This is an integrated clinical and laboratory program which will examine the determinants of human cell mediated immunity in the context of AIDS. Model studies of Leprosy and Leishmaniasis are evaluating the factors responsible for the emigratory, vascular and maturational responses of human skin to delayed type antigens. Cellular dynamics, structural and functional phenotypes of dermal and epidermal populations are considered. The role of the recombinant lymphokines gamma- IFN and IL-2 in this milieu as well as the resulting monokines IL- 1, TNF, arachidonate metabolites and O2 intermediates are under investigation. The selective binding, emigration and biochemical dialogues between mononuclear cells and endothelial cells (EC), interacting on defined substrates leads to a mutually cooperative state. In contrast, PMN when stimulated with TNF and LT while attached to EC, lead to a massive respiratory burst and target cell damage. The alpha-keto acid pyruvate is an important, secretory scavenger of H2O2, protecting targets from oxidative attack. The role of these reactions in TNF induced hemorrhagic necrosis and lethality is under study. Dendritic cells (DC) are central, accessory cells for primary T cell responses. They are particularly enriched in the joint fluids of patients with rheumatoid arthritis (RA) where they cluster with T cells. These T cells will be cloned and their restriction to disease associated HLA-DR4 antigens studied. The secretory activity of monocytes and DC obtained from joints of patients with RA is being examined. The role of LFA associated adhesion promoting receptors during monocyte, T cells and DC interactions is under study at the biochemical and ultrastructural level (immunogold labeling). The natural ligands of these important receptors include surface LPS of gram negative bacteria. Purification and cloning of a novel lymphokine required for human CTL differentiation is underway. The preparation of specific antibodies will allow sensitive bioassays and blocking experiments. CTL granulogenesis will be followed by quantitating the biosynthesis of perforin 1 and the serine esterase. A new clinical program at the Rockefeller University Hospital will evaluate the basic immunological defects in patients with AIDS. Longitudinal analysis of the functions of mononuclear phagocytes, DC, T cell subsets, Langerhans cells will include surface receptors, endocytosis, intracellular killing, secretory repertoire, accessory function, tissue emigration and DTH reactivity. Experiments will characterize the presence of the viral genome in patients' cells and establish their permissiveness to infection in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI024775-04
Application #
3091821
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Haslett, P; Hempstead, M; Seidman, C et al. (1997) The metabolic and immunologic effects of short-term thalidomide treatment of patients infected with the human immunodeficiency virus. AIDS Res Hum Retroviruses 13:1047-54
Moreira, A L; Corral, L G; Ye, W et al. (1997) Thalidomide and thalidomide analogs reduce HIV type 1 replication in human macrophages in vitro. AIDS Res Hum Retroviruses 13:857-63
Klausner, J D; Makonkawkeyoon, S; Akarasewi, P et al. (1996) The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection. J Acquir Immune Defic Syndr Hum Retrovirol 11:247-57
Bender, A; Sapp, M; Schuler, G et al. (1996) Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods 196:121-35
Berman, M E; Xie, Y; Muller, W A (1996) Roles of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in natural killer cell transendothelial migration and beta 2 integrin activation. J Immunol 156:1515-24
Frankel, S S; Wenig, B M; Burke, A P et al. (1996) Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science 272:115-7
Granelli-Piperno, A; Moser, B; Pope, M et al. (1996) Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. J Exp Med 184:2433-8
Tramontana, J M; Utaipat, U; Molloy, A et al. (1995) Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1:384-97
Pope, M; Betjes, M G; Hirmand, H et al. (1995) Both dendritic cells and memory T lymphocytes emigrate from organ cultures of human skin and form distinctive dendritic-T-cell conjugates. J Invest Dermatol 104:11-7
Muller, W A (1995) The use of anti-PECAM reagents in the control of inflammation. Agents Actions Suppl 46:147-57

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