Oral tolerance and EAU: Differences in mechanisms elicited by pre- versus post-priming feeding regimens

Purpose. Most studies of oral tolerance in autoimmune disease involve feeding the autoantigen prior to immunization; i.e. "prophylactic" protocols. For treatment of disease, feeding after the immunization is more clinically relevant; i.e. a therapeutic protocol, since few patients present for treatment prior to onset of disease. Peptides of arrestin/S-Ag have been fed pre- versus post-priming to compare the mechanisms of EAU inhibition elicited by these differing protocols. Methods. Female LEW rats were fed, on alternating days, five times with S-Ag peptides 343-362 or 270-289, or IRBP peptide R16 at either low (200 μg), intermediate (1 mg) or high (5 mg) doses. Controls were fed irrelevant peptides or antigens. The animals were immunized either after the last feeding, or at various times prior to the first feeding. The rats were observed for three weeks for the clinical signs of EAU, and sacrificed for additional in vitro assays. Results. Prefeeding a low dose of S-Ag peptide 343-362 protected from EAU induction by subsequent immunization with S-Ag peptide 270-289. Prefeeding S-Ag peptide 343-362 at the high dose protected only from subsequent priming with 343-362 and not 270-289, suggesting the induction of epitope-sperific clonal unresponsiveness. In contrast, feeding post-priming at any of the doses induced protection only to the fed peptide, and protection was highly dose dependent. Low dose feedings, which are quite effective pre-priming, were only minimally protective when given post-priming. High dose post-priming led to inhibition of in vitro lymphocyte proliferation assays and modest decreases in antibody responses. Conclusions. Our results further support previous studies suggesting that multiple immunomodulating mechanisms are elicited by feeding antigens. Extrapolating to clinical settings, it would appear that feeding antigens/tissues to promote graft survival, which can be done "pre-priming" may require feeding conditions different from those done to inhibit existing autoimmune disease or to inhibit bystander damage resulting from other inflammatory processes.