1985 — 1986 |
Cohn, Zanvil A. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Human Mononuclear Leukocytes in Cancer
We have discovered that gamma interferon appears to be the major macrophage-activating lymphokine in lectin supernatants and leads to a striking enhancement in the production of toxic oxygen intermediates (TOI) by human monocytes. Patients with severe lepromatous leprosy fail to make appreciable gamma-interferon and IL-2 in response to M. leprae. This is thought a factor in the extensive multiplication of the bacilli in dermal macrophages. Human dendritic cells (DC) are important accessory cells for the human allogeneic and syngeneic MLRs, for antibody formation versus T-cell-dependent antigens, and in the mouse as an important passenger leukocyte for graft recognition. Monoclonal antibodies prepared against mononuclear phagocytes have aided in the isolation of human DC. Progress was made in the isolation of the human low affinity Fc receptor and the C3bi receptor by means of monoclonal antibodies. Liganding of the Fc receptor initiates the secretion of TOI and arachidonate metabolites whereas the C3b receptor is inactive. Human monocytes, free of platelets, are important sources of thromboxane as well as leukotrienes B & C. Monocytes selectively bind to the surface of human endothelial cells (EC) triggering the release of prostacyclin (PEX) by EC. The monocyte product leukotriene C (LTC) also leads to PEX secretion. Endothelial cells also degrade LT-C via a gamma glutamyl transpeptidase. L. pneumophila is internalized via a unique coil-like structure and subsequently resides in a nonfused endosome. We have discovered that the Kupffer cell of the liver is selectively deficient in its ability to produce TOI, either in the presence or absence of gamma-IFN and is a permissive host for intracellular pathogens. The resistance of the liver is due to newly emigrated TOI producing monocytes, which localize in granulomas. (MB)
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0.951 |
1985 — 1991 |
Cohn, Zanvil A. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
The Physiology of Macrophages
A broadly based program examining the function of mononuclear phagocytes (MP's) under in vivo and in vitro conditions and focussed on our ability to modulate their role as effector cells in a wide variety of cell mediated reactions. Studies will characterize the cell surface molecules of developmental forms and activated populations by chemical and immunological techniques including the use of monoclonal antibodies. The role of these forms as suppressor cells of B and T lymphocyte mediated reactions and lymphokine production is being evaluated. Model infections with T. cruzi, Toxoplasma gondii and BCG are used to assay the mechanisms by which MP's dispose of various intracellular pathogens. Related studies are characterizing extracellular cytocidal influences on both normal and neoplastic cells. The role of oxygen intermediates in both intracellular and extracellular effector mechanisms is under study as is the nature and influence of secretory molecules, with emphasis on prostaglandins and neutral hydrolases, on inflammation. Detailed studies are underway on the determinants of endocytosis and phagosome-lysosome fusion. The nature of interiorized plasma membrane, its longevity and its recycling back to the cell surface is being evaluated with novel labeling methods which allow us to characterize the vacuoles involved in fluid phase pinocytosis, adsorptive pinocytosis and phagocytosis. Both the polypeptides and lipid moieties of the vacuolar apparatus membranes are under consideration.
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0.951 |
1986 — 1988 |
Cohn, Zanvil A. |
R22Activity Code Description: Undocumented code - click on the grant title for more information. |
Pathobiology of Human Leprosy
This is a proposal to examine the pathobiology of patients with tuberculoid and lepromatous leprosy. In particular, we will define the cellular mechanisms necessary to mount a cell mediated response to M. leprae and to uncover the defects which result in the extensive replication of M. leprae in cutaneous macrophages. For this purpose we will analyze cells obtained from peripheral blood and the dermal lesions by both morphologic and functional studies. Each step in the triggering of T cells, the production of lymphokines and the activation of mononuclear phagocytes to a microbicidal state will be examined. The possible suppressor qualities of T cells and monocytes and soluble factors derived from them will be studied with M. laprae, other purified antigens and lectins, T cell triggering will be monitored by their replication and secretion of IL-2 and Gamma-IFN. Possible defects at the local dermal lesion will be analyzed. The ability of patients to mount a delayed hypersensitivity reaction and mobilize the appropriate subsets of immune cells will be assessed. The capacity of dermal macrophages to ingest, incorporate into a phagolysosome and kill M. leprae in the presence or absence of exogenous Gamma-IFN will be examined.
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0.951 |
1987 — 1991 |
Cohn, Zanvil A. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Cell Mediated Immunity
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.
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0.951 |
1992 |
Cohn, Zanvil A. |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Physiology of Macrophages
We are studying the secretory and endocytic activities of mononuclear phagocytes (MP's) which are involved in all inflammatory disease states and are key elements for host defense against infectious agents and tumors a well as effector cells for tissue damage. This is a multidisciplinary proposal combining our knowledge of the Cell Biology, Biochemistry, Immunology and Pathology of the MP's. Both the secretion of inflammatory mediators and the recognition of foreignness are accomplished via receptor-ligand interactions. Focussing on the Fc and C3 receptors we wish to understand the ligand dependent signals, their transmembrane passage and the cytoplasmic events leading to the production of arachidonate metabolites and the internalization of plasma membrane. Membrane-membrane and membrane-protein interactions associated with phagosome-lysosome fusion and cell mediated cytotoxicity are being approached by ultrastructural, biophysical and immunological techniques. The nature of resident and emigratory macrophages of liver and spleen are studied after enzymatic dissociation of the organ and subsequent phenotypic and biochemical analysis in vitro. Appropriate infections and tumor models will allow us to quantitate the interactions between T cell subsets and MP's in granulomata of the liver and establish the mechanisms controlling their emigration, persistence and turnover. This will be facilitated by the ease of dissociating the liver into single cell suspensions and separating MP's and T cells. Kuppfer cells fail to secrete toxic oxygen intermediates and are permissive hosts for intracellular parasites. We wish to understand this selective inability to express the activated state and will examine underlying biochemical mechanisms and therapeutic delivery systems to reverse this defect. Murine models are being developed to study the bidirectional dialogue between MP's and classes of lipids and lipoproteins.
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0.951 |
1993 |
Cohn, Zanvil A. |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
The Physiology of Macrophage
We are studying the secretory and endocytic activities of mononuclear phagocytes (MP's) which are involved in all inflammatory disease states and are key elements for host defense against infectious agents and tumors a well as effector cells for tissue damage. This is a multidisciplinary proposal combining our knowledge of the Cell Biology, Biochemistry, Immunology and Pathology of the MP's. Both the secretion of inflammatory mediators and the recognition of foreignness are accomplished via receptor-ligand interactions. Focussing on the Fc and C3 receptors we wish to understand the ligand dependent signals, their transmembrane passage and the cytoplasmic events leading to the production of arachidonate metabolites and the internalization of plasma membrane. Membrane-membrane and membrane-protein interactions associated with phagosome-lysosome fusion and cell mediated cytotoxicity are being approached by ultrastructural, biophysical and immunological techniques. The nature of resident and emigratory macrophages of liver and spleen are studied after enzymatic dissociation of the organ and subsequent phenotypic and biochemical analysis in vitro. Appropriate infections and tumor models will allow us to quantitate the interactions between T cell subsets and MP's in granulomata of the liver and establish the mechanisms controlling their emigration, persistence and turnover. This will be facilitated by the ease of dissociating the liver into single cell suspensions and separating MP's and T cells. Kuppfer cells fail to secrete toxic oxygen intermediates and are permissive hosts for intracellular parasites. We wish to understand this selective inability to express the activated state and will examine underlying biochemical mechanisms and therapeutic delivery systems to reverse this defect. Murine models are being developed to study the bidirectional dialogue between MP's and classes of lipids and lipoproteins.
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0.951 |