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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1281-1290. Prepublished online as a Blood First Edition Paper on May 13, 2004; DOI 10.1182/blood-2003-09-3044. This Article Full Text (PDF) All Versions of this Article: 2003-09-3044v1 104/5/1281    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yu, P. W Articles by Rawlings, D. J Search for Related Content PubMed PubMed Citation Articles by Yu, P. W Articles by Rawlings, D. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 4, 2003 Accepted April 15, 2004 Sustained correction of B cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer Phyllis W Yu, Ruby S Tabuchi, Roberta M Kato, Alexander Astrakhan, Stephanie Humblet-Baron, Kevin Kipp, Keun Chae, Wilfried Ellmeier, Owen N Witte, and David J Rawlings* Molecular Biology Institute, Howard Hughes Medical Institute, University Of California, Los Angeles, CA, USA Pediatrics, University Of California, Los Angeles, CA, USA Pediatrics, University Of Washington, Seattle, WA, USA Institute Of Immunology, Medical University, Vienna, Austria Molecular Biology Institute, Howard Hughes Medical Institute, University Of California, Los Angeles, CA, USA; Department Of Microbiology And Molecular Genetics, University Of California, Los Angeles, CA, USA Immunology, University Of Washington, Seattle, WA, USA; Pediatrics, University Of Washington, Seattle, WA, USA * Corresponding author; email: drawling{at}u.washington.edu. X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton's tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum immunoglobulin, and recurrent bacterial infections. Using Btk and Tec doubly deficient mice (Btk-/Tec-) as a model for XLA, we determined if Btk gene therapy could be used to correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU) treated Btk-/Tec- mice was transduced with a retroviral vector expressing human Btk, MSCV-huBtk-SAR (MBS), and transplanted into Btk-/Tec- recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral Btk-dependent, B-lineage development, recovery of peritoneal B1 B cells, and correction of serum IgM and IgG3 levels. Gene transfer also restored T-independent type II immune responses and proliferation in response to B-cell antigen receptor (BCR) engagement. B-cell progenitors derived from Btk-transduced stem cells exhibited a progressive selective advantage as demonstrated by Btk staining. BM derived from primary recipients of Btk-transduced stem cells also rescued Btk dependent function in secondary transplanted hosts. Together, these data demonstrate that gene transfer into hematopoietic stem cells can reconstitute Btk-dependent B-cell development and function in vivo, and strongly support the feasibility of pursuing Btk gene transfer for XLA. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: XLA gene therapy turns a corner Kevin D. Bunting Blood 2004 104: 1236. [Full Text] [PDF] This article has been cited by other articles: S. Guo, G. Z. Ferl, R. Deora, M. Riedinger, S. Yin, J. L. Kerwin, J. A. Loo, and O. N. Witte A phosphorylation site in Bruton's tyrosine kinase selectively regulates B cell calcium signaling efficiency by altering phospholipase C-{gamma} activation PNAS, September 28, 2004; 101(39): 14180 - 14185. [Abstract] [Full Text] [PDF]

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