Tolerance in its classical definition depends on knowing the antigenic epitopes to be recognized, and hence a major drawback of studies in human and experimental autoimmunity is our lack of understanding of the important epitopes. Nevertheless there are a variety of experimental approaches which are finding their way into human application, at least to the clinical trial stage. A major objective is to ensure that in established disease, with an ongoing immune response, the therapeutic strategy does not potentiate rather than suppress the immune response.
Oral tolerance has been described for many years, first by Merril Chase in guinea pigs. Most recently it has been popularized by H. Wiener and colleagues, and clinical trials of bovine collagen type II in rheumatoid arthritis and myelin basic protein in multiple sclerosis are in progress, run by Autoimmune Inc. Multiple mechanisms of oral tolerance have been proposed, from inducing apoptosis at high doses to inducing regulatory T cells at low doses. An improved variant may be inhalation tolerance, via the nose, which is more potent, and has been popularized by David Wraith.
Peptides given systematically, without adjuvant, are of low immunogenicity and are being developed for therapy. Trials of myelin basic protein (MBP) peptides, based on the 89-102 immunodominant region, are in progress, with different variants being run by Neurocrine Inc. and Immunologic. Neurocrinc's trial involves using peptide derivatives known as 'altered peptide ligands', which upon binding to TCR do not elicit a complete immune response, but instead favor induction of tolerance.
Peptides elicit their effects after binding to the major histocompatibility complex (MHC) class I or II binding groove. It was thus proposed that it may be more effective to induce tolerance by treatment with preformed MHC class II-peptide complexes. This is effective in animal models, and a clinical trial of an HLA-DR2-MBP peptide complex is being initiated by Anergen Inc.
In the past, it was considered that saturating MHC peptide-binding grooves with nonimmunogenic peptides may be an effective strategy, but this was found not to be the case. Nonpeptide MHC blockers are in development (Zeneca). There are also clinical trials using immunization with MHC-derived peptides, which are designed to induce anti-MHC autoantibody, for example to the DR4/DR1 conserved 'shared' epitope involved in rheumatoid arthritis (Anergen Inc).
Peptides from the TCR have been shown to induce a protective immune response in experimental allergic encephalomyelitis (EAE), and such an approach is being attempted in humans in phase I studies (Immune Response Inc.).
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