My research is focused on cytokine and alloantibody networks contributing to acute and chronic rejection of cardiac allografts. Alloantibody is an intrinsic component of the immune response to organ transplants and is correlated with decreased graft survival and graft injury. These studies have great relevance to clinical transplantation, because the ever increasing population of highly sensitized patients represents one of the most challenging problems in organ transplantation.

In vitro studies suggest that alloantibodies manifest their effect directly and indirectly. By cross-linking class I MHC molecules on the surface of endothelial cells and smooth muscle cells, alloantibodies can stimulate the synthesis of growth factors (TGF-ß, PDGF and FGF) and secretion of monocyte chemotactic protein-1 (MCP-1). Macrophages can be activated by antibody and complement through Fc and complement receptors. FcgRs, which are expressed on a wide variety of hematopoeitic cells, including macrophages, monocytes and NK cells link cellular and humoral immunity by bridging the antibody specificity to effector cells. Activated macrophages can produce TNF-a and IL-1, which in turn can augment endothelial cell activation.

Using immunoglobulin and complement knock-out mice, we established models to test the mechanisms by which alloantibodies and complement are critical to the process of acute cardiac rejection and pathogenesis of vascular lesions.

In our recent studies we tested the hypothesis that the passive transfer of combinations of different alloantibody subclasses may be different than the effect of these subclasses transferred separately. We documented that although passive transfer of a non-complement activating IgG1 alone does not reconstitute acute graft rejection, it does when combined with a subthreshold dose of IgG2b alloantibodies. IgG1 alloantibodies also augment endothelial injury caused by IgG2b alloantibodies in vivo and stimulate pro-inflammatory phenotype of mouse endothelial cells in the absence of complement. These findings indicate that non-complement activating alloantibodies can augment injury by complement activating alloantibodies.