IMMUNOPHARMACOLOGICAL MODULATION OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS - LOW-DOSE CYCLOSPORINE-A TREATMENT CAUSES DISEASE RELAPSE AND INCREASED SYSTEMIC T-CELL-MEDIATED AND B-CELL-MEDIATED MYELIN-DIRECTEDAUTOIMMUNITY

Therapies with immunosuppressive drugs in autoimmune experimental dise ases often down-regulate disease but sometimes may lead to paradoxical disease exacerbation. To elucidate possible mechanisms behind such ph enomena the effects were studied of mitoxantrone (Mx) and cyclosporin A (CsA) given at high and low doses on clinical course, and on autorea ctive T- and B-cell responses in actively induced experimental allergi c encephalomyelitis (EAE) in Lewis rats. Treatment with Mx and high do se CsA abrogated EAE and decreased dramatically the measured immune re sponses compared to vehicle-treated control EAE rats. Low-dose CsA tre atment caused a disease relapse 20-30 days post immunization (p.i.). T his relapse was accompanied by increased numbers of cells spontaneousl y producing IFN-gamma in the CNS and regional lymph nodes. Furthermore , anti-myelin and anti-M BP secreting cells were increased as were num bers of primed T cells that produced IFN-gamma in response to myelin a ntigens. It was concluded that these aspects of the myelin autoreactiv e 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-directed autoimmunity.