Perrier Quentin, Noble Johan, Lablanche Sandrine
Univ. Grenoble Alpes, INSERM U1055 LBFA, Pharmacy department, Grenoble Alpes University Hospital, Grenoble, France.
Univ. Grenoble Alpes, Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, Grenoble, France; Univ. Grenoble Alpes, INSERM U1209 CNRS UMR 5309, Team Epigenetis Immunity, Metabolism, Cell Signaling and Cancer, Institute for advanced Biosciences, Grenoble, France.
Transplant Rev (Orlando). 2025 Apr;39(2):100913. doi: 10.1016/j.trre.2025.100913. Epub 2025 Mar 2.
Beta-cell replacement therapies, including islet and pancreas transplantation, offer promising results in term of glycemic control for patients with type 1 diabetes experiencing high glycemic variability and severe hypoglycemia. However, long-term insulin independence remains challenging due to progressive graft function decline. Immunosuppressive regimens, especially calcineurin inhibitors such as tacrolimus, are known to be diabetogenic, contributing to the paradox of impaired beta-cell function in a diabetes treatment setting. Recent studies have focused on CTLA4-Ig (e.g., belatacept) as a potential alternative to calcineurin inhibitors, showing promising results in preclinical and clinical models. This review summarizes key advancements and remaining challenges in CTLA4 applications for beta-cell replacement. First, genetic engineering approaches aiming for CTLA4 expression in islets demonstrated initial success in delaying rejection but remain hindered by immune escape and limited integration efficacy. Coating techniques and exogenous CTLA4-Ig administration offer simpler, albeit transient, immunosuppressive effects, which, combined with encapsulation technologies, can improve graft survival. In non-human primate models, islet transplantation with immunosuppressant regimen using CTLA4-Ig combined with agents such as sirolimus or anti-CD154 has shown extended insulin independence, though full immune tolerance remains elusive. A limited number of human studies using belatacept for beta-cell replacement indicate reduced HbA1c levels and avoidance of severe hypoglycemia, yet consistent absence of rejection remains unachieved. Future research on BCR with CTLA4-Ig should explore graft survival in human islets transplantation and refine immunosuppressive protocols to leverage CTLA4-Ig potential in improving long-term graft function, thus enhancing the sustainability of CTLA4-Ig in clinical beta-cell replacement approach.
β细胞替代疗法，包括胰岛移植和胰腺移植，对于血糖波动大且严重低血糖的1型糖尿病患者而言，在血糖控制方面取得了令人鼓舞的成果。然而，由于移植功能的逐渐衰退，长期脱离胰岛素治疗仍然具有挑战性。免疫抑制方案，尤其是诸如他克莫司之类的钙调神经磷酸酶抑制剂，已知具有致糖尿病作用，在糖尿病治疗背景下会导致β细胞功能受损这一矛盾情况。最近的研究聚焦于CTLA4-Ig（如贝拉西普）作为钙调神经磷酸酶抑制剂的潜在替代物，在临床前和临床模型中显示出了令人鼓舞的结果。本综述总结了CTLA4在β细胞替代应用中的关键进展和尚存的挑战。首先，旨在使CTLA4在胰岛中表达的基因工程方法在延迟排斥方面取得了初步成功，但仍受免疫逃逸和整合效率有限的阻碍。包被技术和外源性CTLA4-Ig给药提供了更简单的免疫抑制作用，尽管是短暂的，与封装技术相结合，可以提高移植物存活率。在非人类灵长类动物模型中，使用CTLA4-Ig联合西罗莫司或抗CD154等药物的免疫抑制方案进行胰岛移植已显示出延长的胰岛素非依赖期，尽管完全免疫耐受仍然难以实现。少数使用贝拉西普进行β细胞替代的人体研究表明糖化血红蛋白水平降低且避免了严重低血糖，但仍未实现持续无排斥反应。未来关于CTLA4-Ig的β细胞替代研究应探索人类胰岛移植中的移植物存活情况，并完善免疫抑制方案，以充分利用CTLA4-Ig在改善长期移植物功能方面的潜力，从而提高CTLA4-Ig在临床β细胞替代方法中的可持续性。
