Tags

Type your tag names separated by a space and hit enter

Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency.
Sci Transl Med. 2011 Aug 24; 3(97):97ra79.ST

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+Show Affiliations

Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21865537

Citation

Gaspar, H Bobby, et al. "Long-term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-linked Severe Combined Immunodeficiency." Science Translational Medicine, vol. 3, no. 97, 2011, pp. 97ra79.
Gaspar HB, Cooray S, Gilmour KC, et al. Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2011;3(97):97ra79.
Gaspar, H. B., Cooray, S., Gilmour, K. C., Parsley, K. L., Adams, S., Howe, S. J., Al Ghonaium, A., Bayford, J., Brown, L., Davies, E. G., Kinnon, C., & Thrasher, A. J. (2011). Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Science Translational Medicine, 3(97), 97ra79. https://doi.org/10.1126/scitranslmed.3002715
Gaspar HB, et al. Long-term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-linked Severe Combined Immunodeficiency. Sci Transl Med. 2011 Aug 24;3(97):97ra79. PubMed PMID: 21865537.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. AU - Gaspar,H Bobby, AU - Cooray,Samantha, AU - Gilmour,Kimberly C, AU - Parsley,Kathryn L, AU - Adams,Stuart, AU - Howe,Steven J, AU - Al Ghonaium,Abdulaziz, AU - Bayford,Jinhua, AU - Brown,Lucinda, AU - Davies,E Graham, AU - Kinnon,Christine, AU - Thrasher,Adrian J, PY - 2011/8/26/entrez PY - 2011/8/26/pubmed PY - 2012/2/7/medline SP - 97ra79 EP - 97ra79 JF - Science translational medicine JO - Sci Transl Med VL - 3 IS - 97 N2 - 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. SN - 1946-6242 UR - https://www.unboundmedicine.com/medline/citation/21865537/Long_term_persistence_of_a_polyclonal_T_cell_repertoire_after_gene_therapy_for_X_linked_severe_combined_immunodeficiency_ L2 - http://stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=21865537 DB - PRIME DP - Unbound Medicine ER -