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Mucosal administration of an autoantigen has been shown to be a powerful way of inducing tolerance in both animal and human arthritis clinical trials. Bovine or chicken type II collagen has been administered orally to rheumatoid arthritis patients, resulting in some, although in many cases rather limited, clinical improvement. Animal studies have revealed that the mechanisms that underlie induction of mucosal tolerance include clonal deletion, suppression of the proinflammatory Th1 cells, and the induction of regulatory T cells. These cells, defined as a persistently CD25-expressing subset of CD4(+) cells, are frequently anergic, may produce anti-inflammatory cytokines such as IL-10 and TGF-beta, and are likely to be agents of bystander suppression. A key feature that may affect the induction of these cells and other suppressive mechanisms is the dose of antigen administered. The results from human clinical trials suggest a daily dose of significantly less than 1 mg is optimal. Similarly data from collagen-induced arthritis studies reveal an optimal dose above and below which there is little or no immune suppression. Indeed, the incorrect dose can prime the immune response and aggravate disease. The timing and frequency of administration is also vital to the level of immune tolerance induced and the control of the pathological process. This and other findings derived from animal studies are discussed here in relation to the results from human clinical trials.

The migration of lymphocytes into lymph nodes via high endothelial venules (HEV) is dependent on the expression of L-selectin on the lymphocyte cell surface. HEV express several L-selectin ligands including CD34, GlyCAM-1, MAdCAM-1 and two sulfated glycoproteins (Sgp) of 200 kDa and 170 kDa which remain to be identified. In this investigation, labeling with sodium [ 35 S]sulfate, which is incorporated into and forms part of the functional carbohydrate ligand, has been used to isolate and characterize macromolecular L-selectin ligands. High endothelial cells (HEC) cultured from rat lymph node HEV were shown to express ligands for L-selectin. HEC synthesized two groups of sulfated glycoproteins of 150 kDa and G 200 kDa, which were present in conditioned medium. These coeluted on anion exchange chromatography at 1.0-1.2 M NaCl and supported calcium-dependent L-selectin-mediated cell adhesion. In common with known L-selectin ligands, Sgp 150/ G 200 were shown to be O-sialoglycoproteins; however, in contrast to other ligands, Sgp 150/ G 200 contained chon-droitin sulfate glycosaminoglycan modifications which were required for L-selectin recognition. Chondroitin sulfate-modified ligands for L-selectin were expressed at the HEC surface and by HEV in lymph nodes, suggesting that they may participate in lymphocyte interactions with HEV in vivo.

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