This clinical and laboratory program on AIDS and tuberculosis will attack the challenges posed by these diseases in pathogenesis and therapy. We intend to uncover fundamental aspects of the cell-mediated immune response in man, to emerge with better ways to monitor the immune system in disease, and to improve host resistance. We will consider cell-mediated resistance at three levels. The first is the patient and centers on several ongoing protocols in subproject A. We will evaluate the effects of individual cytokines [IL-2, IFN-gamma] administered intradermally, particularly on responses to HIV-1 antigens, and we will assess the possible role of endogenous cytokine production, e.g., TNFalpha, to explain symptomatology such as fever, wasting, and disease progression. The second level entails cellular interaction systems in culture. In subproject B, the afferent limb of the immune response to HIV-1 and to TB will be studied with a concerted evaluation of dendritic cells, monocytes, helper and killer T cells. Our goal is to define protective T cells against M.Tub. and HIV-1, by generating such cells de novo from select, patient populations. In subproject C we examine the efferent limb of immunity using a model of transendothelial leukocyte migration. We will define the lymphocyte and endothelial stimuli that lead to emigration, and we will recreate the in vivo responses that occur during skin tests for delayed type hypersensitivity and following intradermal injection of recombinant IL-2. The third level of analysis is within cells in subproject D. Can intracellular mediators be identified that reflect stimulation with cytokines like IL-2 and IFN-gamma, both in tissue culture and in patients with AIDS and TB? What intracellular targeting pathways can be defined that might explain the distinct life cycle of HIV-1 in macrophages and T cells? What signalling occurs in monocytes exposed to M.Tub. and do any of these signals lead to enhanced expression of HIV-1? At all levels of this program, we emphasize molecular criteria in primary cell and patient populations. The research plan derives from published and preliminary data in the current funding period.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI024775-09
Application #
2062743
Study Section
Special Emphasis Panel (SRC (66))
Project Start
1987-09-30
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
9
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Other Basic Sciences
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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