期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 12, 期 9, 页码 2384-2394出版社
WILEY
DOI: 10.1111/j.1600-6143.2012.04143.x
关键词
T cell depleting mAb; calcineurin inhibitor; memory T cells; regulatory T cells; kidney transplantation
资金
- Else-Kroner-Fresenius-foundation, Germany [P14/06//A01/06]
- Deutsche Forschungsgemeinschaft [DFG-SFB 650 TP Z2+ 14]
- Federal Ministry of Education and Research
Recent data suggest that donor-specific memory T cells (Tmem) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life-supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor-specific CD4+/ 8+ GFP+ Tmem before transplantation to achieve similar pre-transplant frequencies of donor-specific Tmem as seen in many patients. T cell depletion alone induced long-term graft survival in naive recipients but could not prevent acute rejection in Tmem+ rats, like in patients. Only if T cell depletion was combined with permanent CNI-treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long-term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long-term graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in Tmem+ rats. Our model allows evaluation of novel therapies under clinically relevant conditions.
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