Liver-associated lymphocytes expressing NK1.1 are essential for oral immune tolerance induction in a murine model

Trop, Shivti; Samsonov, Dimitri; Gotsman, Israel; Alper, Ruslana; Diment, Judith; Ilan, Yaron

doi:10.1002/hep.510290334

Cited by 97 publications

(89 citation statements)

References 40 publications

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“…The liver predominates as the organ with the highest number of NKT cells that are found in the sinusoids (13,23). Our data is consistent with NKT cells being involved in the induction of oral tolerance (36). Natural killer T cells, which would be present in our liver NPC proliferative assay, would produce high levels of IL-4 consistent with our results (30).…”

Section: Discussionsupporting

confidence: 89%

“…Likewise, NKT cells can be induced by IL-4 to express Fas ligand (38). Whether or not this can cause apoptosis to activated CD8 + cells circulating in the liver to explain the mechanism of the liver's role in high-dose oral tolerance induction remains to be determined (33,35,36,39). Studies indicated that NKT cells are dispensable in oral tolerance but required in portal vein tolerance (9,40).…”

Section: Discussionmentioning

confidence: 99%

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Role of the Liver in Peripheral Tolerance: Induction Through Oral Antigen Feeding

Chou

Wang

et al. 2004

American Journal of Transplantation

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Using a murine liver transplant model, we studied the liver's role in peripheral tolerance. Livers from BALB/c mice fed with ovalbumin (OVA) at either a low or high dose were transplanted into syngeneic recipients. Non-fed recipients were controls. Orthotopic liver transplantation (OLTx) was followed by OVA immunization and delayed-type hypersensitivity (DTH) challenge. The ex vivo adoptive transfer effect of liver nonparenchymal cells (NPCs) or spleen cells (SCs) from OVA-fed mice was examined. In vitro proliferative assays and cytokine profiles were conducted on NPCs and SCs from transplant recipients.Livers from all OVA-fed mice after 10 days transferred tolerance to OVA-naïve mice. The time course of adoptive transfer of liver NPCs from high-dose OVA-fed mice transferred OVA tolerance within 24 h; low-dose OVA-fed mice required ≥ 4 days to transfer tolerance. The in vitro proliferative response of the NPCs to OVA revealed a decreased response in both dosage groups over the control group.Our results suggest that the liver plays an important role in inducing peripheral tolerance in a mucosal tolerance model, especially feeding high-dose OVA.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Role of the Liver in Peripheral Tolerance: Induction Through Oral Antigen Feeding

Chou

Wang

et al. 2004

American Journal of Transplantation

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“…Prolonged allograft survival in mice by an impaired Th1 cytokine response, with a shift towards Th2 cytokine production has been described in mice injected with ovalbumin into the portal vein before transplantation (18). Antigen administration through the portal vein in an experimental colitis model stimulated liver-associated T NK1.1 lymphocytes with high serum IL-4 and TGF-ß 1 and low IFN-γ levels (19). Furthermore, IL-12 in combination with anti-IL-10 reverses graft prolongation after portal venous immunization (3).…”

Section: Discussionmentioning

confidence: 99%

Induction of oral tolerance and the effect of interleukin-4 on murine skin allograft rejection

Dettino

Duarte

Sato

2004

Braz J Med Biol Res

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“…In fact, Ilan et al (44) reported that hepatic NKT cells play a substantial role in the induction of oral tolerance in experimental colitis model using C57BL/6 mice. NKT cells are characterized by the invariant Ag receptor coded by V␣14J␣281 gene segments (45).…”

Section: Discussionmentioning

confidence: 99%

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

Watanabe

Yoshida

Shirai

et al. 2002

The Journal of Immunology

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Ags administered orally at a high dose are absorbed in immunogenic forms and perfuse the liver, which raises a question regarding the relevance of hepatic lymphocyte activation to the systemic hyporesponsiveness against the ingested Ag. Oral administration of 100 mg of OVA to the mice led to massive cell death of OVA-specific (KJ1-26+) CD4+ T cells by Fas-Fas ligand (FasL)-mediated apoptosis in the liver, which was associated with the emergence of hepatic KJ1-26+CD4+ T cells expressing FasL. Hepatic CD4+ T cells in OVA-fed mice secreted large amounts of IL-4, IL-10, and TGF-β1 upon restimulation in vitro and inhibited T cell proliferation. Adoptive transfer of these hepatic CD4+ T cells to naive mice and subsequent antigenic challenge led to suppression of T cell proliferation as well as IgG Ab responses to OVA; this effect was mostly abrogated by a blocking Ab to FasL. i.p. administration of an Ag at a high dose also generated hepatic CD4+FasL+ T cells with similar cytokine profile as T cells activated by oral administration of Ags at a high dose. Finally, we did not see an increase in FasL+ cells in the hepatic CD4+Vβ8+ T cell subset of MRL/lpr/lpr mice given staphylococcal enterotoxin B, indicating the requirement for Fas-mediated signals. These hepatic CD4+FasL+ regulatory cells may explain the tolerogenic property of the liver and play roles in systemic hyporesponsiveness induced by an Ag administered at a high dose.

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Liver-associated lymphocytes expressing NK1.1 are essential for oral immune tolerance induction in a murine model

Cited by 97 publications

References 40 publications

Role of the Liver in Peripheral Tolerance: Induction Through Oral Antigen Feeding

Role of the Liver in Peripheral Tolerance: Induction Through Oral Antigen Feeding

Induction of oral tolerance and the effect of interleukin-4 on murine skin allograft rejection

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

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