Therapies with immunosuppressive drugs in autoimmune experimental diseases often down-regulate disease but sometimes may lead to paradoxical disease exacerbation. To elucidate possible mechanisms behind such phenomena the effects were studied of mitoxantrone (Mx) and cyclosporin A (CsA) given at high and low doses on clinical course, and on autoreactive T- and B-cell responses in actively induced experimental allergic encephalomyelitis (EAE) in Lewis rats. Treatment with mx and high dose CsA abrogated EAE and decreased dramatically the measured immune responses compared to vehicle-treated control EAE rats. Low-dose CsA treatment caused a disease relapse 20–30 days post immunization (p.i.). This relapse was accompanied by increased numbers of cells spontaneously producing IFN-γ in the CNS and regional lymph nodes. Furthermore, anti-myelin and anti-MBP secreting cells were increased as were numbers of primed T cells that produced IFN-γ in response to myelin antigens. It was concluded that these aspects of the myelin autoreactive immune response correlated well with clinical disease and are useful in evaluating immunotherapeutic intervention. Low-dose CsA treatment may interfere with systemic down-regulatory mechanisms acting on both T- and B-cell myelin-directcd autoimmunity.