The oral administration of CII by gavage to WA/KIR rats before a conventional arthritogenic challenge with bovine CII in FIA reduced the incidence (by 23%) and delayed the onset of collagen-induced arthritis in about 50% of the animals. Selective changes in B cell and T cell responses to CII in animals treated this way are interpreted to indicate a state of tolerance or hyporesponsiveness to CII. Tolerant animals made less serum antibody, to bovine and rat CII, of the IgG2b isotype and more of the IgG1 isotype. Phenotypic and functional analysis of peripheral lymph node cells showed that those from tolerized animals expressed less MHC Class II, proliferated less and secreted less IgG2b anti-CII antibody in response to stimulation in vitro with CII when compared with cells from non-tolerant animals. However, this depression of the immune responses to CII seen in vitro was overcome when the cells were incubated with increasing amounts of CII. Tolerance could be transferred to normal animals. Spleen cells, and nylon wool-filtered splenic T cells (but not mesenteric lymph node cells) adoptively transferred hyporesponsiveness to normal recipients which were then less susceptible to collagen-induced arthritis. Transfer of serum from gavaged animals did not modify the susceptibility of normal recipients to arthritis. Spleen cells from gavaged animals suppressed proliferative and antibody responses in co-cultures in vitro with lymph node cells from animals immunized with CII in FIA. The suppressive spleen cell population contained more cells expressing MHC Class II, in both the CD8+ and CD4+ populations. These studies show that the oral administration of CII alters the subsequent immune response to the arthritogenic challenge and indicate that this oral tolerance of CII is due, not to clonal deletion or anergy, but rather to an antigen-driven active suppression mechanism that affects both T cells and B cells, most likely through the action of regulatory cytokines IL-4, IL-10 and TGF beta.

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