Value of FOXP3 expression in peripheral blood as rejection marker after miniature swine lung transplantation.
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.
Satoda
Naoki
N
Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.
Shoji
Tsuyoshi
T
Wu
Yanling
Y
Fujinaga
Takuji
T
Chen
Fengshi
F
Aoyama
Akihiro
A
Zhang
Ji Tian
JT
Takahashi
Ayuko
A
Okamoto
Toshihiro
T
Matsumoto
Izumi
I
Sakai
Hiroaki
H
Li
Ying
Y
Zhao
Xiangdong
X
Manabe
Toshiaki
T
Kobayashi
Eiji
E
Sakaguchi
Shimon
S
Wada
Hiromi
H
Ohe
Hidenori
H
Uemoto
Shinji
S
Tottori
Junichi
J
Bando
Toru
T
Date
Hiroshi
H
Koshiba
Takaaki
T
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
D017931:DNA Primers; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D054353:Perforin