Stable and functional lymphoid reconstitution of common cytokine receptor γ 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 ye 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 y, 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); (a) 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, (C) 2000 by The American Society of Hematology.