Petrus-Reurer Sandra, Lei Winnie, Tysoe Olivia, Mairesse Maelle, Baez-Ortega Adrian, Jones Julia, Tan Thomas, Rehakova Sylvia, Mahbubani Krishnaa T, Brodie Cara, Han Namshik, Martincorena Inigo, Betts Catherine, Vallier Ludovic, Saeb-Parsy Kourosh
Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK; Milner Therapeutics Institute, University of Cambridge, Cambridge CB2 0AW, UK.
Cell Rep Med. 2025 Jul 15;6(7):102205. doi: 10.1016/j.xcrm.2025.102205. Epub 2025 Jul 7.
Primary human cells cultured in long-term expandable 3D organoid format have great promise as potential regenerative cellular therapies, but their immunogenicity has not yet been fully characterized. In this study, we use in vitro co-cultures and in vivo humanized mouse experimental models to examine autologous and allogeneic immune response to human primary cholangiocyte organoids (PCOs) as treatment for bile duct disorders. Our data demonstrate that PCOs upregulate the expression of human leukocyte antigen (HLA)-I and HLA-II in inflammatory conditions. The allogeneic immune response to PCOs is driven by both HLA-I and HLA-II and is substantially ameliorated by donor-recipient HLA matching. While allogeneic cells display evolving stages of immune rejection in vivo, autologous PCOs induce a low-level immune infiltration into the graft site possibly influenced by acquired mutations in culture, cell viability, and culture matrix. Our findings have important implications for the design and clinical translation of autologous and allogeneic organoid cellular therapies.
以长期可扩增的三维类器官形式培养的原代人细胞作为潜在的再生细胞疗法具有巨大潜力，但其免疫原性尚未得到充分表征。在本研究中，我们使用体外共培养和体内人源化小鼠实验模型来研究自体和异体对人原发性胆管细胞类器官（PCO）治疗胆管疾病的免疫反应。我们的数据表明，PCO在炎症条件下会上调人白细胞抗原（HLA）-I和HLA-II的表达。对PCO的异体免疫反应由HLA-I和HLA-II共同驱动，并且通过供体-受体HLA匹配可得到显著改善。虽然异体细胞在体内显示出免疫排斥的演变阶段，但自体PCO会诱导低水平的免疫细胞浸润到移植部位，这可能受到培养过程中获得性突变、细胞活力和培养基质的影响。我们的研究结果对自体和异体类器官细胞疗法的设计和临床转化具有重要意义。
