Linomide downregulates autoimmunity through induction of TH2 cytokine production by lymphocytes

Linomide is a synthetic immunomodulator that has been shown to protect anim als against a wide range of spontaneously developing or induced autoimmune diseases. We have previously reported that Linomide blocks both the clinica l and the histopathological manifestations of experimental autoimmune encep halomyelitis (EAE) in various animal models. In this study, in an effort to elucidate the mechanisms by which Linomide suppresses EAE, and autoimmunit y in general, we investigated the in vivo effects of this drug on the TH1/T H2 lymphocyte balance, which is important for the induction or inhibition o f autoireactivity. Naive SJL/J mice were treated orally for 15 days with Li nomide (80 mg/kg/day). Spleen cells were obtained at various time points du ring the treatment period and were stimulated in vitro with concanavalin A. Interleukins IL-4, IL-10 and IL-12, transforming growth factor-beta (TGF b eta) and interferon-gamma (IFN gamma) cytokine production was evaluated bot h by means of detection of the cytokines in the medium (by ELISA technique) and by detection of the cytokine mRNA production, using a semiquantitative reverse transcriptase-polymerase chain reaction method. A significant upre gulation of IL-4, IL-10 and TGF beta was observed following treatment with Linomide, which peaked at day 10 (IL-10) or day 15 (IL-4). On the other han d, IL-12 and IFN gamma production were either unchanged or decreased. It se ems therefore that Linomide induces in vivo a shift towards TH2 lymphocytes which may be one of the mechanisms of downregulation of the autoimmune rea ctivity in EAE. Our observations indicate that downregulation of TH1 cytoki nes (especially IL-12) and enhancement of TH2 cytokine production may play an important role in the control of T-cell-mediated autoimmunity. These dat a may contribute to the design of new immunomodulating treatments for a gro up of autoimmune diseases. (C) 1999 Elsevier Science B.V. All rights reserv ed.