Investigators have shown that exposure of a contact sensitizing agent via the mucosa prior to subsequent skin challenge led to unresponsiveness in a portion of patients studied. Orally administered KLH, 50 mg, given daily for 2 weeks over a 3-weck period to human subjects has been reported to decrease subsequent cell-mediated immune responses although antibody responses were not affected. Nasal KLH has also been reported to induce tolerance in humans.
Based on the success of oral tolerance in animals models of diseases and the safety of the approach, human trials have been initiated in multiple sclerosis, rheumatoid arthritis, uveitis, and type 1 diabetes. Although these phase I/II trials have shown positive results, the final demonstration of clinical efficacy of oral antigen in these diseases must await the results of large-scale phase III trials that are in progress, or planned (Table 4). What can be concluded from the initial trials is that there has been no toxicity or exacerbation of disease and results in humans have parallelled in many respects what has been observed in animals. Specifically, in MS patients, MBP- and PLP-specific TGFp-secreting Tn3-type cells have been observed in the peripheral blood of oral myelin-treated but not control patients. These results demonstrate that it is possible to orally immunize via the gut for autoantigen-specific TGFfJ-secreting cells in a human autoimmune disease simply by oral administration of the autoantigen. Furthermore, it also appears that continuous oral administration of oral antigen is required as MS patients had worsening of disability over a 3-year observation when they were not taking oral myelin.
In rheumatoid arthritis, a 280 patient double-blind phase II dosing trial of CII in doses ranging from 20 pg to 2500 pg demonstrated statistically significant positive effects in the group fed the lowest dose (20 pg). Feeding larger doses of bovine CII (1-10 mg) did not show a significant difference between tested and placebo groups though a higher prevalence of responders was reported for the CII-treated groups. These results are consistent with animal studies of orally administered CII in which protection against adjuvant and antigen-induced arthritis, and the generation of bystander suppression, was observed only at the lower fed doses. An open label pilot study of oral collagen in juvenile rheumatoid arthritis found positive results with no toxicity. This lack of toxicity is an important feature for the clinical use of oral tolerance, especially in children, for whom the long-term effects of immunosuppressive drugs is unknown.
In multiple sclerosis, a recently completed 515 patient double-blind phase III trial of single-dose bovine myelin in relapsing-remitting MS did not show differences between placebo and treated groups in the number of relapses. Preliminary analysis of magnetic resonance imaging data showed significant changes favoring oral myelin in certain patient subgroups.
In uveitis, a pilot trial of S-antigen and an S-anti-gen mixture has also recently been completed and showed positive trends with oral bovine S-antigen. Finally, trials have been initiated in new-onset diabetes in which recombinant human insulin is administered orally and trials are planned in subjects at risk for diabetes or part of the diabetes prevention trial (DPT-1).
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