Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer.
X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton 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-deficient mice (BtkTec(-/-)) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU)-treated BtkTec(-/-) mice was transduced with a retroviral vector expressing human Btk and transplanted into BtkTec(-/-) recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral B-lineage development, recovery of peritoneal B1 B cells, and correction of serum immunoglobulin M (IgM) and IgG(3) levels. Gene transfer also restored T-independent type II immune responses, and B-cell antigen receptor (BCR) proliferative responses. B-cell progenitors derived from Btk-transduced stem cells exhibited higher levels of Btk expression than non-B cells; and marking studies demonstrated a selective advantage for Btk-transduced B-lineage cells. BM derived from primary recipients also rescued Btk-dependent function in secondary hosts that had received a transplant. 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.
Yu
Phyllis W
PW
Children's Hospital and Regional Medical Center, 307 Westlake Ave North, Suite 300, Seattle, WA 98109, USA.
Tabuchi
Ruby S
RS
Kato
Roberta M
RM
Astrakhan
Alexander
A
Humblet-Baron
Stephanie
S
Kipp
Kevin
K
Chae
Keun
K
Ellmeier
Wilfried
W
Witte
Owen N
ON
Rawlings
David J
DJ
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D041321:Chromosomes, Human, X; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics
D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse