Interleukin-2 treatment potentiates induction of oral tolerance in a murine model of autoimmunity.

Abstract

The present study addresses the feasibility of potentiating oral tolerance by immunomanipulation, using the murine model of experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal antigen interphotoreceptor retinoid binding protein (IRBP). Three feedings of 0.2 mg IRBP every other day before immunization did not protect against EAU, whereas a similar regimen of five doses was protective. However, supplementing the nonprotective 3x regimen with as little as one injection of 1,000 U of human recombinant interleukin-2 (IL-2) resulted in disease suppression that was equal to that of the protective 5x regimen. The protective effect was maintained across a range of IL-2 doses and times of administration; none of the IL-2 regimens tested resulted in disease enhancement. Peyer's Patch cells of 3X-fed and IL-2-treated mice showed greatly increased production of TGF-fl, IL-4, and IL-10 compared with animals given the nonprotective 3x regimen and to animals given the protective 5x regimen. We propose that IL-2 treatment enhances protection from EAU at least in part by stimulating production of antiinflammatory cytokines by regulatory cells in Payer's Patches. Moreover, the observed lymphokine production patterns suggest that whereas protection induced by the 3x + IL-2 regimen is likely to involve antiinflammatory cytokines, protection induced by the 5X regimen might involve anergy or deletion of the uveitogenic T cells. These results could have practical implications for use of IL-2 as a safe and effective way of potentiating oral tolerance. (J. Clin. Invest. 1994. 94:1668-1672

Threshold Signaling of Human Th0 Cells in Activation and Anergy: Modulation of Effector Function by Altered TCR Ligand

“…We also investigated IL-10 synthesis following exposure of the T cells to anergizing doses of p 2, 28 -40A 34,36 and could detect levels that exceeded those induced by the native peptide. It has been noted that human CD4 ϩ T cells cultured in IL-10 became unresponsive to Ag restimulation (29), while murine cells adopt a regulatory phenotype capable of suppressing Th1 immunity (39). Thus, enhanced autocrine secretion of IL-10 may account for the more profound level of anergy induced by the analogue.…”

Cytokines and Chemokines in Uveitis - Is there a Correlation with Clinical Phenotype?

“…37 Oral tolerance in a murine model with human recombinant IL-2 has been documented to protect against experimental autoimmune uveitis, possibly through the induction of IL-4 and transforming growth factor (TGF)-β. 38 IL-1β, along with IL-1α, makes up the pleiotropic cytokine IL-1. 39 Each has its own receptor, but receptor usage is not highly restricted.…”

A randomized, placebo‐controlled, double‐masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis

“…TNF is predominantly produced by macrophages (9) and has a number of biologic effects, including activation of T cells, proliferation of both T and B cells, and the attraction of macrophages and granulocytes into areas of inflammation (10). TNF also induces macrophages and other inflammatory cells to release substances that sustain an immune response and lead to tissue destruction (11,12). In studies of children with JIA, TNF has been shown to be an integral component in the development of the joint disease.…”