Regulation of human hematopoiesis involves a complex interplay amongst hematopoietic progenitors, mononuclear cell subsets, soluable growth factors and surface regulatory antigenic determinants. The development of new monoclonal antibodies for the identification and characterization of mononuclear subsets, and the development of cytofluorographic and solid-phase immunoabsorption techniques for the isolation of highly purified subclasses of human regulatory cell populations, has permitted further dissection of cellular mechanisms involved in the regulation of the immune response in man. We hypothesize that diverse human mononuclear cells (monocytes, newly fractionated T cell subsets, B cells, NK cells and """"""""null"""""""" cells) play an important and complex role in cellular hematopoietic regulation. Utilization of biochemically purified and cloned human interleukins and lymphokines will help to more precisely characterize the role which pruified subsets of immunoregulatory mononuclear cells play in hematopoietic regulation. Use of relatively homogenous progenitor target cell populations will be a necessary part of this analysis and we plan to extend our use of sequential panning techniques, in combination with density and adherence separation procedures and cytoflurographic sorting, to obtain enriched populations of hematopoitic progenitors and purified populations of immunorgulatory cell subsets. An effective immune response requires collaboration between cell subsets; human la-like molecules function in recognition phenomena to genetically restrict such cellular collaboration and antigen presentation. Work from our laboratory indicates human hematopoietic progenitors are heterogenous with regard to surface antigenic distribution of framework DR determinants, that there is discordant expression of DR supertypic antigens on hematopoietic progenitors, and that human T cell-menocyte collaboration in the genertion of hematopoietic progenitors, and that human T cell-menocyte collaboration in the generation of hematopoietic growth factors may be differentially regulated by different class II genetic loci. These observations support the hypothesis that human HLD-D(DR, DC, MT, SB) region gene products play an important role in the regultion of hematopoietic cell-cell interactions. In this application we plan specifically to 1) assess the effects of purified immunoregulatory cell subsets on growth and differentiation of enriched human marrow hematopoietic progenitors; 2) investigate effects of purified immunologic modulators (interleukins 1, 2 and 3 and Gamma-interferon) on growth of enriched progenitors and on the generation of hematopoietic growth factors by purified immunoregulatory cell subsets; 3) assess the role of human class II HLA-D framework and supertypic antigens, and immunoregulatory class I (QA-like) antigens, in hematopoietic regulation, and 4) assess effects on hematopoietic regulation of altered regulatory cell subsets and lymphokines from patients with the acquired immune deficiency syndrome.
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