Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance.

Abstract

SummaryIn previous studies we showed that a chronic colitis associated with a Thl T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation ofmucosal T cells producing TGF-[3 and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-[3 and secreted increased amounts oflL-4 and IL-10 but lower levels oflFN-~ in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-[3 but decreased IL-12 expression by immunohistochemicat studies and isolated mononuclear cells from HCP-fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration ofanti-TGF-[3 or rlL-12 suggesting a reciprocal relationship between IL-12 and TGF-[3 on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-[3 production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-[3 levels may have relevance to the treatment of human inflammatory bowel disease.

Osteopontin expression by CD103−dendritic cells drives intestinal inflammation

“…TNBS-driven colitis is initiated by intrarectal instillation of a solution of ethanol, which breaks the mucosal barrier, with TNBS, which haptenizes autologous colonic or microflora proteins, leading to Th1 and Th17 responses (64). Despite the fact that the TNBS colitis model was traditionally considered T cell-dependent (65), studies have demonstrated that it can develop in the absence of adaptive immunity (66). Chemical haptens are sensitizers with a high ability to elicit DC migration from the sites of sensitization to draining LNs to present antigens and activate immune responses (67).…”

CD4+ T cells from 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rodents migrate to the recipient's colon upon transfer; down-regulation by CD8+ T cells

“…In addition, Neurath et al [21] showed that these transferred T cells migrate to the recipient's colon, which results in lymphoid infiltrates in the colon. However, from the latter study it is not clear if T cells exclusively migrate to the colon, nor if other inflammatory cells migrate to the colon upon T cell transfer.…”

Activated Self-MHC-Reactive T Cells Have the Cytokine Phenotype of Th3/T Regulatory Cell 1 T Cells

“…Such T cells have a unique cytokine production profile in that they produce high levels of TGF-␤ without necessarily producing either Th1 or Th2 cytokines; therefore, they have been dubbed Th3 T cells (12). Th3 cells producing TGF-␤ have also been shown to occur in experimental models of colitis or diabetes or in HgCl 2 -induced autoimmune disease, and in these instances it is thought that such T cells play an important role in disease prevention or cure (13)(14)(15)(16). Recently, another type of regulatory T cell has been identified (in both mice and humans) that may be related to the aforementioned Th3 T cell.…”