Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.
Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.
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DOI：
10.1016/j.jaci.2018.02.053
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Booth C
中科院分区：
文献类型：
--
作者：
Panchal N;Houghton B;Diez B;Ghosh S;Ricciardelli I;Thrasher AJ;Gaspar HB;Booth C
X连锁淋巴组织增生性疾病1是由编码SLAM相关蛋白（SAP）的SH 2D 1A基因突变引起的，SAP是一种在T、自然杀伤（NK）和NKT细胞中表达的衔接蛋白。缺陷导致T细胞和NK细胞的细胞毒性和T细胞依赖性体液功能异常。临床表现包括噬血细胞性淋巴组织细胞增生症、淋巴瘤和异常丙种球蛋白血症。治愈性治疗仅限于造血干细胞移植，其结果依赖于良好的供体匹配。由于大多数症状是由T细胞功能缺陷引起的，我们研究了SAP基因校正的T细胞的转移是否可以重建已知的效应细胞缺陷。在转移到亚致死剂量照射的Sap缺陷小鼠中之前，用编码人SAP cDNA的γ逆转录病毒载体转导来自Sap缺陷小鼠的CD 3+淋巴细胞。用T依赖性抗原4-羟基-3-硝基苯乙酰鸡丙种球蛋白（NP-CGG）免疫后，通过生发中心形成和抗原特异性应答来评价体液功能的恢复。为了有效地从患者中扩增CD 3+细胞，我们产生了等效的慢病毒SAP载体。通过使用体外细胞毒性和T滤泡辅助细胞功能测定以及体内淋巴母细胞样细胞系淋巴瘤异种移植模型中的肿瘤清除来证明功能恢复。在Sap缺陷小鼠中，20%至40%的基因修饰T细胞植入导致生发中心形成和NP特异性抗体反应显着恢复。来自患者的基因校正的T细胞在体外表现出改善的细胞毒性和T滤泡辅助细胞功能。在体内淋巴瘤模型中，从患者体内连续转移基因校正的细胞毒性T淋巴细胞可将肿瘤负荷降低至与健康供体细胞毒性T淋巴细胞相当的水平。这些数据表明，自体T细胞基因治疗可纠正SAP依赖性缺陷，并可能为X连锁淋巴组织增生性疾病患者提供替代治疗选择1。
X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell–dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene–corrected T cells could reconstitute known effector cell defects. CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.
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小鼠和人类缺乏适配器SAP的NKT细胞发育有缺陷，X连锁淋巴增生性综合征基因产物。
DOI：
10.1084/jem.20042432
发表时间：
2005-03-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pasquier B;Yin L;Fondanèche MC;Relouzat F;Bloch-Queyrat C;Lambert N;Fischer A;de Saint-Basile G;Latour S
通讯作者：
Latour S
影响因子：
32.4
作者：
Nurieva, Roza I.;Chung, Yeonseok;Hwang, Daehee;Yang, Xuexian O.;Kang, Hong Soon;Ma, Li;Wang, Yi-Hong;Watowich, Stephanie S.;Jetten, Anton M.;Tian, Qiang;Dong, Chen
通讯作者：
Dong, Chen
DOI：
10.1016/j.jaci.2015.05.036
发表时间：
2015-10
期刊：
The Journal of allergy and clinical immunology
影响因子：
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作者：
Ma CS;Wong N;Rao G;Avery DT;Torpy J;Hambridge T;Bustamante J;Okada S;Stoddard JL;Deenick EK;Pelham SJ;Payne K;Boisson-Dupuis S;Puel A;Kobayashi M;Arkwright PD;Kilic SS;El Baghdadi J;Nonoyama S;Minegishi Y;Mahdaviani SA;Mansouri D;Bousfiha A;Blincoe AK;French MA;Hsu P;Campbell DE;Stormon MO;Wong M;Adelstein S;Smart JM;Fulcher DA;Cook MC;Phan TG;Stepensky P;Boztug K;Kansu A;İkincioğullari A;Baumann U;Beier R;Roscioli T;Ziegler JB;Gray P;Picard C;Grimbacher B;Warnatz K;Holland SM;Casanova JL;Uzel G;Tangye SG
通讯作者：
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影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
64.8
作者：
Qi, Hai;Cannons, Jennifer L.;Klauschen, Frederick;Schwartzberg, Pamela L.;Germain, Ronald N.
通讯作者：
Germain, Ronald N.