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.
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