Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.
Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
Am J Transplant. 2018 Aug;18(8):2029-2042. doi: 10.1111/ajt.14765. Epub 2018 May 7.
Cytokine-expression profiles revealed IL-1ß highly upregulated in rejecting skin of limb allografts. We investigate the effect of intragraft treatment with a neutralizing IL-1β antibody in limb transplantation. Following allogenic hind-limb transplantation, Lewis rats were either left untreated or treated with anti-lymphocyte serum + tacrolimus (baseline); baseline immunosuppression + anti-IL-1β (1 mg/kg once/week, 6-8 subcutaneous injections) into the transplanted or contralateral limb. Endpoint was rejection grade III or day 100. Graft rejection was assessed by histology, immunohistochemistry, flow cytometry phenotyping of immune cells, and monitoring cytokine expression. Anti-IL-1β injections into the allograft or contralateral limb resulted in a significant delay of rejection onset (controls: 58.60 ± 0.60; group 3: 75.80 ± 10.87, P = .044; group 4: 73.00 ± 6.49, P = .008) and prolongation of graft survival (controls: 64.60 ± 0.87; group 3: 86.60 ± 5.33, P = .002; group 4: 93.20 ± 3.82, P = .002), compared to controls. Although the phenotype of the graft infiltrating immune cells did not differ between groups, significantly decreased skin protein levels of IL-1β, IL-4, IL-13, IP-10, MCP-1, and MCP-3 in long-term-survivors indicate an overall decrease of chemoattraction and infiltration of immune cells as the immunosuppressive mechanism of anti-IL-1β. Inhibition of IL-1β with short-term systemic immunosuppression prolongs limb allograft survival and represents a promising target for immunosuppression in extremity transplantation.
细胞因子表达谱显示白细胞介素-1β（IL-1β）在排斥的肢体同种异体移植物皮肤中高度上调。我们研究了在肢体移植中向移植物内给予中和 IL-1β 抗体的效果。在同种异体后肢移植后，Lewis 大鼠要么不接受治疗，要么接受抗淋巴细胞血清+他克莫司（基线）治疗；基线免疫抑制+抗 IL-1β（1mg/kg/周，6-8 次皮下注射）到移植或对侧肢体。终点为排斥等级 III 或第 100 天。通过组织学、免疫组织化学、免疫细胞流式细胞术表型分析和监测细胞因子表达来评估移植物排斥。将抗 IL-1β 注射到同种异体移植物或对侧肢体中导致排斥发作明显延迟（对照组：58.60±0.60；组 3：75.80±10.87，P=0.044；组 4：73.00±6.49，P=0.008），移植物存活时间延长（对照组：64.60±0.87；组 3：86.60±5.33，P=0.002；组 4：93.20±3.82，P=0.002），与对照组相比。尽管移植物浸润免疫细胞的表型在各组之间没有差异，但长期存活者皮肤中 IL-1β、IL-4、IL-13、IP-10、MCP-1 和 MCP-3 的蛋白水平显著降低表明，作为抗 IL-1β 的免疫抑制机制，趋化因子和免疫细胞的浸润总体减少。短期全身性免疫抑制抑制 IL-1β 可延长肢体同种异体移植物的存活时间，是肢体移植中免疫抑制的一个有前途的靶点。
