HUMAN IG PRODUCTION AND ISOTYPE SWITCHING IN SEVERE COMBINED IMMUNODEFICIENT-HUMAN MICE

Severe combined immunodeficient (SCID) mice were transplanted with dif ferent human fetal organs (SCID-hu mice), including thymus, liver, spl een, and omentum, and the serum levels of human IgM, IgG, IgE, and IgA were measured. In all SCID-hu mice significant levels (up to 590 ng/m l) of IgM were detected, irrespective of the organs transplanted. In c ontrast, IgG was present (up to 530 ng/ml) only when the fetal thymus was transplanted together with the fetal liver, indicating that the pr esence of human T cells is a prerequisite for in vivo isotype switchin g by human B cells in SCID-hu mice. Additional transplantation of feta l spleen did not significantly increase IgG levels. Human IgA and IgE were never detected in the serum of these SCID-hu mice. The peak of Ig M and IgG production was observed 4 months after transplantation. At t hat time, analysis by IEF showed that human IgG present in SCID-hu ser um was at least oligoclonal. Furthermore, all IgG subclasses were repr esented in the human IgG pool. Human B cells were undetectable in the peripheral blood, spleen, and bone marrow of-these SCID-hu mice; in co ntrast, B cells expressing CD19 could be isolated from the SCID-hu thy mus. Considerable proportions of the CD19+ B cells coexpressed CD5, CD 7, CD10, CD40, and CD2. These B cells spontaneously produced IgM and I gG in vitro and could be induced to switch to IgE-producing cells when cocultured with cloned activated CD4+ T cells in the presence of IL-4 . Collectively, these data demonstrate that functionally mature B cell s able to produce IgM and IgG in vivo, and IgE in vitro, are present i n the SCID-hu human thymus.