title: Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency.
abstract: X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine receptor γ chain. These mutations classically lead to complete absence of functional T and natural killer cell lineages as well as to intrinsically compromised B cell function. Although human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation (HSCT) is highly successful in SCID-X1 patients, HLA-mismatched procedures can be associated with prolonged immunodeficiency, graft-versus-host disease, and increased overall mortality. Here, 10 children were treated with autologous CD34(+) hematopoietic stem and progenitor cells transduced with a conventional gammaretroviral vector. The patients did not receive myelosuppressive conditioning and were monitored for immunological recovery after cell infusion. All patients were alive after a median follow-up of 80 months (range, 54 to 107 months), and a functional polyclonal T cell repertoire was restored in all patients. Humoral immunity only partially recovered but was sufficient in some patients to allow for withdrawal of immunoglobulin replacement; however, three patients developed antibiotic-responsive acute pulmonary infection after discontinuation of antibiotic prophylaxis and/or immunoglobulin replacement. One patient developed acute T cell acute lymphoblastic leukemia because of up-regulated expression of the proto-oncogene LMO-2 from insertional mutagenesis, but maintained a polyclonal T cell repertoire through chemotherapy and entered remission. Therefore, gene therapy for SCID-X1 without myelosuppressive conditioning effectively restored T cell immunity and was associated with high survival rates for up to 9 years. Further studies using vectors designed to limit mutagenesis and strategies to enhance B cell reconstitution are warranted to define the role of this treatment modality alongside conventional HSCT for SCID-X1.
authors.affiliation: Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Samantha
authors.initials: S
authors.lastname: Cooray
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsley
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al Ghonaium
authors.forename: Jinhua
authors.initials: J
authors.lastname: Bayford
authors.forename: Lucinda
authors.initials: L
authors.lastname: Brown
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D017988:Gammaretrovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D000090063:Proto-Oncogene Mas; D033581:Stem Cell Transplantation / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology*; D014182:Transplantation, Autologous / Q000379:methods; D053632:X-Linked Combined Immunodeficiency Diseases / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*
chemical_list: D018952:Antigens, CD34; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas