Mononuclear phagocytes differentiate in the marrow and then pass via the blood stream to the tissues and become resident macrophages. In response to the tissue injury and inflammation, young mononuclear phagocytes pour into the affected area and in response to regulatory molecules, produced by lymphocytes or to factors derived from bacteria, undergo profound alterations in many functions. These changes in functions are vital to host defenses against tumors and microbes but can also produce massive tissue damage and destruction. A clear understanding of the physiology of macrophage development and differentiation is thus important. We plan to undertake a combined immunochemical and enzymological approach to study the significance of induction of an intracellular protein cross-linking enzyme, tissue transglutaminase in differentiation processes of the cells of monocytic lineage. The significance of tissue transglutaminase induction and its role in; a) differentiation process of monocytes and monocytic leukemia cells (THP-1) to mature macrophages, b) in acquisition of tumoricidal/microbicidal functions by monocyte and macrophages, and c) in functions such as, the ability of activated macrophages/monocytes to recognize the tumor cells and their ability to participate in antibody-dependent cell mediated cytotoxic reactions will be studied. The role of exogenous/endogenous retinoids in modulation of these functions will be studied. The role of endogenous retinoids in the differentiation process of mononuclear phagocytes will also be investigated by studying the expression of cell surface receptors for serum retinol-binding protein during different stages of development. The results obtained may be of considerable intellectual interest in terms of understanding the macrophage biology. In addition it might suggest approaches for increasing the macrophage tumoricidal and anti-infective activity in cancer and other immunocompromised patients, without an undesirable increase in macrophage/inflammatory activity or in auto-immune response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038751-03
Application #
3176998
Study Section
Experimental Immunology Study Section (EI)
Project Start
1987-01-01
Project End
1990-06-30
Budget Start
1989-01-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Sacks, P G; Oke, V; Mehta, K (1992) Antiproliferative effects of free and liposome-encapsulated retinoic acid in a squamous carcinoma model: monolayer cells and multicellular tumor spheroids. J Cancer Res Clin Oncol 118:490-6
Mehta, K; Rao, U R; Vickery, A C et al. (1990) Significance of transglutaminase-catalyzed reactions in growth and development of filarial parasite, Brugia malayi. Biochem Biophys Res Commun 173:1051-7
Turpin, J; Mehta, K; Blick, M et al. (1990) Effect of retinoids on the release and gene expression of tumor necrosis factor-alpha in human peripheral blood monocytes. J Leukoc Biol 48:444-50
Khera, V; Mehta, K (1989) Transglutaminase levels and immunologic functions of BCG-elicited mouse peritoneal macrophages isolated by centrifugal elutriation. J Leukoc Biol 45:434-43
Naz, R K; Mehta, K (1989) Cell-mediated immune responses to sperm antigens: effects on mouse sperm and embryos. Biol Reprod 41:533-42
Murray, J L; Mehta, K; Lopez-Berestein, G (1988) Induction of adenosine deaminase and 5' nucleotidase activity in cultured human blood monocytes and monocytic leukemia (THP-1) cells by differentiating agents. J Leukoc Biol 44:205-11
Mehta, K; Claringbold, P; Lopez-Berestein, G (1987) Suppression of macrophage cytostatic activation by serum retinoids: a possible role for transglutaminase. J Immunol 138:3902-6
Metha, K; Turpin, J; Lopez-Berestein, G (1987) Induction of tissue transglutaminase in human peripheral blood monocytes by intracellular delivery of retinoids. J Leukoc Biol 41:341-8