Lin C H, Wang Y L, Anggelia M R, Chuang W Y, Cheng H Y, Mao Q, Zelken J A, Lin C H, Zheng X X, Lee W P A, Brandacher G
Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Pathology, Chang Gung Memorial Hospital, Chang Gung Medical College and Chang Gung University, Taoyuan, Taiwan.
Am J Transplant. 2016 Jul;16(7):2030-41. doi: 10.1111/ajt.13694. Epub 2016 Feb 23.
Tolerance induction by means of costimulation blockade has been successfully applied in solid organ transplantation; however, its efficacy in vascularized composite allotransplantation, containing a vascularized bone marrow component and thus a constant source of donor-derived stem cells, remains poorly explored. In this study, osteomyocutaneous allografts (alloOMCs) from Balb/c (H2(d) ) mice were transplanted into C57BL/6 (H2(b) ) recipients. Immunosuppression consisted of 1 mg anti-CD154 on day 0, 0.5 mg CTLA4Ig on day 2 and rapamycin (RPM; 3 mg/kg per day from days 0-7, then every other day for 3 weeks). Long-term allograft survival, donor-specific tolerance and donor-recipient cell trafficking were evaluated. Treatment with costimulation blockade plus RPM resulted in long-term graft survival (>120 days) of alloOMC in 12 of 15 recipients compared with untreated controls (median survival time [MST] ≈10.2 ± 0.8 days), RPM alone (MST ≈33 ± 5.5 days) and costimulation blockade alone (MST ≈45.8 ± 7.1 days). Donor-specific hyporesponsiveness in recipients with viable grafts was demonstrated in vitro. Evidence of donor-specific tolerance was further assessed in vivo by secondary donor-specific skin graft survival and third-party graft rejection. A significant increase of Foxp3(+) regulatory T cells was evident in tolerant animals. Donor cells populated peripheral blood, thymus, and both donor and recipient bone marrow. Consequently, combined anti-CD154/CTLA4Ig costimulation blockade-based therapy induces donor-specific tolerance in a stringent murine alloOMC transplant model.
通过共刺激阻断诱导免疫耐受已成功应用于实体器官移植；然而，其在含有血管化骨髓成分（因而也是供体来源干细胞的恒定来源）的血管化复合异体移植中的疗效仍未得到充分探索。在本研究中，将来自Balb/c（H2(d)）小鼠的骨肌皮同种异体移植物（alloOMC）移植到C57BL/6（H2(b)）受体中。免疫抑制方案包括在第0天给予1mg抗CD154，第2天给予0.5mg CTLA4Ig以及雷帕霉素（RPM；从第0 - 7天每天3mg/kg，然后每隔一天给药3周）。评估了长期同种异体移植物存活、供体特异性耐受以及供体 - 受体细胞迁移情况。与未治疗的对照组（中位存活时间[MST]≈10.2±0.8天）、单独使用RPM（MST≈33±5.5天）和单独使用共刺激阻断（MST≈45.8±7.1天）相比，共刺激阻断联合RPM治疗使15只受体中的12只实现了alloOMC的长期移植物存活（>120天）。在体外证实了具有存活移植物的受体中的供体特异性低反应性。通过二次供体特异性皮肤移植物存活和第三方移植物排斥在体内进一步评估了供体特异性耐受的证据。在耐受动物中，Foxp3(+)调节性T细胞显著增加。供体细胞在受体的外周血、胸腺以及供体和受体的骨髓中均有分布。因此，基于联合抗CD154/CTLA4Ig共刺激阻断的疗法在严格的小鼠alloOMC移植模型中诱导了供体特异性耐受。
