title: Dendritic cell function in transplantation arteriosclerosis is regulated by heme oxygenase 1.
abstract: BACKGROUND
  Heme oxygenase (HO)1 is an important modulator of physiological function with cytoprotective properties. Although HO1 has previously been associated with an improved survival of the vascular allograft in rat models in response to pharmaceutical induction of HO1 the exact mechanism by which HO1 exerts it protective function remains to be elucidated.
  
  
  OBJECTIVE
  We sought to define the role of HO1 in dendritic cells (DCs) function that governs the alloimmune response underlying the development of transplantation associated vasculopathy.
  
  
  RESULTS
  Loss of HO1 in DCs or by small interfering RNA silencing resulted in major histocompatibility complex class II (MHCII) upregulation by CIITA- driven transcriptional regulation and by STAT1 (signal transducers and activators of transcription 1) phosphorylation. As a result, increased MHCII alloantigen presentation by HO1(-/-) DCs directed the primary T-cell response preferentially toward a CD4(+) T-cell, rather than a CD8(+) T-cell reaction. In a murine model for transplantation arteriosclerosis, adoptive transfer of HO1(-/-) DCs before allograft transplantation was indeed associated with pronounced intragraft CD4(+) T-cell infiltration and increased IgG deposition, suggestive of an accelerated development of vasculopathy toward the chronic phase. The role of HO1 in DC-mediated T cell activation was further validated by inhibition of endogenous HO1 in allograft recipients. Inhibition of HO1 in DCs aggravated transplant arteriosclerosis development, by increasing intima hyperplasia, and by activation of a CD4(+) T cells allograft response, mediated by MHCII upregulation.
  
  
  CONCLUSIONS
  These findings demonstrate that HO1 plays an important role in the genetic regulation of the vascular alloimmune response elicited by DCs.
authors.affiliation: Molecular Cardiology Laboratory, Department of Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
authors.forename: M
authors.initials: M
authors.lastname: Noorderloos
authors.forename: Elza D
authors.initials: ED
authors.lastname: van Deel
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.forename: Wijnand
authors.initials: W
authors.lastname: den Dekker
authors.forename: Kim
authors.initials: K
authors.lastname: Wagtmans
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1