Hepatocyte Growth Factor Sustains T Regulatory Cells and Prolongs the Survival of Kidney Allografts in Major Histocompatibility Complex-Inbred CLAWN-Miniature Swine
Hepatocyte Growth Factor Sustains T Regulatory Cells and Prolongs the Survival of Kidney Allografts in Major Histocompatibility Complex-Inbred CLAWN-Miniature Swine
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DOI：
10.1097/tp.0b013e31823be83f
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发表时间：
2012-01-27
期刊：
影响因子：
6.2
通讯作者：
Yamada, Kazuhiko
中科院分区：
文献类型：
--
作者：
Oku, Manei;Okumi, Masayoshi;Yamada, Kazuhiko
背景资料。虽然12天的大剂量FK506可以诱导MGH小型猪完全主要组织相容性复合体(MHC)不相合的同种异体肾耐受，但我们发现相同剂量的FK506不足以诱导CLAWN小型猪的耐受。因此，选择CLAWN猪模型，研究重组人肝细胞生长因子(HGF)的潜在免疫调节作用。10只CLAWN小型猪接受了12天(0-11天)FK506的完全MHC不匹配的肾脏。在这10名受者中，有4人从第11天开始接受7天或14天的重组人肝细胞生长因子治疗。移植肾功能通过每日血肌酐和活组织检查进行评估。进行免疫学检测，包括CD4/CD25DP、FoxP3+细胞和抗供体抗体的产生。在没有HGF的情况下，所有6个CLAWN受者在移植后3周内都出现了严重的急性排斥反应(CRE和GT；9 mg/dL)。相反，在接受HGF治疗7至14天的四只动物中，观察到肾功能稳定的时间超过50天，尽管所有移植物在术后第80天最终都被排斥。FK506单独治疗受者外周血单核细胞中的FoxP3+细胞占外周血单核细胞中CD4+CD25+双阳性细胞(T调节性细胞)的百分比下降，而FK506和HGF联合治疗受者外周血中FoxP3+细胞的百分率无明显下降。这项研究表明，在CLAWN猪中，治疗剂量的FK506不足以诱导跨越完全MHC不匹配屏障的耐受，短期的HGF可以在维持T调节细胞的同时抑制急性排斥反应。据我们所知，这项研究在大型动物移植模型中首次提供了HGF免疫保护作用的证据。
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.