Oral tolerance

Abstract

Summary The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T-cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103+ retinoic acid-dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor-β dependent and express latency-associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin-10 dependent) are induced by nasal antigen and forkhead box protein 3+ iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti-CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti-CD3 monoclonal antibody induces LAP+ Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non-toxic, physiologic approach to reach this goal.

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

“…The doses and concentration of the antigen are often directly correlated with the generation of active and cell-dependent regulatory mechanisms (Turley and Miller, 2010) or with the induction of anergy (Bitar and Whitacre, 1988) or even deletion of antigen-specific T cells (Critchfield et al, 1994;Liblau et al, 1996;Apostolou and von Boehmer, 2004;Judkowski et al, 2004). Likewise, immunological tolerance achieved by oral (Higgins and Weiner, 1988;Weiner, 2000;Weiner et al, 2011) and intranasal (Anderton et al, 1998;Fossati-Jimack et al, 2015) delivery of autoantigens has shown to be mediated by active suppressor mechanisms such as anti-inflammatory cytokines and regulatory cells (Chen et al, 1995;Weiner et al, 2011).…”

Current prospects and future challenges for nasal vaccine delivery

“…66 It has long been known that oral delivery is effective in generating antigen tolerance, through deliberate introduction of the antigen to food. 67 More recently it has been shown that a similar tolerance induction can be achieved via nasal delivery through activation of the DCs in the draining lymph nodes to enhance induction of FoxP3CT-cells. 68 Examples of successful nasal delivery include immunization to suppress atherosclerosis 69,70 and arthritis.…”

Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis

“…Oral tolerance, the induction of systemic immunological tolerance after oral administration of an antigen, has been demonstrated in a number of animal disease models, and has also been suggested as a possible therapy in autoimmune disease [117]. It has long been known that mucosal immunisation may induce systemic tolerance against delayed type of hypersensitivity (DTH) reactions, whereas already established T-cell mediated inflammation is difficult to deviate by mucosal antigen challenge [26,118].…”