Restoration of lymphoid populations in a murine model of X-linked severe combined immunodeficiency by a gene-therapy approach

X-linked severe combined immunodeficiency (XSCID) is a life-threatening syn drome in which both cellular and humoral immunity are profoundly compromise d. This disease results from mutations in the IL2RG gene, which encodes the common cytokine receptor gamma chain, gamma(c). Previously, we generated g amma(c)-deficient mice as a murine model of XSCID. We have now used lethall y irradiated gamma(c)-deficient mice to evaluate a gene therapeutic approac h for treatment of this disease. Transfer of the human gamma(c) gene to rep opulating hematopoietic stem cells using an ecotropic retrovirus resulted i n an increase in T cells, B cells, natural killer (NK) cells, and intestina l intraepithelial lymphocytes, as well as normalization of the CD4:CD8 T-ce ll ratio and of serum Ig levels. In addition, the restored cells could prol iferate in response to interleukin-2 (IL-2). Thus, our results provide adde d support that gene therapy is a feasible therapeutic strategy for XSCID. M oreover, because we used a vector directing expression of human gamma(c) to correct a defect in gamma(c)-deficient mice, these data also indicate that human gamma(c) can cooperate with the distinctive cytokine receptor chains such as IL-2R beta and IL-7R alpha to mediate responses to murine cytokine s in vivo. This is a US government work. There are no restrictions on its u se.