SUPPRESSION OF COLLAGEN-INDUCED ARTHRITIS BY ORAL-ADMINISTRATION OF TYPE-II COLLAGEN - CHANGES IN IMMUNE AND ARTHRITIC RESPONSES MEDIATED BY ACTIVE PERIPHERAL SUPPRESSION

The oral administration of CII by gavage to WA/KIR rats before a conve ntional arthritogenic challenge with bovine CII in FIA reduced the inc idence (by 23%) and delayed the onset of collagen-induced arthritis in about 50% of the animals. Selective changes in B cell and T cell resp onses to CII in animals treated this way are interpreted to indicate a state of tolerance or hyporesponsiveness to CII. Tolerant animals mad e less serum antibody, to bovine and rat CII, of the IgG2b isotype and more of the IgG1 isotype. Phenotypic and functional analysis of perip heral lymph node cells showed that those from tolerized animals expres sed less MHC Class II, proliferated less and secreted less IgG2b anti- CII antibody in response to stimulation in vitro with CII when compare d with cells from non-tolerant animals. However, this depression of th e immune responses to CII seen in vitro was overcome when the cells we re incubated with increasing amounts of CII. Tolerance could be transf erred 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 susceptib le to collagen-induced arthritis. Transfer of serum from gavaged anima ls did not modify the susceptibility of normal recipients to arthritis . Spleen cells from gavaged animals suppressed proliferative and antib ody responses in co-cultures in vitro with lymph node cells from anima ls immunized with CII in FIA. The suppressive spleen cell population c ontained more cells expressing MHC Class II, in both the CD8+ and CD4 populations. These studies show that the oral administration of CII a lters the subsequent immune response to the arthritogenic challenge an d indicate that this oral tolerance of CII is due, not to clonal delet ion or anergy, but rather to an antigen-driven active suppression mech anism that affects both T cells and B cells, most likely through the a ction of regulatory cytokines IL-4, IL-10 and TGFbeta.