title: Presensitization accelerates chronic allograft rejection in a heterotopic rat tracheal allograft model with immunosuppression.
abstract: BACKGROUND
  In the field of organ transplantation, the effect of pretransplant humoral allosensitization on the organ transplant outcome has been highlighted. To clarify the correlation of presensitization with chronic rejection that can lead to a poor prognosis in transplant recipients, we examined humoral alloreactivity and allograft rejection in sensitized recipients by using a rat heterotopic tracheal transplant model.
  
  
  METHODS
  An MHC fully incompatible combination strain was used in this study. Lewis (LEW) rats sensitized by transplantation with Brown Norway (BN) skin grafts received tracheal segments from BN rats in the dorsal subcutaneous pouch. Four allogenic groups (n=5) were investigated. Group 1, non-sensitized recipients without cyclosporine A (CsA) administration; group 2, non-sensitized recipients with CsA administration; group 3, sensitized recipients without CsA administration; and group 4, sensitized recipients with CsA administration. In the immunosuppressant groups (groups 2 and 4), the recipients were administered a subcutaneous injection of CsA (25 mg x kg(-1) x day(-1)) for 3 days from the day of operation. All recipients were sacrificed 21 days after transplantation. Tracheal segments were extracted from the recipients and histologically evaluated with regard to the following parameters: (1) airway lining epithelial loss, (2) lymphocyte/plasma cell infiltration, and (3) luminal obliteration due to granulation tissue formation and/or fibrosis. In order to analyze alloantibody (allo-Ab) responses, sera samples were tested by the flow cytometric cross-match (FCXM) technique.
  
  
  RESULTS
  Histological findings revealed that the chronic rejection score in sensitized recipients treated with CsA was significantly higher than that in non-sensitized recipients treated with CsA (9.0+/-1.2 vs. 3.0+/-0.54, p<0.05). In other words, CsA therapy reduced the rejection score in non-sensitized recipients, but not in sensitized recipients. No significant differences were observed in the level of IgM Abs among the groups. However, donor-specific IgG Abs were induced after presensitization by donor skin grafting prior to tracheal transplantation. Heterotopic tracheal implantation also induced IgG Ab production. This elevation in the Ab levels was inhibited by CsA treatment in non-sensitized recipients. Conversely, the Ab levels were significantly higher in sensitized recipients than in non-sensitized recipients, regardless of CsA administration.
  
  
  CONCLUSIONS
  Our data showed that presensitization accelerates chronic allograft rejection with a marked elevation in the level of donor specific IgG Abs. These results suggest that presensitization will be a significant risk factor for the lung transplant recipient, furthermore, the effect of immunosuppression might be insufficient in sensitized recipients.
authors.affiliation: Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Okumoto
authors.forename: Masaomi
authors.initials: M
authors.lastname: Yamane
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sano
authors.forename: Motoi
authors.initials: M
authors.lastname: Aoe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D000917:Antibody Formation; D016572:Cyclosporine; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology*; D007114:Immunization / Q000009:adverse effects*; D007074:Immunoglobulin G / Q000097:blood; D007165:Immunosuppression Therapy; D051381:Rats; D011919:Rats, Inbred Strains; D014019:Tissue Donors; D014132:Trachea / Q000473:pathology / Q000637:transplantation*
chemical_list: D000906:Antibodies; D006680:HLA Antigens; D007074:Immunoglobulin G; D016572:Cyclosporine