the role played by the IL-2-IL-2R and IL-15-IL-15R systems in normal and abnormal T-cell function and the use of these insights to develop IL-2R directed therapy for leukemia. As part of his study of HTLV-I-associated adult T-cell leukemia (ATL) Waldmann co-discovered a cytokine, IL-15, that stimulates T-cell proliferation, and that is necessary for NK cell development. IL-15 protein is posttranscriptionally regulated by 14 upstream AUGs of the 5 UTR, two unusual signal peptides, and the C-terminus of the mature protein. The two signal peptide isoforms and alternative processing of one isoform direct the intracellular trafficking of IL-15 into the nucleus, cytoplasm and two secretory ER pathways. The complex intracellular trafficking patterns of IL-15 with its impediments to translocation added to the impediments to translation may be required due to the potency of IL-15 as an inflammatory cytokine. In terms of a more positive role, intracellular infection may relieve the burdens on translation and translocation to yield effective IL-15 expression and secretion. In T- and NK cells the IL-15 receptor includes IL-2/IL15Rt b and gc which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15Ra. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel IL-15RX subunit. In mast cells IL-15 signaling involves JAK2/STAT5 activation rather than the JAK1/JAK3 and STAT5/STAT3 system used in activated T-cells. The Waldmann lab has demonstrated a role for IL-15, IL-2 and their receptors in HTLV-I-associated ATL and tropical spastic paraparesis (TSP). Spontaneous proliferation of T cells ex vivo in TSP and chronic ATL was abrogated by the simultaneous addition of antibodies to IL-2 and IL-15 receptors supporting the view that there are autocrine stimulating loops involving these cytokines and their receptors in this disease.One of the most critical contributions of the Waldmann lab was the recognition that the IL-2R represents an extraordinarily useful therapeutic target. The scientific basis for this approach is that resting cells do not express the alpha subunit of IL-2R whereas this receptor subunit is abundantly expressed by malignant cells including leukemic cells in ATL. A model of human HTLV- I-associated ATL has been established in immunodeficient mice that is being used to evaluate potential therapeutic agents. The FDA approved humanized anti-Tac (Zenapax) for use in humans to prevent acute kidney transplant rejection. Furthermore, Hu-anti-Tac therapy led to reduction in HTLV-I proviral load and spontaneous lymphoproliferation in TSP patients and provided effective treatment for intermediate and posterior uveitis. In a clinical trial involving 90Y-anti-Tac (anti-IL- 2Ra) therapy for patients with HTLV-I-associated ATL, this group observed a partial or complete remission in over 50% of patients. New agents under active development include humanized antibodies directed toward private and shared cytokine receptors (e.g., IL-2/15Rb) armed with a-emitting radionuclides (212Bi, 213Bi, 211At), geldanamycin linked to an anti-HER-2 mAb, as well as small molecular agents that inhibit the tyrosine kinase JAK3 and STAT5 which are required for IL-2, IL-4, IL-7, IL-9, and IL-15 action. Thus new insights concerning receptors and signaling pathways used by malignant cells taken in conjunction with the ability to produce humanized antibodies armed with radionuclides are providing novel perspectives for the treatment of select neoplastic diseases. - adult T cell leukemia (ATL), human T cell lymphotrophic virus I (HTLV-I), interleukin-2, interleukin-2 receptor, interleukin-, , - Human Subjects & Human Subjects: Minor under 18 Years Old
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