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Biomaterials-based immunomodulation enhances survival of murine vascularized composite allografts
Biomaterials Science ( IF 5.8 ) Pub Date : 2023-05-02 , DOI: 10.1039/d2bm01845d
Sven D Sommerfeld 1 , Xianyu Zhou 2, 3 , Joscelyn C Mejías 1 , Byoung Chol Oh 2 , David R Maestas 1, 4 , Georg J Furtmüller 2 , Philippe A Laffont 1 , Jennifer H Elisseeff 1, 4 , Gerald Brandacher 2
Affiliation  

Vascularized composite allotransplantation (VCA) is a restorative option for patients suffering from severe tissue defects not amenable to conventional reconstruction. However, the toxicities associated with life-long multidrug immunosuppression to enable allograft survival and induce immune tolerance largely limit the broader application of VCA. Here, we investigate the potential of targeted immunomodulation using CTLA4-Ig combined with a biological porcine-derived extracellular matrix (ECM) scaffold that elicits a pro-regenerative Th2 response to promote allograft survival and regulate the inflammatory microenvironment in a stringent mouse orthotopic hind limb transplantation model (BALB/c to C57BL/6). The median allograft survival time (MST) increased significantly from 15.0 to 24.5 days (P = 0.0037; Mantel–Cox test) after adding ECM to the CTLA4-Ig regimen. Characterization of the immune infiltration shows a pro-regenerative phenotype prevails over those associated with inflammation and rejection including macrophages (F4/80hi+CD206hi+MHCIIlow), eosinophils (F4/80lowSiglec-F+), and T helper 2 (Th2) T cells (CD4+IL-4+). This was accompanied by an increased expression of genes associated with a Type 2 polarized immune state such as Il4, Ccl24, Arg1 and Ym1 within the graft. Furthermore, when ECM was applied along with a clinically relevant combination of CTLA4-Ig and Rapamycin, allograft survival was prolonged from 33.0 to 72.5 days (P = 0.0067; Mantel–Cox test). These studies implicate the clinical exploration of combined regimens involving local application of pro-regenerative, immunomodulatory biomaterials in surgical wound sites with targeted co-stimulatory blockade to reduce adverse effects of immunosuppression and enhance graft survival in VCA.

中文翻译:

基于生物材料的免疫调节可提高小鼠血管化复合同种异体移植物的存活率

血管化复合同种异体移植(VCA)对于患有严重组织缺陷且无法接受传统重建的患者来说是一种恢复选择。然而,与终生多药免疫抑制相关的毒性使同种异体移植物能够存活并诱导免疫耐受,这在很大程度上限制了 VCA 的更广泛应用。在这里,我们研究了使用 CTLA4-Ig 与生物猪源性细胞外基质 (ECM) 支架相结合进行靶向免疫调节的潜力,该支架可引发促再生 Th2 反应,以促进同种异体移植物存活并调节严格的小鼠原位后肢中的炎症微环境移植模型(BALB/c 至 C57BL/6)。中位同种异体移植存活时间(MST)从 15.0 天显着增加至 24.5 天(P= 0.0037; 在 CTLA4-Ig 方案中添加 ECM 后进行 Mantel-Cox 试验。免疫浸润的特征显示促再生表型优于与炎症和排斥相关的表型,包括巨噬细胞 (F4/80 hi+ CD206 hi+ MHCII low )、嗜酸性粒细胞 (F4/80 low Siglec-F + ) 和 T 辅助细胞 2 (Th2 ) T 细胞 (CD4 + IL-4 + )。伴随着与 2 型极化免疫状态相关的基因表达增加,例如Il4Ccl24Arg1Ym1移植物内。此外,当 ECM 与临床相关的 CTLA4-Ig 和雷帕霉素组合一起应用时,同种异体移植物的存活率从 33.0 天延长至 72.5 天(P = 0.0067;Mantel-Cox 检验)。这些研究涉及联合治疗方案的临床探索,包括在手术伤口部位局部应用促再生、免疫调节生物材料,并进行靶向共刺激阻断,以减少免疫抑制的副作用并提高 VCA 移植物的存活率。
更新日期:2023-05-02
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