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Hepatocyte Growth Factor Sustains T Regulatory Cells and Prolongs the Survival of Kidney Allografts in Major Histocompatibility Complex-Inbred CLAWN-Miniature Swine

Oku, Manei1,2; Okumi, Masayoshi1; Shimizu, Akira1,3; Sahara, Hisashi1; Setoyama, Kentaro1; Nishimura, Hiroaki1; Sada, Masaharu1; Scalea, Joseph3; Ido, Akio2; Sachs, David H.3; Tsubouchi, Hirohito2; Yamada, Kazuhiko1,3,4

doi: 10.1097/TP.0b013e31823be83f
Basic and Experimental Research

Background. Although 12 days of high dose of FK506 permits the induction of tolerance of fully major histocompatibility complex (MHC)-mismatched allogeneic kidneys in MGH-miniature swine, we found that the same dose of FK506 is insufficient to induce such tolerance CLAWN-miniature swine. The CLAWN swine model was therefore chosen to study the potential immunoregulatory effects of human-recombinant hepatocyte growth factor (HGF).

Methods. Ten CLAWN miniature swine received fully MHC-mismatched kidneys with 12 days (days 0–11) of FK506. Among these 10 recipients, 4 received 7 or 14 days of human-recombinant HGF starting at day 11. Graft function was assessed by daily serum creatinine and biopsies. Immunologic assays, including CD4/CD25 DP and FoxP3+ cells and development of antidonor antibodies, were performed.

Results. Without HGF, all six CLAWN recipients developed severe acute rejection (Cre >9 mg/dL) within 3 weeks of transplantation. In contrast, in the four animals that received HGF for 7 to 14 days, stable renal function was observed for more than 50 days, although all grafts were ultimately rejected by postoperative day 80. Percent FoxP3+ cells in the CD4+CD25+ double positive population (T regulatory cells) in peripheral blood monocyte cells decreased in recipients with FK506 induction monotherapy while no reduction was observed in recipients treated with FK506 and HGF.

Conclusion. This study demonstrates that in CLAWN swine treated with a dose of FK506 insufficient to induce tolerance across a fully MHC mismatched barrier, a short course of HGF may inhibit acute rejection while maintaining T regulatory cells. To our knowledge, this study provides the first evidence in a large animal transplantation model of HGF's immunoprotective effects.

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1Division of Xenotransplantation Surgery, Frontier Science Research Center, Kagoshima University, Sakuragaoka, Kagoshima, Japan.

2Department of Digestive and Life-Style Related Disease, Kagoshima University Graduate School of Medical and Dental Science, Sakuragaoka, Kagoshima, Japan.

3Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA.

This work was supported by Grant-in-Aid for Scientific Research (B) 19390422 (M.S. and K.Y.), Grant-in-Aid for Scientific Research (A) 19209043 (K.Y) and the Kagoshima University Research Awards (K.Y.).

The authors declare no conflicts of interest.

Address correspondence to: Kazuhiko Yamada, M.D., Ph.D., Organ Replacement and Xenotransplant Surgery Section, Frontier Science Research Center, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan. E-mail: kaz.yamada@tbrc.mgh.harvard.edu

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.transplantjournal.com).

Received 28 July 2011. Revision requested 17 August 2011.

Accepted 6 October 2011.

© 2012 Lippincott Williams & Wilkins, Inc.