Cobalt protoporphyrine IX-mediated heme oxygenase-I induction alters the inflammatory cytokine response, but not antigen presentation after experimental allogeneic bone marrow transplantation

Abstract

Acute graft-versus-host disease (aGvHD) remains the major cause of mortality after allogeneic stem cell transplantation. Acute GvHD can be partially prevented when heme oxygenase-1 (HO-1) is induced in the recipient prior to transplantation but the mechanisms are not fully understood. Using a murine haploidentical bone marrow transplantation (BMT) model (C57Bl/6 right curved arrow B6D2F1) we tested whether HO-1 induction altered the alloreactive T cell response or rather modulated the inflammatory cytokine profile early after BMT. In vivo administration of cobalt protoporphyrin IX (CoPP) did not affect the expression of MHC class I and II or the costimulatory molecules CD80 and CD86 on murine peritoneal and on splenic dendritic cells (DCs). Allospecific T cell proliferation and interferon gamma secretion did not differ in mixed lymphocyte reactions using either CoPP-pretreated allogeneic recipients or control-treated DCs as stimulators. Furthermore, splenic DCs, isolated one to four days after BMT from CoPP-pretreated recipients did not show any differences in the expression of costimulatory molecules compared to untreated controls, and T cell expansion and the cytolytic capacity 14 days after BMT were equal in the control and CoPP-treated allogeneic groups. Serum tumor necrosis factor alpha levels were significantly reduced in CoPP-treated allogeneic recipients when compared to allogeneic controls and did not differ from the syngeneic recipients. Our results indicate that the protective effects of CoPP-mediated HO-1 induction on survival and aGvHD after allogeneic BMT involve a reduction in the proinflammatory cytokine milieu rather than alteration in allospecific T cell stimulation.