Value of FOXP3 Expression in Peripheral Blood as Rejection Marker After Miniature Swine Lung Transplantation

Presented at the American Transplant Congress (ATC), May 2007, San Francisco, California, and at the 28th annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), April 2008, Boston, Massachusetts where Naoki Satoda was a nominee for the Philip K. Caves Award.

Received 13 April 2008; received in revised form 1 August 2008; accepted 21 August 2008.

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.

a Department of Thoracic Surgery, Kyoto University, Kyoto, Japan

b Innovation Center for Immunoregulation Technologies and Drugs, Transplant Tolerance Unit, Kyoto University, Kyoto, Japan

c Department of Organ Preservation Technology, Kyoto University, Kyoto, Japan

d Department of Diagnostic Pathology, Kyoto University, Kyoto, Japan

e Organ Replacement Research Center, Jichi Medical School, Shimono, Japan

f Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

g Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

h Japan Farm CLAWN Institute, Isa, Kagoshima, Japan

Reprint requests: Takaaki Koshiba, MD, PhD, Innovation Center for Immunoregulation Technologies and Drugs, Transplant Tolerance Unit, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Telephone: 81-75-751-4328. Fax: 81-75-751-4328

Supported by grants-in-aids from the Ministry of Health, Labor and Welfare; Astellas Pharma, Inc.; and Otsuka Pharmaceutical.

PII: S1053-2498(08)00615-3

doi:10.1016/j.healun.2008.08.006

7 of 19