Document 0674
 DOCN  M9550674
 TI    The immunosuppressive drug thalidomide induces T helper cell type 2
       (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and
       antigen-stimulated human peripheral blood mononuclear cell cultures.
 DT    9505
 AU    McHugh SM; Rifkin IR; Deighton J; Wilson AB; Lachmann PJ; Lockwood CM;
       Ewan PW; Molecular Immunopathology Unit, MRC Centre, Cambridge, UK.
 SO    Clin Exp Immunol. 1995 Feb;99(2):160-7. Unique Identifier : AIDSLINE
       MED/95153896
 AB    Thalidomide is an effective immunomodulatory drug in man, but its
       mechanism of action remains unclear. We hypothesized that, in addition
       to its reported inhibitory effects on production of monocyte-derived
       tumour necrosis factor-alpha (TNF-alpha), thalidomide might be effective
       at the level of Th immunoregulation. In a comparative study with the
       immunosuppressant cyclosporin A, we have demonstrated a potent and
       specific effect of thalidomide on cytokine production relating to the
       distinct Th1 and Th2 subsets. It induced and enhanced the production of
       IL-4 and IL-5 and, at the same dose (1000 ng/ml), significantly
       inhibited interferon-gamma (IFN-gamma) production in phytohaemagglutinin
       (PHA)-stimulated human peripheral blood mononuclear cell (PBMC)
       cultures. Stimulation of PBMC with recall antigen
       (streptokinase:streptodornase (SKSD)) at 144 h in the absence of
       thalidomide resulted in a predominantly Th1 response, with the
       production of IFN-gamma and IL-2. Thalidomide switched this response
       from a Th1 to a Th2 type. The effect was most pronounced at 1000 ng/ml
       thalidomide, where inhibition of IFN-gamma and enhancement of IL-4
       production was maximal. In unstimulated cultures thalidomide alone
       induced IL-4 production. Cyclosporin A, in contrast, inhibited both Th1
       and Th2 cytokine production by PHA-stimulated PBMC. Time course data
       from thalidomide-treated cultures revealed that the augmented IL-4
       production diminished as the culture time increased, whereas IFN-gamma
       production was significantly increased. This response might be due to
       activation-induced apoptosis of Th2 cells or the induction of Th2 cell
       anergy, in the continued presence of stimulating agents, with the
       emergence of IFN-gamma-secreting Th1 cells when Th2 antagonism declines.
       The effects of thalidomide and related compounds may enhance our
       understanding of the mechanisms of T helper cell selection, offer the
       possibility of controlled therapeutic switching between Th1 and Th2
       responses, and may lead to a rational approach for the treatment of some
       T cell-mediated immunological disorders.
 DE    Cells, Cultured  Cyclosporine/PHARMACOLOGY  Cytokines/*BIOSYNTHESIS
       Enzyme-Linked Immunosorbent Assay  Human  Immunosuppressive
       Agents/*PHARMACOLOGY  Lymphocyte Transformation/DRUG EFFECTS  Support,
       Non-U.S. Gov't  T-Lymphocytes, Helper-Inducer/*DRUG EFFECTS/*IMMUNOLOGY
       Thalidomide/*PHARMACOLOGY  Th1 Cells/DRUG EFFECTS/IMMUNOLOGY  Th2
       Cells/DRUG EFFECTS/IMMUNOLOGY  JOURNAL ARTICLE

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