losartan-potassium and Immunologic-Deficiency-Syndromes

My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection.

Topics: Allergy and Immunology; Animals; Erythropoietin; History, 20th Century; History, 21st Century; Humans; Immunoglobulins; Immunologic Deficiency Syndromes; Immunotherapy; Interleukins; National Institutes of Health (U.S.); T-Lymphocytes; United States

We have studied the hematopoietic system of the immunodeficient mouse mutant, viable motheaten (mev/mev). These mice usually die by 9 weeks of age from severe pneumonitis. The lungs at that time are infiltrated with granulocytes, macrophages, and lymphocytes. Granulocyte and macrophage precursor cells (CFU-GM) are dramatically increased in the spleens of mev/mev mice, whereas the bone marrow population of these precursors is decreased when compared with littermate control animals. The CFU-GM population retained its normal dependence on granulocyte-macrophage colony-stimulating factor (GM-CSF) for proliferation and differentiation. In contrast, the frequency of an erythroid precursor (CFU-E) was dramatically increased in spleen and showed increased sensitivity to erythropoietin (Epo). Moreover, a splenic CFU-E subpopulation formed normally appearing erythroid colonies in the absence of exogenous Epo. The bone marrow CFU-E population was significantly diminished in size when compared with either wildtype C57BL/6J mice or mice heterozygous for the mev allele. Unlike the CFU-E population, erythroid burst-forming unit (BFU-E) frequency in mev/mev mice was diminished both in bone marrow and in spleen, although the total number of splenic BFU-E was increased because of splenomegaly in these animals. BFU-E retained their dependence on the presence of both Epo and a source of interleukin 3 (IL-3) for proliferation and differentiation into erythroid bursts. Spleen cells from mev/mev mice, when stimulated in vitro with pokeweed mitogen, failed to produce significant quantities of IL-3. Comparison with medium or +/mev heterozygotes revealed that mev/mev spleen cell-conditioned medium showed a 40-fold reduction in burst-promoting activity. Thus, in viable motheaten mice, there is a major shift in hematopoiesis from bone marrow to spleen, which is accompanied by a diminished capacity of spleen cells to produce burst-promoting activity. These data and those from other studies suggest that the hematopoietic microenvironment of marrow may be impaired in this mutant.

Topics: Aging; Animals; Colony-Forming Units Assay; Colony-Stimulating Factors; Erythroblasts; Erythropoietin; Female; Granulocytes; Hematopoietic Stem Cells; Immunologic Deficiency Syndromes; Lymphokines; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Mice, Mutant Strains; Tissue Inhibitor of Metalloproteinases

Cell-cell interactions between mature T cells and peripheral blood null cells induce erythropoietin-stimulated differentiation of peripheral blood-derived erythroid progenitors. By the use of complement-fixing cytolytic murine hybridoma and antibody uniquely reactive with mature T lymphocytes, this dependence of immature peripheral blood erythroid burst-forming unit (BFU-E) differentiation upon mature T cells or a T cell conditioned medium is confirmed. By using the same antibody, it is demonstrated that the differentiation of mature bone marrow BFU-E does not require either mature T cells or lymphocyte mitogenic factor. These findings do not preclude the presence in the bone marrow of other cells, perhaps even immature T cells, that influence erythropoietin-dependent erythroid differentiation of mature marrow BFU-E.

Topics: Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Erythropoiesis; Erythropoietin; Hematopoietic Stem Cells; Humans; Immunologic Deficiency Syndromes; T-Lymphocytes