Retroviral transduction of IL-7Ralpha into IL-7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia.
Defects in the gene for the IL-7 receptor (R) alpha chain are one cause of severe combined immunodeficiency disease (SCID) based on a strict requirement for IL-7 in T lymphoid development and survival. We tested the feasibility and potentially undesirable consequences of IL-7Ralpha gene transfer as a therapy for this genetic defect. The murine IL-7Ralpha gene was introduced into IL-7Ralpha(-/-) bone marrow progenitors using retrovirus and transplanted into Rag(-/-) recipient mice. Both alphabeta and gammadelta T cells were reconstituted in thymus and spleen showing proof of principle. B-cell development was also restored in some mice, but their numbers were much lower than in the T-cell compartment. Splenomegaly was observed due to an increase in neutrophils. We showed that hematopoietic progenitors, after transfection with IL-7Ralpha, could respond to IL-7 in vitro by a striking production of neutrophils and other myeloid cells. These data indicate that although IL-7 is a critical lymphopoietin, ectopic expression of its receptor on multipotential progenitors can also induce production of myeloid cells, presumably through survival and proliferation signals that are not restricted to lymphoid cells. This supports the stochastic model of progenitor differentiation, in which cytokines give permissive and not instructive signals.
Jiang
Q
Q
Laboratory of Molecular Regulation, National Cancer Instutute, NIH, Frederick, MD 21702-1201, USA.
Li
W-Q
WQ
Aiello
F B
FB
Klarmann
K D
KD
Keller
J R
JR
Durum
S K
SK
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009504:Neutrophils / Q000166:cytology; D020395:Receptors, Interleukin-7 / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D014161:Transduction, Genetic / Q000379:methods*
D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain