Immune responses reflect a complex interplay of cellular and extracellular components which define the microenvironment of a tissue. Therefore, factors that locally influence the microenvironment and re-establish tolerance might be beneficial to mitigate immune-mediated reactions, including the rejection of a transplant. In this study, we demonstrate that pre-incubation of donor tissue with the immune modulator soluble CD83 (sCD83) significantly improves graft survival using a high-risk corneal transplantation model. The induction of tolerogenic mechanisms in graft recipients was achieved by a significant upregulation of Tgfb, Foxp3, Il27, and Il10 in the transplant and an increase of regulatory dendritic cells (DCs), macrophages (Mφ), and T cells (Tregs) in eye-draining lymph nodes. The presence of sCD83 during in vitro DC and Mφ generation directed these cells toward a tolerogenic phenotype leading to reduced proliferation-stimulating activity in MLRs. Mechanistically, sCD83 induced a tolerogenic Mφ and DC phenotype, which favors Treg induction and significantly increased transplant survival after adoptive cell transfer. Conclusively, pre-incubation of corneal grafts with sCD83 significantly prolongs graft survival by modulating recipient Mφ and DCs toward tolerance and thereby establishing a tolerogenic microenvironment. This functional strategy of donor graft pre-treatment paves the way for new therapeutic options in the field of transplantation.

中文翻译：

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角膜供体组织与 sCD83 的预孵育通过诱导交替激活的巨噬细胞和致耐受性树突细胞提高移植物存活率

免疫反应反映了细胞和细胞外成分的复杂相互作用，这些成分定义了组织的微环境。因此，局部影响微环境和重建耐受性的因素可能有利于减轻免疫介导的反应，包括移植排斥反应。在这项研究中，我们证明使用高风险角膜移植模型，将供体组织与免疫调节剂可溶性 CD83 (sCD83) 预孵育可显着提高移植物存活率。通过显着上调Tgfb、Foxp3、Il27和Il10来实现移植物受体中致耐受机制的诱导在移植中以及眼引流淋巴结中调节性树突细胞 (DC)、巨噬细胞 (Mφ) 和 T 细胞 (Treg) 的增加。体外 DC 和 Mφ 生成期间 sCD83 的存在将这些细胞导向致耐受性表型，导致 MLR 中增殖刺激活性降低。从机制上讲，sCD83 诱导致耐受性 Mφ 和 DC 表型，这有利于 Treg 诱导并显着增加过继细胞转移后的移植存活率。结论是，角膜移植物与 sCD83 的预孵育通过调节受体 Mφ 和 DCs 的耐受性从而建立致耐受性微环境，显着延长了移植物存活期。这种供体移植物预处理的功能策略为移植领域的新治疗选择铺平了道路。