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.
Showing the most recent 10 out of 20 publications
