Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy.
Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy.
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DOI：
10.1007/s10875-021-01034-2
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发表时间：
2021-10
影响因子：
9.1
通讯作者：
Yin, Li
中科院分区：
文献类型：
--
作者：
Baloh, Carolyn H.;Borkar, Samiksha A.;Chang, Kai-Fen;Yao, Jiqiang;Hershfield, Michael S.;Parikh, Suhag H.;Kohn, Donald B.;Goodenow, Maureen M.;Sleasman, John W.;Yin, Li
关键词：
腺苷脱氨酶（ADA）缺乏通过淋巴细胞内有毒代谢物的积累引起严重的联合免疫缺陷（SCID）。最近，ADA缺乏症已成功地治疗使用慢病毒转导的自体CD 34+细胞携带ADA基因。T和B细胞功能似乎完全恢复，但在许多患者中，B细胞数量仍然很低，并且缺乏对基因治疗后免疫球蛋白重链（IgHV）库的评估。我们对一名接受慢病毒基因治疗的儿童的外周血淋巴细胞中的IgHV库进行了深度测序，并与健康婴儿和成人的IgHV库进行了比较。基因治疗后，IG多样性随着时间的推移而增加，如V、D和J基因使用、N-添加、CDR 3长度、体细胞超突变程度和IG类别转换所证明的。基因治疗后出现了主要的IgHM、IgHG和IgHA CDR 3长度，表明针对抗原的寡克隆扩增成功。这为在ADA缺陷的基因治疗后的B细胞重建中进行分子监测的可行性和实用性提供了概念证明。基于深度测序，基因治疗产生了与健康婴儿相似的分子多样性的IgHV库。
Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) through an accumulation of toxic metabolites within lymphocytes. Recently, ADA deficiency has been successfully treated using lentiviral-transduced autologous CD34+ cells carrying the ADA gene. T and B cell function appears to be fully restored but in many patients’ B cell numbers remain low and assessments of the immunoglobulin heavy (IgHV) repertoire following gene therapy are lacking. We performed deep sequencing of IgHV repertoire in peripheral blood lymphocytes from a child following lentivirus-based gene therapy for ADA deficiency and compared to the IgHV repertoire in healthy infants and adults. After gene therapy, Ig diversity increased over time as evidenced by V, D, and J gene usage, N-additions, CDR3 length, extent of somatic hypermutation, and Ig class-switching. There was emergence of predominant IgHM, IgHG, and IgHA CDR3 lengths after gene therapy indicating successful oligoclonal expansion in response to antigens. This provides proof of concept for the feasibility and utility of molecular monitoring in following B cell reconstitution following gene therapy for ADA deficiency. Based on deep sequencing, gene therapy resulted in an IgHV repertoire with molecular diversity similar to healthy infants.
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影响因子：
9.1
作者：
Cagdas, Deniz;Cetinkaya, Pinar Gur;Tezcan, Ilhan
通讯作者：
Tezcan, Ilhan
DOI：
10.1016/j.bbmt.2017.04.026
发表时间：
2017-08
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
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作者：
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通讯作者：
Cowan MJ
影响因子：
9.1
作者：
Buckley, Rebecca H.;Win, Chan M.;Moser, Barry K.;Parrott, Roberta E.;Sajaroff, Elisa;Sarzotti-Kelsoe, Marcella
通讯作者：
Sarzotti-Kelsoe, Marcella
影响因子：
17.1
作者：
Gaspar, H. Bobby;Cooray, Samantha;Thrasher, Adrian J.
通讯作者：
Thrasher, Adrian J.
影响因子：
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作者：
Giudicelli, Veronique;Lefranc, Marie-Paule
通讯作者：
Lefranc, Marie-Paule