title: Induction of heme oxygenase-1 in the donor reduces graft immunogenicity.
abstract: There is increasing evidence that the induction of the enzyme heme oxygenase-1 (HO-1) improves both graft function and survival. Although it has been shown that HO-1 promotes graft protection, it remains unknown whether it reduces graft immunogenicity by modulating dendritic cells. In the current experiment, we investigated the impact of HO-1 induction on frequencies and trafficking of donor-derived dendritic cells (DCs). Kidneys from DA rats were transplanted into untreated Lewis recipients. Donor animals were treated with cobalt protoporphyrin (CoPP; 5 mg/kg IP) 24 hours prior to organ harvesting to induce HO-1. Controls remained untreated or received zinc protoporphyrin (ZnPP; 20 mg/kg, IP) to block HO-1 induction. Analyses of grafts, spleens, lymph nodes and blood of Lewis recipients were performed at days 1 and 3 posttransplantation. Donor-specific DCs were determined by flow cytometry using haplotype-specific mAb against RT1(ab) and mAb against OX62(+) antigens. Cell markers (CD4/CD8(+) T cells, ED1(+) monocytes, MHC class II(+) CD86(+) DC) were measured by immunohistochemical staining. T-cell alloreactivity of recipient splenocytes was measured by ELISPOT. Induction of HO-1 reduced frequencies of donor-derived DCs in the graft and recipient compartments, which was associated with reduced frequencies of CD4(+) T cells and CD8(+) T cells and alloreactivity. Expression of costimulatory molecule CD86 and MHC class II antigens were also reduced, although not significantly. Thus, induction of HO-1 reduced graft immunogenicity. These mechanisms may explain the protective effects of HO-1 induction.
authors.affiliation: Departments of General and Transplantation Surgery and Medical Immunology, Charité, Berlin, Germany.
authors.forename: P N A
authors.initials: PN
authors.lastname: Martins
authors.forename: H
authors.initials: H
authors.lastname: Kessler
authors.forename: A
authors.initials: A
authors.lastname: Jurisch
authors.forename: A
authors.initials: A
authors.lastname: Reutzel-Selke
authors.forename: J
authors.initials: J
authors.lastname: Kramer
authors.forename: A
authors.initials: A
authors.lastname: Pascher
authors.forename: J
authors.initials: J
authors.lastname: Pratschke
authors.forename: P
authors.initials: P
authors.lastname: Neuhaus
authors.forename: H D
authors.initials: HD
authors.lastname: Volk
authors.forename: S G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D009392:Nephrectomy; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D020858:Tissue and Organ Harvesting; D014184:Transplantation, Homologous / Q000276:immunology / Q000502:physiology
chemical_list: D000949:Histocompatibility Antigens Class II; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1