Treatment of rodents with the immunosuppressive agent cyclosporine A (CsA) following syngeneic bone marrow transplantation (BMT) results in the development of a graft-versus-host disease (GVHD)-like syndrome, termed syngeneic GVHD (SGVHD). We have recently demonstrated the development of a TH1-like (IL-12,IFN-gamma) cytokine response during the course of murine SGVHD. These findings have led to the hypothesis that early macrophage activation is central to the development of SGVHD. In vivo depletion and inhibition studies will be performed to examine the role of macrophages in the pathogenesis of this disease. Using cells isolated from SGVHD animals, the degree of macrophage activation will be examined in vitro by the measurement of reactive oxygen intermediates and nitric oxide (NO). Lipopolysaccharide (LPS) has been shown to be a potent macrophage activating agent and has been implicated in the development of allogeneic GVHD. The participation of LPS in the induction of SGVHD will be investigated using LPS-responsive and non- responsive animals. Autologous/syngeneic GVHD is being examined clinically and experimentally for graft-versus-leukemia (GVL) responses. Recently, we have shown that mice with SGVHD to reject a primary, but not a secondary tumor challenge with an autologous class II B cell lymphoma, suggesting the involvement of non-specific effector mechanisms. In contrast, tumor expression of MHC class II molecules has been shown to result in the development of T cell-mediated specific anti-tumor immunity. The role of tumor class II expression in the generation of non-specific and specific anti-tumor immunity in SGVHD challenged with class II plus and class II minus tumors mice will be determined. The nature and specificity of the anti-tumor effector mechanisms (cytokine and lymphoid) present in tumor-bearing mice with syngeneic GVHD will be analyzed in vivo and in vitro. Finally, the ability of adjuvant cytokine therapy to facilitate the development of specific anti-tumor immunity will be determined. The analysis of murine SGVHD should present a unique opportunity to study the immune responses which participate in the development of potential immunotherapeutic GVL properties following syngeneic BMT.
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