Donor HO-1 Expression Inhibits Intimal Hyperplasia in Unmanipulated Graft Recipients: A Potential Role for CD8+ T-Cell Modulation by Carbon Monoxide

BACKGROUND: Induction of heme oxygenase (HO)-1 expression protects transplanted organs from humoral rejection and ischemia-reperfusion injury, but induction in recipient immune cells also has direct immunomodulatory effects. Although many studies have examined the impact of HO-1 after transplantation, it is still unclear whether HO-1 expression solely in the donor tissue can influence the recipient T-cell response. METHODS: Donor mice were treated with hemin to transiently upregulate HO-1. Control or HO-1-expressing aortas were transplanted into fully mismatched, completely unmanipulated recipients, and harvested at 6 weeks to assess neointimal area and T-cell infiltration. T cells were isolated from draining lymph nodes to assess cytokine production. In vitro, T-cell proliferative and cytokine responses to allogeneic donor dendritic (DC) and endothelial cells expressing HO-1 were examined. RESULTS: Neointimal area was significantly (P<0.01) reduced in HO-1-expressing grafts. Hemin pretreated endothelial cells significantly inhibited proliferation (P<0.01) and interferon (IFN)-gamma production (P =0.01) in allogeneic CD8 T cells. This effect was mimicked by a carbon monoxide-releasing molecule. No phenotypic or functional changes were observed after incubation of T cells with hemin-treated dendritic cells. T-cell infiltration of HO-1-expressing donor aortas was significantly reduced (P<0.001), but proportions of IFN-gamma-producing T cells harvested from regional lymph nodes were similar. CONCLUSIONS: Organs expressing cytoprotective HO-1 have a direct influence on the recipient immune response. Given the important role of CD8 T cells and IFN-gamma in chronic rejection, these data suggest that donor HO-1 expression may be useful to augment other immunosuppressive therapies to prolong graft survival and inhibit intimal hyperplasia.