Suppression of Collagen Induced Arthritis by Oral Administration of Type II Collagen: Changes in Immune and Arthritic Responses Mediated by Active Peripheral Suppression

Abstract

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.

Antigen‐specific suppression of established arthritis in mice by dendritic cells deficient in NF‐κB

“…IL-10 and TGF␤ are important partners that drive the immunoregulatory response after tolerizing immunotherapy with either mucosal antigen, allergenspecific immunotherapy, or DCs (35)(36)(37)(38)(39)(40)(41). After specific immunotherapy, allergen-specific T cell immunity deviates toward the production of IL-10 and TGF␤, and allergen-specific IgA, IgG1, and IgG4 isotypes are induced (35,36).…”

Antibodies to Lysophosphatidylcholine Are Decreased in Borderline Hypertension

“…In general, immunological tolerance may be induced by an oral intake of an antigen, as exemplified by collagen II in rheumatoid arthritis rat models. 32 Whether oral tolerance may also be present as a specific response against certain lipidcontaining and even oxidized compounds in the food is not known. To clarify this issue, further research both in animal models and in humans is warranted.…”

Prevention of autoimmune disease due to lymphocyte modulation by the B-subunit ofEscherichia coli heat-labile enterotoxin

“…Our finding that protection could be achieved even once the pathological immune response to CII was established demonstrates that EtxB-receptor interaction can modulate an existing immune response. Alternative strategies for preventing inflammatory disorders have included the induction of mucosal tolerance after oral or intranasal delivery of autoantigens or peptides (38)(39)(40). Interestingly, a recent report demonstrated that direct chemical coupling of myelin basic protein (MBP) to cholera toxin B subunit (CtxB) can reduce the intragastric dose of MBP required to induce tolerance for delayed type hypersensitivity and consequent protection from experimental autoimmune encephalomyelitis (41).…”