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Review
. 2011 May;241(1):241-59.
doi: 10.1111/j.1600-065X.2011.01017.x.

Oral tolerance

Affiliations
Review

Oral tolerance

Howard L Weiner et al. Immunol Rev. 2011 May.

Abstract

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.

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Figures

Fig. 1
Fig. 1. Mechanisms of oral tolerance induction
Oral antigen crosses from the intestine into the GALT in a number of ways. It can enter via M cells, be sampled by DC processes that penetrate the lumen, or be taken up by intestinal epithelial cells. DCs in the gut are unique in that they can drive Treg differentiation from Foxp3 cells. These properties of DCs relate to their being conditioned by commensal bacteria, TGF-β and IL-10 from gut epithelial cells, and their expression of retinoic acid, which is provided in the form of vitamin A in the diet and appears to be constitutively expressed by gut DCs. CD11b monocytes may also play a role in the induction of Tregs, and the induction of Tregs occurs in the MLNs and involves both C-C motif receptor 7 (CCR7) and CCR9. Co-stimulation by PDL1-programmed cell death ligand (PDL) is also important for the induction of Tregs. Macrophages are stimulated to produce TGF-β after uptaking apoptotic epithelial cells or apoptotic T cells following high-dose tolerance. Lower doses of antigen favor the induction of Tregs, whereas higher doses of antigen favor anergy / deletion as a mechanism of tolerance induction. The liver may also play a role in oral tolerance induction and antigen (high dose) may be rapidly taken up by the liver, where it is processed by plasmacytoid DCs that induce anergy/ deletion and Tregs. A number of different types of Tregs may be induced or expanded in the gut including CD4+CD25+Foxp3+ iTregs, nTregs, Tr1 cells, LAP+ Tregs (Th3 cells), CD8+ Tregs, and γδT cells. TGF, transforming growth factor; RA, retinoic acid; DC, dendritic cells; LAP, latencyassociated peptide; Foxp3, forkhead box protein; IL, interleukin; MLN, mesenteric lymph nodes.
Fig. 2
Fig. 2. Regulatory T-cell cascade following induction of Th3 type Tregs by oral antigen or oral anti-CD3
A Th3 cell is a CD4+CD25Fox-p3 7LAP+ cell that exists in the peripheral immune compartment and is triggered by TCR signaling in the gut by oral antigen. Following triggering in the gut, the Th3 cell secretes TGF-β. Secreted TGF-β acts to maintain naturally occurring CD4+CD25+Foxp3+ Tregs, suppress Th1 and Th2 responses, and in concert with IL-6 may induce Th17 responses. Secreted TGF-β from Th3 cells also acts on CD4+Foxp3 cells and converts them to iTregs, which are Foxp3+CD25+LAP. Depending on the milieu, these cells may become Foxp3+CD4+CD25+LAP+. These induced Tregs may also condition DCs to secrete IL-27 and in turn induce IL-10-secreting Tr1 cells. LAP, latency-associated peptide; TGF, transforming growth factor; TCR, T-cell receptor; GALT, gut-associated lymphoid tissue; Foxp3, forkhead box protein 3; IL, interleukin; DC, dendritic cell.
Fig. 3
Fig. 3. Intestinal closed loop experiments demonstrating binding of anti-CD3 to DCs in the gut
Mice with a targeted deletion of chemokine receptor CX3CR1 with eGFP insertion (HC. Reinecker, Massachusetts General Hospital) have all monocytes and DCs in the gut labeled with eGFP (green). Mice were anesthetized, stomach opened, and a closed loop was created in a part of the small intestine. Alexa Fluor 700 labeled anti-CD3 (2C11 clone) antibody (blue) was injected into the loop and the intestinal loop harvested 45 min later. The intestinal content was cleared with PBS before imaging with confocal microscopy using multitracking for 2-color imaging. Image acquisition was carried out with Volocity software. DCs are labeled green and anti-CD3 antibody labeled blue. Green = DCs; blue = anti-CD3 monoclonal antibody. GFP, green fluorescence protein; DC, dendritic cell; PBS, phosphate buffered saline.
Fig. 4
Fig. 4. Immune regulatory pathways in the gut induced by AHR ligands
AHR ligands such as ITE in the gut either from commensal bacteria or administered orally act directly on T cells and DCs in the gut to induce Foxp3+ iTregs and Foxp3 Tr1 cells. Both Tregs and AHR ligands condition DCs to amplify Treg induction through the production of IL-27 and retinoic acid. AHR, aryl hydrocarbon receptor; ITE, 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester; DC, dendritic cell; Foxp3, forkhead box protein 3; IL, interleukin; TGF, transforming growth factor; RA, retinoic acid.
Fig. 5
Fig. 5. Oral insulin effect most evident in subjects with baseline IAA ≥300
A subgroup of islet autoantibody relatives with the highest level of insulin autoantibodies showed delayed progression to diabetes when treated with oral insulin to induce mucosal tolerance. Survival curve depicting time to diagnosis of type 1 diabetes in the Diabetes Prevention Trial 1 (DPT-1) oral insulin trial, for the subset of subjects with baselineconfirmed IAA level of 300 nU/ml or above. Skyler, JSS. Ann NY Acad Sci 2008. 1150: p 194. IAA, insulin autoantibody.

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