title: Value of FOXP3 expression in peripheral blood as rejection marker after miniature swine lung transplantation.
abstract: BACKGROUND
  Outcome for highly immunogenic lung transplantation remains unsatisfactory despite the development of potent immunosuppressants. The poor outcome may be the result of a lack of minimally invasive methods to detect early rejection. There is emerging clinical evidence that, paradoxically, expression of forkhead box P3 (FOXP3, a specific marker for the regulatory T cells) is upregulated within rejecting grafts.
  
  
  METHODS
  Orthotopic lung transplantation was performed using miniature swine without immunosuppression. Rejection was monitored by chest radiography and open lung biopsy. Expressions levels of FOXP3, perforin, Fas-L and IP-10 mRNA were quantified in the peripheral blood. In addition, rescue immunosuppressive therapy (steroid plus tacrolimus) was administered on post-operative day (POD) 4 or 6.
  
  
  RESULTS
  Early rejection was detected by open lung biopsy, but misdiagnosed by chest radiography on POD 4. Expression of FOXP3 in the peripheral blood reached its highest value as early as POD 4, followed by a decline. Such an increase of FOXP3 was not observed in recipients given high-dose tacrolimus. Neither perforin, Fas-L or IP-10 in the peripheral blood exhibited significant fluctuations in the early phase of rejection. Rescue immunosuppressive therapy from POD 4, when peak FOXP3 was seen, prolonged graft survival (27.2 days, versus 9.1 days without immunosuppression, p < 0.001), in contrast to POD 6, when rejection was suspected by chest radiography (11.5 days, p = not statistically significant [NS]).
  
  
  CONCLUSIONS
  In a miniature swine lung transplantation model, the FOXP3 mRNA level in the peripheral blood was upregulated at an early phase of rejection. The clinical implication of this finding remains to be elucidated.
authors.affiliation: Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Satoda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shoji
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wu
authors.forename: Takuji
authors.initials: T
authors.lastname: Fujinaga
authors.forename: Fengshi
authors.initials: F
authors.lastname: Chen
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoyama
authors.forename: Ji Tian
authors.initials: JT
authors.lastname: Zhang
authors.forename: Ayuko
authors.initials: A
authors.lastname: Takahashi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Okamoto
authors.forename: Izumi
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakai
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhao
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Manabe
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Wada
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohe
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Junichi
authors.initials: J
authors.lastname: Tottori
authors.forename: Toru
authors.initials: T
authors.lastname: Bando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.forename: Takaaki
authors.initials: T
authors.lastname: Koshiba
mesh_terms: D000208:Acute Disease; D000818:Animals; D017931:DNA Primers; D053222:Fas Ligand Protein / Q000097:blood / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000097:blood* / Q000235:genetics*; D006084:Graft Rejection / Q000097:blood* / Q000175:diagnosis; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D054353:Perforin / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics*; D015424:Reperfusion / Q000379:methods; D013552:Swine; D013556:Swine, Miniature
chemical_list: D017931:DNA Primers; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D054353:Perforin