INCREASED INTERLEUKIN-12 PRODUCTION IN PROGRESSIVE MULTIPLE-SCLEROSIS- INDUCTION BY ACTIVATED CD4(-CELLS VIA CD40 LIGAND() T)

Multiple sclerosis (MS) is a chronic inflammatory disease of the centr al nervous system postulated to be a cell-mediated autoimmune disease in which interferon gamma (IFN-gamma) plays an important role. There i s increased IFN-gamma secretion in MS, and IFN-gamma administration in duces exacerbations of disease. We found that interleukin 12 (IL-12) w as responsible for raised IFN-gamma secretion in MS as anti-IL-12 anti bodies reversed raised anti-CD3 induced IFN-gamma in MS patients to no rmal levels. Furthermore, we found a marked increase in T cell recepto r-mediated IL-12 secretion in progressive MS patients vs. controls (24 .8 +/- 7.7 pg/ml vs. 1.5 +/- 1.0 pg/ml, P = 0.003) and vs. relapsing-r emitting patients (3.7 +/- 1.4 pg/ml, P < 0.05). Investigation of the cellular basis for raised IL-12 demonstrated that T cells from MS pati ents induced IL-12 secretion from non-T cells, and that T cells from M S patients could even drive non-T cells from normal subjects to produc e increased IL-12. Anti-CD40 ligand antibody completely blocked IL-12 secretion induced by activated T cells, and we found increased CD40 li gand expression by activated CD4(+) T cells in MS patients vs, control s. The CD40 ligand-dependent Th1-type immune activation was observed i n the progressive but not in the relapsing-remitting form of MS, sugge sting a link to disease pathogenesis and progression and providing a b asis for immune intervention in the disease.