EFFECTS OF MYCOPHENOLATE MOFETIL ON NASAL MUCOSAL TOLERANCE INDUCTION

PURPOSE. The authors investigated mucosal tolerance therapy as a treat ment for autoimmune conditions, including uveitis. Although nasal anti gen administration was unable to suppress the disease when given to pr imed animals, previous studies of experimental autoimmune uveoretiniti s (EAU) have shown that nasal antigen administration can maintain dise ase suppression Pi hen combined with oral cyclosporin h. This study ai med to determine whether mucosal tolerance can be induced when EAU is suppressed with mycophenolate Mofetil (MM) and whether tolerance can b e maintained a-hen immunosuppression with MM is stopped. METHODS. Lewi s rats were immunized with retinal extract, and then they received eit her oral MM 7 to 20 days after immunization or retinal extract intrana sally in combination With oral MM on days 7 to 20. Therafter, weekly n asal administration of the antigen was given until the termination of the experiment at day 38. One group of control animals received the dr ug vehicle orally and phosphate-buffered saline intranasally. Clinical and histologic changes were assessed along with changes in immune sta tus including delayed-type hypersensitivity, antibody responses to ret inal antigens, and flow cytometric phenotyping of infiltrating ocular leukocytes. RESULTS. EAU was delayed, but not prevented, by a short-te rm course of MM (7-20 days after immunization). Tolerance to the retin al extract could not be induced during MM treatment by nasal retinal e xtract administration. Despite the delay in onset of EAU in MM and in MM- and nasal antigen-treated animals, profound target organ damage oc curred as seen in untreated controls with EAU. However, fluoroscein-ac tivated cell sorter analysis of retinal leukocytic infiltrate indicate d that there was a reduced macrophage recruitment at all time points, whereas lymphocyte infiltration was reduced in proportion to the overa ll reduction in leukocyte infiltration during therapy. CONCLUSIONS. Na sal retinal antigen administration does not induce tolerance or mainta in disease suppression when combined with MM therapy during the effect or stage of the (auto)immune response. MM therapy delays disease onset , but target organ damage occurs when therapy is stopped, despite a ma rked inhibition of macrophage-monocyte infiltration into the chorioret ina.