Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Plastic and Reconstructive Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, Connecticut.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, Connecticut.
J Surg Res. 2023 Nov;291:176-186. doi: 10.1016/j.jss.2023.04.028. Epub 2023 Jul 8.
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.
尽管血管化复合组织移植（VCA）在临床上取得了成功，但为了防止移植物排斥，仍需要全身免疫抑制。即使使用强效的免疫抑制方案（他克莫司、霉酚酸酯和类固醇），大多数患者仍会经历多次排斥反应，通常在同一年内。必须不断权衡全身副作用的风险与免疫抑制不足的风险，从而避免急性和慢性排斥。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引起了关注。这种策略也可能与 VCA 的未来有关。
我们讨论了基因工程的话题，并回顾了该领域的最新进展，这些进展证明了在 VCA 背景下研究工具（如簇状规律间隔短回文重复序列/Cas9）是合理的。
我们根据最新的基因表达数据为 VCA 提出了具体的策略。这包括众所周知的诱导耐受策略。具体来说，通过敲除 CD40 来靶向抗原呈递细胞与受体衍生 T 细胞的相互作用可能是有效的。VCA 的新颖之处在于发现供体衍生的 T 淋巴细胞可能在面部移植的移植物排斥中发挥特殊作用。我们建议在移植前通过敲除移植中供体衍生免疫细胞长期存在所必需的基因来靶向这些细胞（例如，通过移植的体外灌注）。
尽管近年来 VCA 的可行性已得到证明，但使用簇状规律间隔短回文重复序列/Cas9 等工具继续改进免疫调节策略，可能会开发出减轻与该救命手术排斥相关的局限性的方法。
