The long term goal of this work is to develop immunotherapy against virus infections and cancer through intervention in the mononuclear phagocyte (MP) system. To achieve this goal, we must first establish the mechanisms involved in the generation of diversity in the MP system. Such information is necessary before immunotherapy will achieve its clinical potential for virus infections such as herpes simplex virus (HSV) and cytomegaloviruses (CMV) in immunosuppressed patients as those with AIDS. We propose two complementary experimental approaches. First, we will use independent, yet overlapping depletion methods to establish the in vitro cellular relationships in mice among various MP and natural killer (NK) cells. We will compare our previous results obtained using 89Sr to """"""""marrow- ectomize"""""""" mice, with those obtained by using two novel depletion methods--monoclonal antibody NK1.1 to deplete mice selectively of NK cells, and dimethylene diphosphate (DMDP) toxin encapsulated in liposomes to deplete mice selectively of various tissue macrophages (MO). We will use combinations of treatments to produce mice that are selectively deficient in circulating monocytes, tissue MO and NK cells. Secondly, as a complementary approach to the first objective, we will stably label resident peritoneal MO in vitro, and elucidate the in vivo interrelationships and sources of MP and NK cells with antiviral functions. The fate of the MO population will be followed in normal and selectively depleted mice. We will determine effects on the effector cell populations and on natural and immunomodulator enhanced resistance to HSV -2 and CMV infections. The results will establish whether the various effector populations are independently regulated, which effector cells are required for various types of antiviral resistance, and whether immunotherapy can be effective in severely depleted hosts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025751-03
Application #
3139314
Study Section
(SRC)
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
3
Fiscal Year
1989
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
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
Kunder, S C; Wu, L; Morahan, P S (1993) Role of NK cells in immunomodulator-mediated resistance to herpesvirus infection. Antiviral Res 21:103-18
Kunder, S C; Wu, L; Morahan, P S (1993) Protection against murine cytomegalovirus infection in aged mice and mice with severe combined immunodeficiency disease with the biological response modifiers polyribosinic-polycytidylic acid stabilized with L-lysine and carboxymethylcellulose, maleic anh Antiviral Res 21:233-45
Kunder, S C; Kelly, K M; Morahan, P S (1993) Biological response modifier-mediated resistance to herpesvirus infections requires induction of alpha/beta interferon. Antiviral Res 21:129-39
Wu, L; Morahan, P S; Leary, K (1993) Regulation of herpes simplex virus type 1 gene expression in nonpermissive murine resident peritoneal macrophages. J Leukoc Biol 53:61-5
Wu, L; Morahan, P S (1992) Macrophages and other nonspecific defenses: role in modulating resistance against herpes simplex virus. Curr Top Microbiol Immunol 179:89-110
Morahan, P S; Pinto, A J (1992) Biologic response modifiers as antivirals in immunosuppressed hosts. Adv Exp Med Biol 319:243-51
Hendrzak, J A; Pinto, A J; Morahan, P S (1992) Intrinsic resistance to herpes simplex virus type 1 infection in liver Kupffer cells and peritoneal macrophages from normal and immunomodulator-treated mice. Nat Immun 11:26-33
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

Showing the most recent 10 out of 18 publications