Castagnoli Riccardo, Delmonte Ottavia Maria, Calzoni Enrica, Notarangelo Luigi Daniele
Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
Department of Pediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.
Front Pediatr. 2019 Aug 8;7:295. doi: 10.3389/fped.2019.00295. eCollection 2019.
Primary immunodeficiencies (PID) are disorders that for the most part result from mutations in genes involved in immune host defense and immunoregulation. These conditions are characterized by various combinations of recurrent infections, autoimmunity, lymphoproliferation, inflammatory manifestations, atopy, and malignancy. Most PID are due to genetic defects that are intrinsic to hematopoietic cells. Therefore, replacement of mutant cells by healthy donor hematopoietic stem cells (HSC) represents a rational therapeutic approach. Full or partial ablation of the recipient's marrow with chemotherapy is often used to allow stable engraftment of donor-derived HSCs, and serotherapy may be added to the conditioning regimen to reduce the risks of graft rejection and graft versus host disease (GVHD). Initially, hematopoietic stem cell transplantation (HSCT) was attempted in patients with severe combined immunodeficiency (SCID) as the only available curative treatment. It was a challenging procedure, associated with elevated rates of morbidity and mortality. Overtime, outcome of HSCT for PID has significantly improved due to availability of high-resolution HLA typing, increased use of alternative donors and new stem cell sources, development of less toxic, reduced-intensity conditioning (RIC) regimens, and cellular engineering techniques for graft manipulation. Early identification of infants affected by SCID, prior to infectious complication, through newborn screening (NBS) programs and prompt genetic diagnosis with Next Generation Sequencing (NGS) techniques, have also ameliorated the outcome of HSCT. In addition, HSCT has been applied to treat a broader range of PID, including disorders of immune dysregulation. Yet, the broad spectrum of clinical and immunological phenotypes associated with PID makes it difficult to define a universal transplant regimen. As such, integration of knowledge between immunologists and transplant specialists is necessary for the development of innovative transplant protocols and to monitor their results during follow-up. Despite the improved outcome observed after HSCT, patients with severe forms of PID still face significant challenges of short and long-term transplant-related complications. To address this issue, novel HSCT strategies are being implemented aiming to improve both survival and long-term quality of life. This article will discuss the current status and latest developments in HSCT for PID, and present data regarding approach and outcome of HSCT in recently described PID, including disorders associated with immune dysregulation.
原发性免疫缺陷病（PID）是一类大多由参与免疫宿主防御和免疫调节的基因突变所致的疾病。这些病症的特征是反复感染、自身免疫、淋巴细胞增殖、炎症表现、特应性和恶性肿瘤的各种组合。大多数PID是由于造血细胞固有的遗传缺陷。因此，用健康供体造血干细胞（HSC）替代突变细胞是一种合理的治疗方法。通常使用化疗对受体骨髓进行全量或部分清除，以使供体来源的HSC稳定植入，并且可以在预处理方案中加入血清疗法以降低移植物排斥和移植物抗宿主病（GVHD）的风险。最初，造血干细胞移植（HSCT）仅作为唯一可用的治愈性治疗方法用于重症联合免疫缺陷（SCID）患者。这是一个具有挑战性的过程，发病率和死亡率较高。随着时间的推移，由于高分辨率HLA分型的可用性、替代供体和新干细胞来源的更多使用、毒性较小的减低强度预处理（RIC）方案的发展以及用于移植物操作的细胞工程技术，PID的HSCT结果有了显著改善。通过新生儿筛查（NBS）计划在感染并发症发生之前早期识别受SCID影响的婴儿，并使用下一代测序（NGS）技术进行快速基因诊断，也改善了HSCT的结果。此外，HSCT已被应用于治疗更广泛的PID，包括免疫失调疾病。然而，与PID相关的广泛临床和免疫表型使得难以定义通用的移植方案。因此，免疫学家和移植专家之间的知识整合对于开发创新的移植方案以及在随访期间监测其结果是必要的。尽管HSCT后观察到结果有所改善，但重症PID患者仍然面临短期和长期移植相关并发症的重大挑战。为了解决这个问题，正在实施新的HSCT策略，旨在提高生存率和长期生活质量。本文将讨论PID的HSCT的现状和最新进展，并展示最近描述的PID（包括与免疫失调相关的疾病）中HSCT的方法和结果的数据。
