Oral tolerance in disease

The poor success in controlling small bowel (SB) allograft rejection is partially attributed to the unique immune environment in the donor intestine. We hypothesized that Ag-induced activation of donor-derived T cells contributes to the initiation of SB allograft rejection. To address the role of donor T cell activation in SB transplantation, SB grafts from DO11.10 TCR transgenic mice (BALB/c, H-2Ld+) were transplanted into BALB/c (isografts), or single class I MHC-mismatched (Ld-deficient) BALB/c H-2dm2 (dm2, H-2Ld−) mutant mice (allografts). Graft survival was followed after injection of control or antigenic OVA323–339 peptide. Eighty percent of SB allografts developed severe rejection in mice treated with antigenic peptide, whereas <20% of allografts were rejected in mice treated with control peptide (p < 0.05). Isografts survived >30 days regardless of OVA323–339 administration. Activation of donor T cells increased intragraft expression of proinflammatory cytokine (IFN-γ) and CXC chemokine IFN-γ-inducible protein-10 mRNA and enhanced activation and accumulation of host NK and T cells in SB allografts. Treatment of mice with neutralizing anti-IFN-γ-inducible protein-10 mAb increased SB allograft survival in Ag-treated mice (67%; p < 0.05) and reduced accumulation of host T cells and NK cells in the lamina propria but not mesenteric lymph nodes. These results suggest that activation of donor T cells after SB allotransplantation induces production of a Th1-like profile of cytokines and CXC chemokines that enhance infiltration of host T cells and NK cells in SB allografts. Blocking this pathway may be of therapeutic value in controlling SB allograft rejection.

Section: S Mall Bowel (Sb)mentioning

confidence: 99%

Donor T Cell Activation Initiates Small Bowel Allograft Rejection Through an IFN-γ-Inducible Protein-10-Dependent Mechanism

Zhang¹,

Kaptanoğlu²,

Haddad

et al. 2002

“…These Ags induce an Ag-specific state of systemic immunologic unresponsiveness, a phenomenon called oral tolerance (5). Breakdown of oral tolerance is associated with severe immunopathology as observed in patients with inflammatory bowel disease (6,7), in which Th1 and Th17 reactivity are a major driving force in the disease process (8,9). T cells in the inflamed mucosa are characterized by high expression of the activation Ag CD69 (10).…”

mentioning

confidence: 99%

CD69 Regulates Type I IFN-Induced Tolerogenic Signals to Mucosal CD4 T Cells That Attenuate Their Colitogenic Potential

Radulovic

Manta

Rossini

et al. 2012

CD69 is highly expressed by lymphocytes at mucosal surfaces. We aimed to investigate the role of CD69 in mucosal immune responses. The expression of CD69 by CD4 T cells isolated from the spleen, mesenteric lymph nodes, small intestinal lamina propria, and colonic lamina propria was determined in specific pathogen-free B6 and TCR transgenic animals, as well as in germ-free B6 mice. Transfer colitis was induced by transplanting RAG−/− mice with B6 or CD69−/−CD45RBhigh CD4 T cells. CD69 expression by CD4 T cells is induced by the intestinal microflora, oral delivery of specific Ag, and type I IFN (IFN-I) signals. CD4 T cells from CD69−/− animals produce higher amounts of the proinflammatory cytokines IFN-γ, TNF-α, and IL-21, whereas the production of TGF-β1 is decreased. CD69-deficient CD4 T cells showed reduced potential to differentiate into Foxp3+ regulatory T cells in vivo and in vitro. The transfer of CD69−/−CD45RBhigh CD4 T cells into RAG−/− hosts induced an accelerated colitis. Oral tolerance was impaired in CD69−/− and IFN-I receptor 1-deficient mice when compared with B6 and OT-II × RAG−/− animals. Polyinosinic-polycytidylic acid treatment of RAG−/− mice transplanted with B6 but not CD69−/− or IFN-I receptor 1-deficient CD45RBhigh CD4 T cells attenuated transfer colitis. CD69 deficiency led to the increased production of proinflammatory cytokines, reduced Foxp3+ regulatory T cell induction, impaired oral tolerance, and more severe colitis. Hence, the activation Ag CD69 plays an important role in regulating mucosal immune responses.

“…Initial reports suggested that the production of IL-10 was enhanced in low-dose oral tolerance (12,13,36), and IL-10-producing clones have been isolated from animals tolerized by feeding myelin basic protein (12,13,36). Moreover, mucosal administration of IL-10 orally enhances tolerance after mucosal autoantigen exposure in an experimental model of autoimmune encephalomyelitis (37).…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies implicated CD8 ϩ T cells as suppressor cells in oral tolerance; however, it appears that CD4 ϩ T cells can fulfill this role as well, and can transfer oral tolerance in vivo (12,13). This response was previously attributed to down-regulation of Th1 CD4…”

mentioning

confidence: 98%

Enhanced Oral Tolerance in Transgenic Mice with Hepatocyte Secretion of IL-10

Safadi

Álvarez

Ohta

et al. 2005

Several cytokines derived from Th3 and Tr1 cells, including IL-10, are believed to regulate oral tolerance, but direct evidence is lacking. We have explored the potential role of IL-10 by generating transgenic (TG) mice with sustained hepatocyte-specific expression of rat IL-10. TG mice expressed rat IL-10 downstream of a transthyretin promoter, which led to serum levels that were increased 10- to 100-fold compared with normal animals. Animals were orally administered 1 mg of whole OVA for 5 consecutive days, with control animals receiving PBS. There were six animal groups: Either OVA or PBS were fed orally to rat IL-10 TG mice, non-TG wild-type mice without IL-10 administration, and non-TG wild-type mice administered rat IL-10 systemically. On day 8, all mice were immunized with two injections of OVA, and then analyzed on day 18. T cell proliferation responses were reduced by 65.8 ± 14.3% after feeding of OVA in rIL-10 TG animals, compared with 39.4 ± 15.6% in the non-TG mice (p = 0.02). Anti-OVA titers were expressed as fold increase over naive non-TG mice. After feeding, titers decreased by ∼33% (from 3- to 2-fold) in TG animals and, to a lesser extent, in non-TG animals. IFN-γ secretion by cultured popliteal lymphocytes decreased in TG animals by 83% after feeding and by 69% in non-TG animals. IL-4 secretion increased 4-fold in TG-fed mice, but did not significantly change in non-TG OVA-fed animals. In contrast to hepatic TG expression of rIL-10, systemic administration of rIL-10 had only a modest effect on tolerance. IL-10, when transgenically expressed in the liver enhances mucosal tolerance to an oral Ag.