Effects of mycophenolate mofetil on nasal mucosal tolerance induction.
OBJECTIVE
The authors investigated mucosal tolerance therapy as a treatment for autoimmune conditions, including uveitis. Although nasal antigen administration was unable to suppress the disease when given to primed animals, previous studies of experimental autoimmune uveoretinitis (EAU) have shown that nasal antigen administration can maintain disease suppression when combined with oral cyclosporin A. This study aimed to determine whether mucosal tolerance can be induced when EAU is suppressed with mycophenolate Mofetil (MM) and whether tolerance can be maintained when immunosuppression with MM is stopped.


METHODS
Lewis rats were immunized with retinal extract, and then they received either oral MM 7 to 20 days after immunization or retinal extract intranasally in combination with oral MM on days 7 to 20. Thereafter, weekly nasal administration of the antigen was given until the termination of the experiment at day 38. One group of control animals received the drug vehicle orally and phosphate-buffered saline intranasally. Clinical and histologic changes were assessed along with changes in immune status including delayed-type hypersensitivity, antibody responses to retinal antigens, and flow cytometric phenotyping of infiltrating ocular leukocytes.


RESULTS
EAU was delayed, but not prevented, by a short-term course of MM (7-20 days after immunization). Tolerance to the retinal extract could not be induced during MM treatment by nasal retinal extract administration. Despite the delay in onset of EAU in MM and in MM- and nasal antigen-treated animals, profound target organ damage occurred as seen in untreated controls with EAU. However, fluoroscein-activated cell sorter analysis of retinal leukocytic infiltrate indicated that there was a reduced macrophage recruitment at all time points, whereas lymphocyte infiltration was reduced in proportion to the overall reduction in leukocyte infiltration during therapy.


CONCLUSIONS
Nasal retinal antigen administration does not induce tolerance or maintain disease suppression when combined with MM therapy during the effector stage of the (auto)immune response. MM therapy delays disease onset, but target organ damage occurs when therapy is stopped, despite a marked inhibition of macrophagemonocyte infiltration into the chorioretina.
Dick
A D
AD
University of Aberdeen, Department of Ophthalmology, Scotland, UK.
Kreutzer
B
B
Laliotou
B
B
Forrester
J V
JV
D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006968:Hypersensitivity, Delayed / Q000276:immunology; D018928:Immunity, Mucosal / Q000187:drug effects; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007958:Leukocyte Count; D008264:Macrophages / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009297:Nasal Mucosa / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000276:immunology; D012173:Retinitis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014605:Uveitis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
D001324:Autoantigens; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid