The long term goal of this work is to establish the mechanisms involved in the generation of diversity in the mononuclear (MP) system, in order to develop optimum immunotherapy against cancer and viruses through immunopharmacologic manipulation of MP. The clinical potential of therapy using MP has not been fully realized, in part due to our lack of understanding of the origins of the heterogeneity that is extant in this cell system. We propose two independent experimental approaches to address the issue of the origins of macrophages (MO) with antitumor activity against peritoneal and liver tumors selective depletion and stable cell labelling. The selective cell depletion methods to establish the in vivo relationships among circulating monocytes, resident peritoneal Mo (Res89PMO), and resident liver Kupffer cell Mg (Res KC) are: treatment of mice with 89Sr to """"""""marrow-ectomize"""""""" mice and produce monocytopenia, or with the toxin dichlormethylene diphosphonate encapsulated in liposomes (DMDP-L) to deplete splenic and liver M0. We will use a stable labelling procedure with the fluorescent dye, PKH-1, to label Res PMO and KC in vivo. The fate of the stably labelled Res PMO and KC, in relation, to circulating MP, will be followed in response to peritoneal or liver tumors in intact mice and in the mice treated vith 89Sr or DMDP-L. The effect of the inormomodulators, gamma interferon and BCG, on the host response to tumors and antitumor efficacy in intact and depleted mice will also be measured. The peritoneal model will be the multicellular spheroid of the EMT6 mammary tumor, a model for intracavity immunotherapy of the peritoneal effusions common after breast-cancer. The liver tumor model will be intrasplenic injection of EMT6 or B16 melanoma tumor cells to establish whether inflammatory or resident M0 are the predominant MP involved in the natural host response to tumors in intact and depleted mice and which MP populations are activated for antitumor activity inmmunodulators. These data will also establish whether these various populations are independently regulated, and under what conditions immunotherapy can be effective in severely bone marrow immunosuppressed patients.
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