Al-Herz Waleed, Chu Julia I, van der Spek Jet, Raghupathy Raj, Massaad Michel J, Keles Sevgi, Biggs Catherine M, Cockerton Lucinda, Chou Janet, Dbaibo Ghassan, Elisofon Scott A, Hanna-Wakim Rima, Kim Heung Bae, Lehmann Leslie E, McDonald Douglas R, Notarangelo Luigi D, Veys Paul, Chatila Talal A, Geha Raif S, Gaspar H Bobby, Pai Sung-Yun
Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; Department of Pediatrics, Al-Sabah Hospital, Kuwait City, Kuwait.
Division of Hematology-Oncology, Boston Children's Hospital, Boston, Mass; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Mass.
J Allergy Clin Immunol. 2016 Sep;138(3):852-859.e3. doi: 10.1016/j.jaci.2016.02.022. Epub 2016 Apr 6.
Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited.
We sought to analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution.
We performed a retrospective chart review of 11 patients with DOCK8 deficiency and measured DOCK8 expression and cytokine production.
Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; 9 patients received busulfan-based conditioning regimens. Survival was excellent (10 [91%] of 11 patients alive), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. Although eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naive CD8(+) T cells and switched memory B cells, and TH1/TH2 cytokine imbalance improved in most patients. Although the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T-cell chimerism and low B-cell and myeloid cell chimerism (0% to 46%). Almost all switched memory B cells were of donor origin. All patients, including those with mixed chimerism, mounted robust antibody responses to vaccination.
Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.
细胞分裂素8（DOCK8）缺陷可通过异基因造血干细胞移植（HSCT）治愈。目前关于移植结果的报道仍然有限。
我们试图分析DOCK8缺陷患者HSCT的结果，并报告导致混合嵌合体的方法是否能带来临床相关的免疫重建。
我们对11例DOCK8缺陷患者进行了回顾性病历审查，并检测了DOCK8表达和细胞因子产生情况。
11例患者中，7例接受了来自相关供体的HSCT，4例接受了来自无关供体的HSCT；9例患者接受了基于白消安的预处理方案。患者生存率极佳（11例患者中有10例[91%]存活），其中包括1例接受过肝移植的患者。患者感染的频率和严重程度有显著改善。虽然所有患者的湿疹均已消退，但部分患者仍存在食物过敏和高IgE水平。多数患者的淋巴细胞减少、嗜酸性粒细胞增多、初始CD8(+) T细胞和转换记忆B细胞数量减少以及TH1/TH2细胞因子失衡情况有所改善。8例匹配的相关或无关供体受者具有完全供体嵌合体，而3例不匹配的无关供体HSCT受者均具有高水平的供体T细胞嵌合体以及低水平的B细胞和髓细胞嵌合体（0%至46%）。几乎所有转换记忆B细胞均来源于供体。所有患者，包括混合嵌合体患者，对疫苗接种均产生了强烈的抗体反应。
异基因HSCT改善了DOCK8缺陷患者的感染和特应性症状。在混合嵌合体患者中，供体来源的T细胞和转换记忆B细胞的选择性优势促进了细胞免疫和体液免疫的恢复以及对机会性感染的防护。
