The proposed studies are designed to determine whether the diversity in anatomical location and of functional properties of macrophages (M0) is to a significant extent ontogenetically determined or due solely to the response of the blood monocyte to local influences for maturation, stimulation and activation. Our first approach to this question is to study in mice the mechanisms of renewal of tissue populations in monocyte depleted animals, the distribution and fate of the monocyte and the active and latent functional characteristics of tissue M0 in the absence of monocytic input. For this purpose we administer the bone-seeking isotope, 89-Sr, to destroy the radioactive precursors of monocytes in bone marrow. This results in a profound monocytopenia within 72 hours sustained for at least 31 days in intact and splenectomized mice whereas resident macrophages (RM) populations remain at normal numbers. We propose in addition to study in this model: a) the use of 45Ca as a more economical and more stable alternative to 89-Sr; b) the effects of selective bone marrow irradiation on marrow-derived Langerhans cells. In a second approach alloantigens and H-Y antigens will be employed as markers in mice rendered histocompatible in order to quantitatively assess the entry and exit of blood borne cells in M0 populations. These genetic markers will also be used in conjunction with appropriate monoclonal antibodies to study the fate of the monocyte. A third approach will be to study active and latent functional capacities of RM in monocyte deprived mice in vitro and in vivo. Lastly we propose to study clonogenic stem cells for M0 in marrow, blood, spleen, and peritoneal cavity following bone marrow depletion in 89Sr treated animals. Colony stimulating activities and inhibitors in these tissues and fluids will be determined in parallel with the clonogenic studies. In summary, the models employed should provide the means to determine the respective roles of monocyte-independent and monocyte-dependent M0 in fundamental host defense mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017162-06
Application #
3127011
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1980-09-01
Project End
1987-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost
Name
East Carolina University
Department
Type
Schools of Medicine
DUNS #
City
Greenville
State
NC
Country
United States
Zip Code
27858
Schmidt, M; McConnell, T J; Hoffman, D R (1996) Production of a recombinant imported fire ant venom allergen, Sol i 2, in native and immunoreactive form. J Allergy Clin Immunol 98:82-8
Shibata, Y (1995) Prostaglandin E2 release triggered by phagocytosis of latex particles. A distinct association with prostaglandin synthase isozymes in bone marrow macrophages. J Immunol 154:2878-87
Shibata, Y; Bjorkman, D R; Schmidt, M et al. (1994) Macrophage colony-stimulating factor-induced bone marrow macrophages do not synthesize or release prostaglandin E2. Blood 83:3316-23
Shibata, Y; McCaffrey, P G; Minowada, J et al. (1992) Regulation of phospholipase A2 activation and arachidonic acid metabolism in an interleukin-3-dependent macrophage-like cell line. J Leukoc Biol 51:32-8
Oghiso, Y; Yamada, Y; Shibata, Y (1992) Exudation of proliferative macrophages in local inflammation in the peritoneum. J Leukoc Biol 52:421-4
Shibata, Y; Volkman, A (1991) Restoration of prostaglandin releasing macrophage populations in lethally irradiated mice with spleen cells from bone marrow-depleted donors. J Leukoc Biol 49:397-406
Hoffman, D R; Jacobson, R S; Schmidt, M et al. (1991) Allergens in Hymenoptera venoms. XXIII. Venom content of imported fire ant whole body extracts. Ann Allergy 66:29-31
Treadwell, E L; Muller, U R; Volkman, A (1991) Extraction and differentiation of the Su autoantigen from calf thymus nuclei. J Immunol Methods 142:157-67
Shibata, Y; McCaffrey, P G; Sato, H et al. (1990) Calcium ionophore but not phorbol ester promotes eicosanoids release by proliferating interleukin-3-dependent bone marrow cells. Blood 76:1586-92
Hoffman, D R; Smith, A M; Schmidt, M et al. (1990) Allergens in Hymenoptera venom. XXII. Comparison of venoms from two species of imported fire ants, Solenopsis invicta and richteri. J Allergy Clin Immunol 85:988-96

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