Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

Abstract

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-β) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.

Immune reactivity to type VII collagen: implications for gene therapy of recessive dystrophic epidermolysis bullosa

“…In later clinical trials, immunosuppression or induction of immune tolerance [40][41][42][43][44][45][46] may also allow the inclusion of patients who show a positive naive reaction against type VII collagen in ELISPOT and ELISA assays. More widely, these predictive and monitoring tests may be applied to other therapy approaches under consideration for RDEB, involving injection of allogenic or genetically engineered autologous fibroblasts or administration of recombinant type VII collagen protein.…”

The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases

“…This widely used model of multiple sclerosis, experimental autoimmune encephalomyelitis, has been invaluable in elucidating the pathogenesis of this debilitating disease and in creating new therapeutic approaches. 102 The role of the components of the microbiota in the pathogenesis of disease using this experimental model has recently been documented by Kasper's group, and the results of this study have been used to propose a novel treatment. 103,104 The gut-brain axis is a bidirectional communication system through which the brain modulates gastrointestinal function and through which the gastrointestinal system is monitored by the brain.…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…94,95 The extension of this suppression to immune responses against other disease-related auto-Ags is a phenomenon referred to as bystander suppression. 93,94,96 This is made possible partly by the suppressive cytokines secreted by Ag-non-specific Tregs. This phenomenon holds great promise for the future since any auto-Ag, capable of inducing a Treg compartment, could inhibit the destructive immunologic actions characteristic for an autoimmune disease when administered in a tolerogenic way.…”

“…The β-cell targeted autoimmune response quickly spreads to other epitopes from the same Ag (intramolecular spreading) and/or to epitopes from other Ags (intermolecular spreading) situated in the close proximity. 92,93 This process of epitope spreading contains a lot of similarities with the spreading of protection when bystander suppression is induced. In several autoimmune disease models, like experimental autoimmune encephalomyelitis (EAE) and T1D, administration of an auto-Ag through a tolerogenic route drives the downregulation of the immune response to that specific auto-Ag, mostly through the induction of a Treg compartment.…”