Stable and functional lymphoid reconstitution of common cytokine receptor gamma chain deficient mice by retroviral-mediated gene transfer.
Mutations in the gene encoding the common cytokine receptor gamma chain (gamma(c)) are responsible for human X-linked severe combined immunodeficiency disease (SCIDX1). We have used a gamma(c)-deficient mouse model to test the feasibility and potential toxicity of gamma(c) gene transfer as a therapy for SCIDX1. A retrovirus harboring the murine gamma(c) chain was introduced into gamma(c)-deficient bone marrow cells, which were then transplanted into alymphoid RAG2/gamma(c) double-deficient recipient mice. Circulating lymphocytes appeared 4 weeks postgraft and achieved steady-state levels by 8 weeks. The mature lymphocytes present in the grafted mice had integrated the gamma(c) transgene, expressed gamma(c) transcripts, and were able to proliferate in response to gamma(c)-dependent cytokines. The gamma(c)-transduced animals demonstrated (1) normal levels of immunoglobulin subclasses, including immunoglobulin G1 (IgG1) and IgG2a (which are severely decreased in gamma(c)(-) mice); (2) the ability to mount an antigen-specific, T-dependent antibody response showing effective in vivo T-B cell cooperation, and (3) the presence of gut-associated cryptopatches and intraepithelial lymphocytes. Importantly, peripheral B and T cells were still present 47 weeks after a primary graft, and animals receiving a secondary graft of gamma(c)-transduced bone marrow cells demonstrated peripheral lymphoid reconstitution. That gamma(c) gene transfer to hematopoietic precursor cells can correct the immune system abnormalities in gamma(c)(-) mice supports the feasibility of in vivo retroviral gene transfer as a treatment for human SCIDX1.
Soudais
C
C
INSERM U429, Hôpital Necker, Paris, France.
Shiho
T
T
Sharara
L I
LI
Guy-Grand
D
D
Taniguchi
T
T
Fischer
A
A
Di Santo
J P
JP
D000818:Animals; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D005803:Genes, Immunoglobulin; D015316:Genetic Therapy; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics* / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology*; D051379:Mice; D018121:Receptors, Cytokine / Q000235:genetics* / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy
D007142:Immunoglobulin gamma-Chains; D018121:Receptors, Cytokine