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 (ga mma(c)) are responsible for human X-linked severe combined immunodeficiency disease (SCIDX1), We have used a gamma(c)-deficient mouse model to test th e 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 al ymphoid RAG2/gamma(c) double-deficient recipient mice. Circulating lymphocy tes appeared 4 weeks postgraft and achieved steady-state levels by 8 weeks. The mature lymphocytes present in the grafted mice had integrated the gamm a(c) transgene, expressed gamma(c) transcripts, and were able to proliferat e in response to y, dependent cytokines. The gamma(c)-transduced animals de monstrated (1) normal levels of immunoglobulin subclasses, including immuno globulin G1 (IgG1) and IgG2a (which are severely decreased in gamma(c)(-) m ice); (a) the ability to mount an antigen-specific, T-dependent antibody re sponse showing effective in vivo T-B cell cooperation, and (3) the presence of gut-associated cryptopatches and intraepithelial lymphocytes, Important ly, peripheral B and T cells were still present 47 weeks after a primary gr aft, and animals receiving a secondary graft of gamma(c)-transduced bone ma rrow cells demonstrated peripheral lymphoid reconstitution. That gamma(c) g ene transfer to hematopoietic precursor cells can correct the immune system abnormalities In gamma(c)(-) mice supports the feasibility of In vivo retr oviral gene transfer as a treatment for human SCIDX1, (C) 2000 by The Ameri can Society of Hematology.