Induction of heme oxygenase-1 before conditioning results in improved survival and reduced graft-versus-host disease after experimental allogeneic bone marrow transplantation.
Acute graft-versus-host disease (aGVHD) remains one of the main obstacles after allogeneic bone marrow transplantation (BMT). Using a well-established mouse BMT model in which aGVHD is induced across a haploidentical mismatch, we show that the expression of heme oxygenase-1 (HO-1) can be induced by cobalt-protoporphyrin IX (CoPP) in aGVHD target organs such as liver and bowel and that the induction of HO-1 before BMT results in improved overall survival and reduced aGVHD. Serum levels of proinflammatory cytokines were markedly reduced in CoPP-treated animals. Recipients displayed less damage to the intestinal mucosa, and this resulted in reduced serum lipopolysaccharide levels at day 6 after transplantation. Peritoneal cells and CD45(+) liver cells isolated from mice that received transplants strongly expressed HO-1 and displayed a reduction in the expression of activation markers such as CD11b, CD80, and major histocompatibility complex class I. This resulted in reduced T-cell activation ex vivo. These results demonstrate that the induction of HO-1 before high-dose conditioning protects the host in multiple ways and effectively ameliorates aGVHD.
Gerbitz
Armin
A
Department of Hematology/Oncology, University of Regensburg, Germany. armin.gerbitz@med.uni-muenchen.de
Ewing
Patricia
P
Wilke
Andrea
A
Schubert
Thomas
T
Eissner
Günther
G
Dietl
Barbara
B
Andreesen
Reinhard
R
Cooke
Kenneth R
KR
Holler
Ernst
E
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D003035:Cobalt / Q000008:administration & dosage*; D016207:Cytokines / Q000097:blood; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000097:blood / Q000209:etiology / Q000401:mortality; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000276:immunology; D051547:Heme Oxygenase-1; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D011524:Protoporphyrins / Q000008:administration & dosage*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous
D015703:Antigens, CD; D016207:Cytokines; D008565:Membrane Proteins; D011524:Protoporphyrins; D003035:Cobalt; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse