DBA/1 mice were administered type II collagen (CII) or collagen peptides intranasally before systemic immunization to determine whether tolerance could be induced and autoimmune arthritis suppressed. Although prior experiments have demonstrated that collagen given intravenously or orally is effective, the respiratory mucosal route offers several theoretical advantages for dosing peptides, in addition to ease of use. Intact CII, CB11 and a synthetic peptide containing the immunodominant T-cell epitope recognized by H-2q mice were all effective in reducing the incidence and severity of arthritis and the immune response to CII. Since previous studies have demonstrated the importance of IgG2 antibody subclasses to the induction of collagen-induced arthritis, total immunoglobulin G (IgG), IgG1, and IgG2a and IgG2b were measured. IgG2 antibody subclasses were significantly downregulated by the treatment regimen, whereas a slight decrease in IgG1 antibodies was noted that was not significant. In an effort to determine the mechanism by which arthritis was attenuated, cervical lymph node and spleen cells from treated mice were cultured separately with CII and supernatants tested for the presence of T-cell lymphokines. The cells provided a T-helper 2 (Th2)-like response to CII, with T cells from lymph nodes secreting interleukin-4 (IL-4) and splenocytes secreting both IL-4 and IL-10, whereas a Th1-like response was detected in immunized mice not tolerized with CII. These findings indicate that the downregulation of arthritis that occurs with intranasal administration of CII is associated with Th2-type lymphokine profile and a decrease in complement-fixing antibody subclass.