Olariu Radu, Denoyelle Julie, Leclère Franck M, Dzhonova Dzhuliya V, Gajanayake Thusitha, Banz Yara, Hayoz Michael, Constantinescu Mihai, Rieben Robert, Vögelin Esther, Taddeo Adriano
Department of Plastic, Reconstructive, and Hand Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
Department of Clinical Research, University of Bern, Bern, Switzerland.
J Surg Res. 2017 Oct;218:49-57. doi: 10.1016/j.jss.2017.05.046. Epub 2017 Jun 10.
Immunosuppressive therapies derived from solid organ transplantation are effective in promoting survival of vascularized composite allotransplantation (VCA), but they cause serious side effects that are difficult to justify for this non-life-saving procedure. Unlike solid organ transplantation, hand and face transplants offer the possibility of site-specific immunosuppression for reducing systemic exposure while increasing intra-graft concentrations of the drug. Therefore, in this study, we tested whether a single intra-graft injection tacrolimus could promote VCA survival.
Brown Norway-to-Lewis hind limb transplantations were performed, and animals were left untreated (group I), treated with a daily injection of 1-mg/kg tacrolimus for 21 days (group 2) or injected with 7-mg tacrolimus directly into the transplanted limb on day 1 (group III). Graft rejection was monitored, and animals were sacrificed at grade 3 rejection or 200 days after transplantation.
Intra-graft injection of tacrolimus significantly prolonged allograft survival as compared to untreated animals or animals treated with systemic tacrolimus. Half of the intra-graft-treated rats rejected their graft on average at day 70.5. Interestingly, the other half remained rejection-free for more than 200 days without signs of kidney or liver toxicity. In these animals, tacrolimus was detected in the VCA skin but not in the blood until day 200. Long-term survival was not linked to induction of donor-specific tolerance but to a higher level of lymphocyte chimerism.
Intra-graft delivery of tacrolimus may promote VCA survival by increasing tissue drug availability and promoting the establishment of transient chimerism and thus long-term graft acceptance.
源自实体器官移植的免疫抑制疗法在促进血管化复合异体移植（VCA）存活方面有效，但会引发严重副作用，而对于这种非挽救生命的手术来说，这些副作用难以合理化。与实体器官移植不同，手和面部移植提供了局部特异性免疫抑制的可能性，可减少全身暴露，同时提高移植组织内药物浓度。因此，在本研究中，我们测试了单次移植组织内注射他克莫司是否能促进VCA存活。
进行了从棕色挪威大鼠到刘易斯大鼠的后肢移植，动物分为未治疗组（I组）、每天注射1mg/kg他克莫司共21天的治疗组（2组）或在第1天直接向移植肢体注射7mg他克莫司的治疗组（III组）。监测移植物排斥反应，在3级排斥反应或移植后200天时处死动物。
与未治疗动物或接受全身他克莫司治疗的动物相比，移植组织内注射他克莫司显著延长了同种异体移植物的存活时间。接受移植组织内治疗的大鼠中有一半平均在第70.5天排斥其移植物。有趣的是，另一半在超过200天的时间里未发生排斥反应，且没有肾脏或肝脏毒性迹象。在这些动物中，直到第200天在VCA皮肤中检测到他克莫司，但血液中未检测到。长期存活与诱导供体特异性耐受无关，而是与更高水平的淋巴细胞嵌合有关。
移植组织内递送他克莫司可能通过增加组织药物可用性、促进短暂嵌合的建立从而促进长期移植物接受来提高VCA存活。
