PENTOXIFYLLINE, A PHOSPHODIESTERASE INHIBITOR, INDUCES IMMUNE DEVIATION IN PATIENTS WITH MULTIPLE-SCLEROSIS

The outcome of immune responses can be predicted by the lymphokine pro duction pattern of the participating cells. Cytokines of the T helper type 1 (Th1) cells mediate inflammatory responses and delayed-type hyp ersensitivity (DTH), whereas Th2-like T cells predominantly produce cy tokines, which stimulate antibody production by B cells. Immunoregulat ory therapy of autoimmune diseases with unknown antigens may be achiev ed by inhibiting the production of inflammatory cytokines and inductio n of protective cytokines of Th2-like T cells. To determine the immuno regulatory capacity of the phosphodiesterase inhibitor pentoxifylline (PTX), which is known to suppress the production of tumor necrosis fac tor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), this drug was used in mitogen and antigen-stimulated lymphocyte cultures as well as in patients with multiple sclerosis. PTX significantly decreased TNF-a lpha and interleukin-12 (IL-12), whereas it increased IL-4 and IL-10 p roduction. In addition, PTX inhibited cell proliferation, which was as sociated with a marked reduction in CD25 (IL-2 receptor alpha-chain) a nd CD54 (intercellular adhesion molecule-1; ICAM-1) expression. Increa sing doses of PTX significantly reduced TNF-alpha and IL-12 mRNA expre ssion of blood mononuclear cells, but increased IL-4 and IL-10 express ion in eight patients with relapsing-remitting multiple sclerosis. The se results indicate that PTX modulates immune reactions favouring a Th 2-like response and may therefore be useful for the treatment of autoi mmune diseases with a dominant Th1-like T cell response.