title: Replacement of graft-resident donor-type antigen presenting cells alters the tempo and pathogenesis of murine cardiac allograft rejection.
abstract: BACKGROUND
  Graft-resident antigen presenting cells (APCs) are potent stimulators of the alloresponse. To test whether replacement of graft-resident donor-type APCs with those of recipient-type alters allorecognition and the pathogenesis of both acute and chronic rejection, we created chimeric hearts for transplantation into naive recipients.
  
  
  METHODS
  To replace donor-type APCs with those of recipient-type, chimeric animals were created by bone marrow transplantation (BMT) in fully allogeneic mouse and rat strain combinations. The degree of APC replacement in chimeric organs was assessed phenotypically and functionally. Chimeric hearts were transplanted heterotopically into untreated recipients.
  
  
  RESULTS
  Flow cytometric and immunohistochemical analysis did not detect residual bone marrow recipient-type APCs in mouse BMT chimeras. Although semi-quantitative reverse transcription polymerase chain reaction detected 0.001-0.01% residual cells, APCs isolated from chimeric organs were functionally unable to stimulate donor-type cells. When transplanted into naive recipients, chimeric mouse hearts had significantly prolonged survival but were nevertheless rejected acutely. Similar results were obtained in the ACI --> LEW rat strain combination. However, in the PVG --> DA rat model, the majority of chimeric hearts survived >100 days and all long-surviving hearts developed cardiac allograft vasculopathy.
  
  
  CONCLUSIONS
  BMT leads to near complete replacement of organ-resident APCs. The virtual absence of donor-type APCs in chimeric hearts delays or prevents acute rejection in a strain-dependent manner. In contrast, this type of graft modification does not prevent cardiac allograft vasculopathy. This suggests that, although the CD4+ direct pathway may play a role in acute rejection, it is not essential for the development of chronic rejection in rodent cardiac allografts.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Health System, Philadelphia 19104, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Krasinskas
authors.forename: S D
authors.initials: SD
authors.lastname: Eiref
authors.forename: A D
authors.initials: AD
authors.lastname: McLean
authors.forename: D
authors.initials: D
authors.lastname: Kreisel
authors.forename: A E
authors.initials: AE
authors.lastname: Gelman
authors.forename: S H
authors.initials: SH
authors.lastname: Popma
authors.forename: J S
authors.initials: JS
authors.lastname: Moore
authors.forename: B R
authors.initials: BR
authors.lastname: Rosengard
mesh_terms: D000208:Acute Disease; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D002678:Chimera / Q000276:immunology; D002908:Chronic Disease; D017931:DNA Primers / Q000235:genetics; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D014184:Transplantation, Homologous
chemical_list: D017931:DNA Primers; D000949:Histocompatibility Antigens Class II