title: The histology of subcutaneously implanted donor bronchial rings correlates with rejection scores of lung allografts in a primate lung transplant model.
abstract: BACKGROUND
  The diagnosis of acute rejection in lung transplantation generally relies on transbronchial biopsies. This invasive procedure may be associated with bronchial bleeding or pneumothorax and may not be feasible in patients with severely compromised lung function. The hypothesis of the current study was that histopathological findings of donor bronchial segments implanted into the subcutaneous tissue of lung allograft recipients would predict lung tissue rejection scores, thus providing the clinician with an alternate source of information.
  
  
  METHODS
  Unilateral left lung transplantation was performed in 34 cynomolgus monkeys as part of a drug efficacy study. After completion of the transplant procedure, 4 bronchial ring segments of the explanted recipient left lung and 4 bronchial ring segments of the non-transplanted right donor lung were implanted subcutaneously in the abdominal region. Lung allograft rejection was evaluated by open lung biopsies of the allograft performed on postoperative (PO) Day 14 and during sacrifice on PO Day 28. At the time of each biopsy, 2 donor and 2 recipient subcutaneous bronchial rings were explanted. Histologic evaluation of the lung tissue samples was performed according to the working formulation of the International Society for Heart and Lung Transplantation. Bronchial rings were independently evaluated by assessing the degree of airway narrowing; percentage of intact epithelial coverage as well as its specific histology (respiratory ciliated, flattened cuboidal, squamous); presence of lymphocytes, macrophages or spindle cells; and presence of peribronchial inflammation, luminal fibrosis, lymphocytic bronchitis or luminal mucous. Statistical analysis was performed by logistic regression.
  
  
  RESULTS
  In the recipient bronchial rings, there was no evidence of airway narrowing. There was 98% epithelial coverage, 71% that were respiratory ciliated cells, and there was no inflammation. Donor bronchial rings showed no airway narrowing for monkeys with grade A0 to A2 rejection in tissue biopsies and a maximum narrowing (41.2%) with A4 rejection. Epithelial cell coverage was approximately 100% with grade A0-A2 and 44+/-11% with A4 rejection. Lymphocytic bronchitis was most severe in A4 rejection and minimal in A0 to A2 rejection. By logistic regression analysis, independent predictors of a likelihood of rejection were the degree of airway obliteration, the percentage of epithelial cell coverage, the degree of lymphocytic bronchitis and the product of respiratory and flattened cuboidal cell coverage.
  
  
  CONCLUSIONS
  The current data show that histologic alterations of subcutaneously implanted donor bronchial rings correlate with lung tissue biopsy scores based on the ISHLT working formulation. Because subcutaneous bronchial rings can be explanted under local anesthesia, they may provide useful information for the diagnosis of acute allograft rejection in patients with impaired lung function, patients that obtaining lung tissue samples may not be feasible.
authors.affiliation: Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California 94305-5407, USA. Hausen@leland.stanford.edu
authors.forename: B
authors.initials: B
authors.lastname: Hausen
authors.forename: G J
authors.initials: GJ
authors.lastname: Berry
authors.forename: P
authors.initials: P
authors.lastname: Dagum
authors.forename: T
authors.initials: T
authors.lastname: Ikonen
authors.forename: U
authors.initials: U
authors.lastname: Christians
authors.forename: N
authors.initials: N
authors.lastname: Briffa
authors.forename: L
authors.initials: L
authors.lastname: Hook
authors.forename: R E
authors.initials: RE
authors.lastname: Morris
mesh_terms: D000208:Acute Disease; D000818:Animals; D001706:Biopsy; D001980:Bronchi / Q000473:pathology* / Q000637:transplantation*; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000473:pathology*; D007165:Immunosuppression Therapy / Q000379:methods; D016015:Logistic Models; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000379:methods / Q000473:pathology* / Q000706:statistics & numerical data; D008252:Macaca fascicularis; D008297:Male; D012867:Skin; D018709:Statistics, Nonparametric; D016042:Transplantation, Heterotopic / Q000473:pathology* / Q000706:statistics & numerical data; D014184:Transplantation, Homologous