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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3027-3036
Restoration of Lymphoid Populations in a Murine Model of X-Linked
Severe Combined Immunodeficiency by a Gene-Therapy Approach
Mindy Lo,
Michael L. Bloom,
Kazunori Imada,
Maria Berg,
Julie M. Bollenbacher,
Eda T. Bloom,
Brian L. Kelsall, and
Warren J. Leonard
From the Laboratory of Molecular Immunology, National Heart, Lung,
and Blood Institute, National Institutes of Health (NIH), Bethesda;
Hematology Branch, National Heart, Lung, and Blood Institute, NIH,
Bethesda; the Center for Biologics Evaluation and Research, Food and
Drug Administration, Bethesda; and the Laboratory of Clinical
Investigation, National Institute of Allergy and Infectious Diseases,
Bethesda, MD.
X-linked severe combined immunodeficiency (XSCID) is a
life-threatening syndrome in which both cellular and humoral immunity are profoundly compromised. This disease results from mutations in the
IL2RG gene, which encodes the common cytokine receptor  chain, c. Previously, we generated
c-deficient mice as a murine model of XSCID. We have now
used lethally irradiated c-deficient mice to evaluate a
gene therapeutic approach for treatment of this disease. Transfer of
the human c gene to repopulating hematopoietic stem
cells using an ecotropic retrovirus resulted in an increase in T cells,
B cells, natural killer (NK) cells, and intestinal intraepithelial
lymphocytes, as well as normalization of the CD4:CD8 T-cell ratio and
of serum Ig levels. In addition, the restored cells could proliferate
in response to interleukin-2 (IL-2). Thus, our results provide added
support that gene therapy is a feasible therapeutic strategy for XSCID.
Moreover, because we used a vector directing expression of human
c to correct a defect in c-deficient mice, these data also indicate that human c can
cooperate with the distinctive cytokine receptor chains such as
IL-2R and IL-7R to mediate responses to murine cytokines in vivo.
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