title: Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity.
abstract: BACKGROUND
  We herein report the first case of X-linked agammaglobulinemia (XLA) that underwent allogeneic stem cell transplantation using reduced intensity conditioning (RIC). We chronologically observed the reconstitution of humoral immunity in this case.
  
  
  METHODS
  The patient was a 28-year-old Japanese male with XLA who previously had life-threatening infectious episodes and was referred for the possible indication of allogeneic stem cell transplantation. After a thorough discussion within specialists from different backgrounds, we decided to perform allogeneic peripheral stem cell transplantation from his HLA-identical elder brother. Due to the non-malignant nature of XLA, we selected RIC consisting of fludarabine, cyclophosphamide, anti-thymocyte globulin, and 3 Gy of total body irradiation. Neutrophil engraftment was achieved on day 11 with complete donor chimerism. No major complications, except for stage 1 skin graft-versus-host disease, were observed. The patient was discharged on day 75 and has been followed as an outpatient without any infectious episodes for more than 500 days.
  
  
  CONCLUSIONS
  Regarding immune reconstitution, CD19(+) cells, IgA, and IgM, which were undetectable before allogeneic stem cell transplantation (allo-SCT), started to increase in number 10 days after allo-SCT and continued to increase for more than 1 year. Anti-B antibodies appeared as early as day 10. Total IgG levels decreased after the discontinuation of IgG replacement and spontaneously recovered after day 350. However, most anti-viral IgG titers, except EB virus-virus capsid antigen IgG, disappeared after the discontinuation of IgG replacement. A seasonal vaccination to influenza was performed on day 148, with neither anti-influenza type A nor type B being positive after the vaccination. The transient transfer of allergic immunity to orchard grass was observed. Similar Bruton's tyrosine kinase (BTK) expression levels in monocytes and B-cells were observed between the patient and healthy control. B-cells in the peripheral blood (PB) of the patient on day 279 showed sufficient proliferation after a CD40L and IL-21 or CD40L and CpG stimulation. Effective immunoglobulin production and class switching were also observed after a CD40L and IL-21 or CpG stimulation. Signal joint kappa-deleting recombination excision circles (sjKRECs) became positive 16 days post-SCT, increased to 6300 copies/μg DNA at 42 days, and were maintained at a high level thereafter. The recovery of T-cell receptor excision circles (TRECs) was slow, but became detectable 1 year post-hematopoietic stem cell transplantation (HSCT).
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. kame@hyo-med.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikegame
authors.affiliation: Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. kimai.ped@tmd.ac.jp.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. motoy.mob@gmail.com.
authors.forename: Motoi
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. nrb52665@yahoo.co.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. hkanegane.ped@tmd.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. tmorio.ped@tmd.ac.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. kaidak@hyo-med.ac.jp.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Kaida
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. tinoue@hyo-med.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. somat@hyo-med.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Soma
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. tamakhi@hyo-med.ac.jp.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Tamaki
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. masaya@hyo-med.ac.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Okada
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan. ogawah@hyo-med.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000328:Adult; D000361:Agammaglobulinemia / Q000276:immunology / Q000628:therapy*; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D040181:Genetic Diseases, X-Linked / Q000276:immunology / Q000628:therapy*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007070:Immunoglobulin A / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008297:Male; D033581:Stem Cell Transplantation / Q000379:methods*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014916:Whole-Body Irradiation
chemical_list: D000961:Antilymphocyte Serum; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine