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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035961-07
Application #
3173473
Study Section
Experimental Immunology Study Section (EI)
Project Start
1983-01-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1993-03-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Barth, M W; Hendrzak, J A; Melnicoff, M J et al. (1995) Review of the macrophage disappearance reaction. J Leukoc Biol 57:361-7
Wallace, P K; Eisenstein, T K; Meissler Jr, J J et al. (1995) Decreases in macrophage mediated antitumor activity with aging. Mech Ageing Dev 77:169-84
Wallace, P K; Morahan, P S (1994) Role of macrophages in the immunotherapy of Lewis lung peritoneal carcinomatosis. J Leukoc Biol 56:41-51
Hendrzak, J A; Wallace, P K; Morahan, P S (1994) Optimizing the detection of cell surface antigens on elicited or activated mouse peritoneal macrophages. Cytometry 17:349-56
Barth, M W; Morahan, P S (1994) Role of macrophages in the host response to Lewis lung peritoneal carcinomatosis. Cancer Immunol Immunother 38:233-42
Pinto, A J; Stewart, D; van Rooijen, N et al. (1991) Selective depletion of liver and splenic macrophages using liposomes encapsulating the drug dichloromethylene diphosphonate: effects on antimicrobial resistance. J Leukoc Biol 49:579-86
Sit, M F; Tenney, D J; Rothstein, J L et al. (1988) Effect of macrophage activation on resistance of mouse peritoneal macrophages to infection with herpes simplex virus types 1 and 2. J Gen Virol 69 ( Pt 8):1999-2010
Dempsey, W L; Hwu, P; Russell, D H et al. (1988) Bone marrow derived macrophages have polyamine and ectoenzyme phenotypes distinct from resident macrophages. Life Sci 42:2019-27
Morahan, P S; Dempsey, W L; Volkman, A et al. (1986) Antimicrobial activity of various immunomodulators: independence from normal levels of circulating monocytes and natural killer cells. Infect Immun 51:87-93
Dempsey, W L; Smith, A L; Morahan, P S (1986) Effect of inapparent murine hepatitis virus infections on macrophages and host resistance. J Leukoc Biol 39:559-65

Showing the most recent 10 out of 12 publications