Heme oxygenase-1 is essential for and promotes tolerance to transplanted organs.
This investigation focused on obtaining a further understanding of the role of heme oxygenase-1 (HO-1) in tolerance induction. Hearts from C57BL/6 (H-2b) mice survived long-term when transplanted into BALB/c (H-2d) recipients treated with the tolerance-inducing regimen of anti-CD40L antibody (MR-1) plus donor-specific transfusion (DST). Grafts did not, however, survive long-term in (HO-1-/-) recipients given the same treatment. Similarly, long-term survival induced by DST was ablated when HO-1 activity was blocked by zinc protoporphyrin IX (ZnPPIX). We further asked whether modulation of HO-1 expression/activity could be used to promote the induction of graft tolerance. DST alone (day 0) failed to promote any prolongation of survival of DBA/2 (H-2d) hearts transplanted into B6AF1 (H-2(b,k/d)) recipients. However, long-term survival and (dominant peripheral) tolerance were readily induced when DST was combined with induction of HO-1 expression by cobalt protoporphyrin IX (CoPPIX). HO-1 induction plus DST led to a significant up-regulation of Foxp3, TGF-beta, IL-10, and CTLA4, which suggests a prominent role for CD4+CD25+ regulatory T cells (Tregs). In fact, the tolerogenic effect of HO-1 plus DST was dependent on CD4+CD25+ Tregs as suggested by adoptively transferring these cells into irradiated recipients under various regimens. Taken together, these findings show that expression of HO-1 in a graft recipient can be essential for long-term graft survival and for induction of tolerance and that modulation of HO-1 expression/activity can be used therapeutically to synergize in the generation of graft tolerance.
Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Kenichiro
K
Yamashita
Robert
R
Ollinger
James
J
McDaid
Hideyasu
H
Sakahama
Hongjun
H
Wang
Shivraj
S
Tyagi
Eva
E
Csizmadia
Neal R
NR
Smith
Miguel P
MP
Soares
Fritz H
FH
Bach
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D016027:Heart Transplantation / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins; D013601:T-Lymphocytes / Q000378:metabolism; D023001:Transplantation Tolerance
D011524:Protoporphyrins; C017803:zinc protoporphyrin; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1