Defects in Immunoregulatory Cell Receptors in Patients w

Clinical Sciences

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Abstract

Dr. Waldmann's 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 in the use of these insights to develop IL-2R and IL-15R directed therapies for leukemia, autoimmune disease, and to prevent allograft rejection. As part of his studies of HTLV-I-associated adult T-cell leukemia (ATL), Waldmann co-discovered a cytokine, IL-15, that stimulates T-cell proliferation, is necessary for NK cell and NK T cell development, and is critical for the maintenance of CD8 memory T-cells. There is multifaceted control of IL-15 expression including transcriptional control mediated by interferon, IRF-1 and NFkB, as well as regulation at the levels of translation and intracellular trafficking of the cytokine. In T- and NK-cells the IL-15 receptor involves the private IL-15R alpha subunit as well as IL-2R beta shared with IL-2. As a consequence of this sharing of receptors, IL-2 and IL-15 also share some functions, especially in innate NK-mediated immunity. However, as supported by observations in an IL-15 transgenic mouse developed in the Waldmann lab, in adaptive immunity the two cytokines have distinct and competative functions. IL-2 is a critical factor in activation-induced cell death (AICD) leading to the death by suicide of self-reactive lymphocytes. IL-2 also inhibits the persistence of memory phenotype CD8 cells. Thus IL-2 favors peripheral tolerance to self antigens. In contrast, IL-15 inhibits AICD and facilitates the development and persistence of CD8 memory phenotype T-cells. Thus IL-15 favors the persistence of lymphocytes, especially those involved in the memory response to pathogens. Most recently Dr. Waldmann's group demonstrated that IL-15R alpha provides novel contributions to IL-15 functions. Consistent with high-affinity interactions between IL-15 and IL-15R alpha, these two molecules form stable complexes on the cell surface of activated monocytes. The formation of IL-15/IL-15R alpha complexes induces a transendosomal recycling of IL-15 leading to the persistence of surface-bound IL-15 due to the constant reappearance of IL-15 on plasma membranes. These complexes on activated monocytes present IL-15 in trans to target cells such as CD8+ T-cells that express only IL-2/ 15R beta and gamma c upon cell-cell interaction. The actions of IL-15 on AICD and memory T-cells and its activation of the expression of TNF alpha and inflamatory chemokines carries with it the risk that is realized that disorders of IL-15 expression would lead to the development of inflammatory autoimmune diseases. For example, the Waldmann lab has demonstrated a role for IL-15 and its receptor 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 self-stimulatory loops involving these cytokines and their receptors in this disease. The number of antigen (aa 11-19 of HTLV-I-encoded tax protein) reactive memory CD8 cells are exceptionally high in the circulation of patients with TSP. The addition of antibodies to IL-15 ex vivo to such peripheral blood mononuclear cells leads to the rapid (within 2 days) disappearance of these antigen-specific memory CD8 cells that participate in the pathogenesis of the disease. One of the most critical contributions of the Waldmann lab was the recognition that IL-2R and IL-15R represent extraordinarily useful therapeutic targets. 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 was established in immunodeficient mice that is being used to evaluate potential therapeutic agents. The FDA approved humanized anti-Tac (daclizumab, Zenapax) produced in the Waldmann Lab for use in humans to prevent acute kidney transplant rejection. Furthermore, Dr. Waldmann and coworkers demonstrated that Hu-anti-Tac therapy led to a reduction in HTLV-I proviral load and spontaneous lymphoproliferation in TSP patients and provided effective therapy for intermediate and posterior uveitis. In a clinical trial involving 90 Y-anti-Tac (anti-IL-2R alpha therapy for patients with HTLV-I-associated ATL, the Waldmann group observed a partial or complete remission in over 50% of patients. New agents under active development include humanized antibodies directed toward IL-2/15R beta that block all IL-15 action. This antibody will be used in the treatment of human IL-2/15R beta-expressing leukemia as well as inflammatory autoimmune disorders. Furthermore, there is a broad program directed toward the development of IL-2 and IL-15 receptor-directed monoclonal antibodies armed with alpha-emitting radionuclides 213Bi, 211At and a 3 step pretargeting approach involivng, an anti-Tac steptavidin, fusion protein, a clearing agent followed by radio labelled DOTA-biotin. Additional agents under development include geldanamycin linked to an anti-HER2 mAb, as well as small molecular weight inhibitors of 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 anti-receptor antibodies armed with radionuclides are providing novel perspectives for the treatment of select neoplastic diseases, autoimmune disorders, and to prevent allograft rejection.