Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3358-3365
Correction of X-Linked Immunodeficient Mice by Competitive
Reconstitution With Limiting Numbers of Normal Bone Marrow Cells
Jurg Rohrer and
Mary Ellen Conley
From the Department of Immunology, St Jude Children's Research
Hospital, Memphis, TN; and the Department of Pediatrics, University of
Tennessee, Memphis, TN.
Gene therapy for inherited disorders is more likely to succeed if
gene-corrected cells have a proliferative or survival advantage compared with mutant cells. We used a competitive reconstitution model
to evaluate the strength of the selective advantage that Btk normal
cells have in Btk-deficient xid mice. Whereas 2,500 normal bone
marrow cells when mixed with 497,500 xid cells restored serum
IgM and IgG3 levels to near normal concentrations in 3 of 5 lethally
irradiated mice, 25,000 normal cells mixed with 475,000 xid
cells reliably restored serum IgM and IgG3 concentrations and the
thymus-independent antibody response in all transplanted mice.
Reconstitution was not dependent on lethal irradiation, because
sublethally irradiated mice all had elevated serum IgM and IgG3 by 30 weeks postreconstitution when receiving 25,000 normal cells.
Furthermore, the xid defect was corrected with as few as 10%
of the splenic B cells expressing a normal Btk. When normal donor cells
were sorted into B220+/CD19+ committed B
cells and B220
/CD19 cell populations,
only the B220/CD19 cells provided
long-term B-cell reconstitution in sublethally irradiated mice. These
findings suggest that even inefficient gene therapy may provide
clinical benefit for patients with XLA.
