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Blood. 1998 Dec 1;92(11):4090-7.

gammac gene transfer in the presence of stem cell factor, FLT-3L, interleukin-7 (IL-7), IL-1, and IL-15 cytokines restores T-cell differentiation from gammac(-) X-linked severe combined immunodeficiency hematopoietic progenitor cells in murine fetal thymic organ cultures.

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Institut National de la santé et de la Recherche Médicale U429 et Centre de Transfusion Sanguine, Hôpital Necker-Enfants Malades, Paris Cedex, France.


X-linked severe combined immunodeficiency (SCID-Xl) is a rare human inherited disorder in which early T and natural killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common gammac chain that participates in several cytokine receptors including the interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. We have shown in a previous report that gammac gene transfer into SCID-Xl bone marrow (BM) cells restores efficient NK cell differentiation. In this study, we have focused on the introduction of the gammac gene into SCID-Xl hematopoietic stem cells with the goal of obtaining differentiation into mature T cells. For this purpose, we used the in vitro hybrid fetal thymic organ culture (FTOC) system in which a combination of cytokines consisting of stem cell factor (SCF), Flt-3L, IL-7, IL-1, and IL-15 is added concomitantly. In this culture system, CD34(+) marrow cells from two SCID-Xl patients were able to mature into double positive CD4(+) CD8(+) cells and to a lesser degree into CD4(+) TCRbeta+ single positive cells after retroviral-mediated gammac gene transfer. In addition, examination of the output cell population at the TCR DJbeta1 locus exhibited multiple rearrangements. These results indicate that restoration of the gammac/JAK/STAT signaling pathway during the early developmental stages of thymocytes can correct the T-cell differentiation block in SCID-Xl hematopoietic progenitor cells and therefore establishes a basis for further clinical gammac gene transfer studies.

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