背景:尽管血管化复合同种异体移植(VCA)在临床上取得了成功,全身免疫抑制对于预防同种异体移植排斥反应仍然是必要的.即使使用有效的免疫抑制方案(他克莫司,霉酚酸酯,和类固醇),大多数患者经历了几次排斥反应,往往在同一年。必须不断权衡全身副作用的风险与免疫抑制不足的风险,因此,急性和慢性排斥反应。在这种情况下,基因组编辑已成为减少对毒性免疫抑制方案需求的潜在工具,并在实体器官移植和异种移植领域获得关注。该策略也可能与VCA的未来相关。
方法:我们讨论了基因工程的主题,并回顾了该领域的最新进展,这些进展证明了研究工具的合理性,例如在VCA的背景下,成簇的规则间隔短回文重复/Cas9。
结果:我们根据最新的基因表达数据提出了VCA的具体策略。这包括众所周知的耐受性诱导策略。具体来说,通过CD40敲除靶向抗原呈递细胞和受体来源的T细胞之间的相互作用可能是有效的.VCA的新颖性是发现供体来源的T淋巴细胞可能在面部移植的同种异体移植排斥中起特殊作用。我们建议在移植前靶向这些细胞(例如,通过离体灌注移植物)通过敲除同种异体移植物中供体来源的免疫细胞长期持续存在所需的基因。
结论:尽管近年来证明了VCA的可行性,使用成簇的间隔短回文重复序列/Cas9等工具对免疫调节策略的持续改进可能会导致开发出减轻与这种赋予生命的程序排斥相关的局限性的方法.
Despite the clinical success in vascularized composite allotransplantation (VCA), systemic immunosuppression remains necessary to prevent allograft rejection. Even with potent immunosuppressive regimens (tacrolimus, mycophenolate mofetil, and steroids), most patients experience several rejection episodes, often within the same year. The risk of systemic side effects must constantly be weighed against the risk of under-immunosuppression and, thus, acute and chronic rejection. In this context, genomic editing has emerged as a potential tool to minimize the need for toxic immunosuppressive regimens and has gained attention in the fields of solid organ transplantation and xenotransplantation. This strategy may also be relevant for the future of VCA.
We discuss the topic of genetic engineering and review recent developments in this field that justify investigating tools such as clustered regularly interspaced short palindromic repeats/Cas9 in the context of VCA.
We propose specific strategies for VCA based on the most recent gene expression data. This includes the well-known strategy of tolerance induction. Specifically, targeting the interaction between antigen-presenting cells and recipient-derived T cells by CD40 knockout may be effective. The novelty for VCA is a discovery that donor-derived T lymphocytes may play a special role in allograft rejection of facial transplants. We suggest targeting these cells prior to transplantation (e.g., by ex vivo perfusion of the transplant) by knocking out genes necessary for the long-term persistence of donor-derived immune cells in the allograft.
Despite the demonstrated feasibility of VCA in recent years, continued improvements to immunomodulatory strategies using tools like clustered regularly interspaced short palindromic repeats/Cas9 could lead to the development of approaches that mitigate the limitations associated with rejection of this life-giving procedure.