Cobalt protoporphyrine IX-mediated heme oxygenase-I induction alters the inflammatory cytokine response, but not antigen presentation after experimental allogeneic bone marrow transplantation.
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.
Department of Hematology and Oncology, University of Regensburg, Medical School, D-93053 Regensburg, Germany. patricia.ewing@klinik.uni-regensburg.de
Patricia
P
Ewing
Gerhard C
GC
Hildebrandt
Simone
S
Planke
Reinhard
R
Andreesen
Ernst
E
Holler
Armin
A
Gerbitz
D000208:Acute Disease; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006086:Graft vs Host Disease / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D016207:Cytokines; D018836:Inflammation Mediators; D011524:Protoporphyrins; D014409:Tumor Necrosis Factor-alpha; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1