Nasal administration of retinal antigens maintains immunosuppression of uveoretinitis in cyclosporin-A-treated Lewis rats: future treatment of endogenous posterior uveoretinitis?
OBJECTIVE
Current treatment of autoimmune endogenous posterior uveoretinitis (EPU) is limited by drug toxicity, unpredictable relapses on dose reduction and resistance to therapy. Administration of autoantigens via gastrointestinal or respiratory mucosa prior to antigen exposure induces immune hyporesponsiveness (mucosal tolerance) to further antigen sensitisation. In this study we assessed whether mucosal tolerance induction was possible after immunisation with retinal antigens in experimental autoimmune uveoretinitis (EAU) in animals that were short-term immunosuppressed with cyclosporin A (CsA) to determine whether mucosal administration of retinal antigens can maintain immunosuppression in sensitised and immunosuppressed individuals.


METHODS
Female Lewis rats were immunised with retinal extract (RE) and then treated as follows. Group 1 received no specific therapy and served as control; group 2 were fed CsA from day 7 to day 20 post-immunisation; group 3 received inhalational tolerance therapy with RE in addition to CsA; tolerance therapy was continued after day 20 when CsA was stopped. Experiments varying the timing and dosage of both tolerising and immunising antigen were also performed, the details of which are described. Incidence, day of onset and clinical activity were recorded and histopathological assessment of intraocular inflammation, in particular the extent of autoimmune target-organ damage, was graded semiquantitatively.


RESULTS
Compared with controls and group 2, group 3 showed both a marked delay in disease onset and a reduction in disease severity. This effect was both dose and dose-timing dependent. Tissue damage assessed in terms of preservation of rod outer segments was significantly less in group 3.


CONCLUSIONS
The success of combination therapy, clinically, remains unknown at present but these results support continuing present clinical trials of mucosal tolerance therapy and in particular have future implications for either maintaining or inducing immunosuppression in autoimmune diseases in combination with present immunosuppressive therapies.
Kreutzer
B
B
Department of Ophthalmology, Medical School, University of Aberdeen, Scotland, UK.
Laliotou
B
B
Cheng
Y F
YF
Liversidge
J
J
Forrester
J V
JV
Dick
A D
AD
D000281:Administration, Intranasal; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage*; D001327:Autoimmune Diseases / Q000473:pathology / Q000517:prevention & control*; D003131:Combined Modality Therapy; D016572:Cyclosporine / Q000627:therapeutic use; D003888:Desensitization, Immunologic / Q000379:methods*; D005260:Female; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000276:immunology*; D015866:Uveitis, Posterior / Q000473:pathology / Q000517:prevention & control*
D001324:Autoantigens; D007166:Immunosuppressive Agents; D016572:Cyclosporine