Subcutaneous (s.c.) immunization of rats with the human 60-kDa heat shock protein (HSP)-derived peptide 336-351 induced clinical and/or histological uveitis in 80 % of rats. Subsequent experiments to prevent the development of uveitis by oral or nasal administration of the peptide have failed. Instead, uveitis was induced in 74.6 % of rats given the peptide orally (5 times), in 75 % given the peptide nasally (5 times) or 91.7 % of those administered the peptide by both routes (10 times). Histological examination showed that any one route of administration of the peptide elicited iridocyclitis in 42.2 % but loss of photoreceptors only in 4.9 % of rats. In contrast, sequential administrations of the peptide by a combined mucosal-s.c. route resulted in iridocyclitis in only 25 % but loss of photoreceptors in 40 % of animals. Examination of mRNA from CD4-enriched splenic cells by reverse transcription-PCR failed to yield significant differences in Th1 or Th2 cytokines. Treatment with monoclonal antibody (mAb) to CD4 yielded a dose-dependent decrease in uveitis from 82 % to 25 %. Similarly, treatment with IL-4 significantly decreased the development of uveitis from 68 % to 30.4 %. Conversely, treatment of the rats with mAb to CD8 greatly enhanced the onset of uveitis (from about 22 days in the controls to 11 days) and all the rats developed uveitis by day 24. Thus, CD4+ cells mediate, whereas CD8+ cells suppress the development of uveitis. We suggest that this novel experimental mucosal model of induction of uveitis by the human 60-kDa HSP-derived peptide 336-351, which is specific in stimulating T cell responses in Behcet's disease, is consistent with the oro-genital onset of this disease and the development of uveitis.