Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK.
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
Br J Haematol. 2021 Feb;192(3):433-443. doi: 10.1111/bjh.17070. Epub 2020 Sep 10.
The application of therapeutic T cells for a number of conditions has been developed over the past few decades with notable successes including donor lymphocyte infusions, virus-specific T cells and more recently CAR-T cell therapy. Primary immunodeficiencies are monogenetic disorders leading to abnormal development or function of the immune system. Haematopoietic stem cell transplantation and, in specific candidate diseases, haematopoietic stem cell gene therapy has been the only definitive treatment option so far. However, autologous gene-modified T cell therapy may offer a potential cure in conditions primarily affecting the lymphoid compartment. In this review we will highlight several T cell gene addition or gene-editing approaches in different target diseases with a focus on what we have learnt from clinical experience and promising preclinical studies in primary immunodeficiencies. Functional T cells are required not only for normal immune responses to infection (affected in CD40 ligand deficiency), but also for immune regulation [disrupted in IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-Linked) due to dysfunctional FOXP3 and CTLA4 deficiency] or cytotoxicity [defective in X-lymphoproliferative disease and familial haemophagocytic lymphohistiocytosis (HLH) syndromes]. In all these candidate diseases, restoration of T cell function by gene therapy could be of great value.
在过去的几十年中，治疗性 T 细胞在许多疾病中的应用得到了发展，其中包括供者淋巴细胞输注、病毒特异性 T 细胞，以及最近的 CAR-T 细胞疗法。原发性免疫缺陷是导致免疫系统发育或功能异常的单基因疾病。造血干细胞移植，以及在特定候选疾病中，造血干细胞基因治疗是迄今为止唯一的确定性治疗选择。然而，自体基因修饰 T 细胞疗法可能为主要影响淋巴系统的疾病提供潜在的治愈方法。在这篇综述中，我们将重点介绍几种针对不同靶疾病的 T 细胞基因添加或基因编辑方法，重点介绍我们从原发性免疫缺陷症的临床经验和有前途的临床前研究中学到的知识。功能性 T 细胞不仅对于正常的抗感染免疫反应（在 CD40 配体缺陷中受到影响）是必需的，而且对于免疫调节（由于 FOXP3 和 CTLA4 功能障碍导致 IPEX 综合征（免疫失调、多内分泌腺病、肠病、X 连锁）中断）或细胞毒性（在 X 连锁淋巴组织增生性疾病和家族性噬血细胞性淋巴组织细胞增多症（HLH）综合征中受到影响）也是必需的。在所有这些候选疾病中，通过基因治疗恢复 T 细胞功能可能具有重要价值。
