Gastroenterology

Gastroenterology

Volume 126, Issue 7, June 2004, Pages 1771-1778
Gastroenterology

Basic-alimentary tract
Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease

https://doi.org/10.1053/j.gastro.2004.03.076Get rights and content

Abstract

Background & Aims: Defective suppressor/regulatory T-cell activation has been proposed as a mechanism to explain the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Previous studies have suggested that inappropriate activation of CD4+ T cells may occur in the gastrointestinal tract in these patients. Because suppressor/regulatory T cells are thought to be one mechanism for the promotion of oral tolerance, we attempted to induce tolerance in normal controls (n = 21) and patients with either Crohn’s disease (CD, n = 12) or ulcerative colitis (UC, n = 13). Methods: Subjects were fed keyhole limpet hemocyanin (KLH) before subcutaneous immunization and booster immunization. Blood for KLH-induced T-cell proliferation and serum for anti-KLH antibody was obtained at baseline and after feeding, immunization, and booster. Results: In the control group, KLH feeding (50 and 250 mg) before immunization and booster resulted in reduced KLH-specific T-cell proliferation compared with the group that was not fed KLH (P < 0.002). However, both CD and UC patients showed significantly enhanced proliferation, without tolerance induction, when compared with baseline values (P < 0.035 and 0.02, respectively). Serum antibody to KLH was present only after immunization in the control group; however, anti-KLH antibody was seen after oral administration in both the UC and CD groups. Conclusions: Taken together, these data suggest that oral antigen administration does not result in tolerance in CD and UC patients, and might actually result in active immunity. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD.

Section snippets

Induction of oral tolerance

The ability to induce tolerance to the neoantigen KLH involved a modification of the protocol established by Husby et al.8 Patients and normal controls were fed KLH (Calbiochem, La Jolla, CA) at a dose of 5, 50, or 250 mg in 5 mL of phosphate-buffered saline on days 0–5 and 10–15. KLH was used because of its prior use in the study by Husby et al.8 as well as its general use as a potent immunogen in in vivo and in vitro studies. On day 26 patients were given 100 μg of KLH (in sterile

Determination of the dose of antigen required for induction of oral tolerance in normal controls

Because one of the goals of this study was to determine whether there was a defect in mucosal immunoregulation in IBD patients, we initially attempted to define low-dose tolerance in humans (the dose that results in the activation of regulatory T cells). The previously published study by Husby et al.8 used only a dose of 50 mg of KLH. Immune responses after Ag feeding were compared with nonfed controls. As seen in Figure 1A, in the absence of oral Ag administration, SC immunization with KLH

Discussion

The hallmark of the mucosal immune system in the gastrointestinal tract is one of generalized immunosuppression and nonresponsiveness.11, 12 This appears to be a direct consequence of the distinct demands placed on the immune system of the gut as opposed to those demands imposed systemically. Oral tolerance is a phenomenon that reflects this immunosuppressed tone. Although tolerance has been well described in inbred mouse models,6, 7 studies relating to oral tolerance in humans have been rare.8

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    Supported by National Institutes of Health grants AI23504, AI24671, and AI44236, and a grant from Autoimmune Inc., Boston, MA (L.M.). L.C. received a student fellowship award from the CCFA. L.T. was the recipient of a Crohn’s & Colitis Foundation of America research fellowship award.

    1

    A portion of this work appeared as part of the doctoral thesis of T.A.K.

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