Cellular and molecular mechanisms of liver tolerance

Crispe, Ian Nicholas; Giannandrea, Matthew; Klein, Ingo; John, Beena; Sampson, B; Wuensch, Sherry A.

doi:10.1111/j.1600-065x.2006.00435.x

Cited by 218 publications

(177 citation statements)

References 163 publications

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“…Although KCs in HBV-carrier mice did not exhibit any obvious tolerance-associated phenotypic changes (Fig. S6), which may be explained by residing in a sustained typical liver-tolerant environment (1,25), these data strongly suggest that KCs contribute to systemic immune tolerance by inducing HBV-specific Tr1-like cell generation in an IL-10-dependent manner. (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…peripheral tolerance | unresponsive T he liver is a unique organ that favors induction of immune tolerance rather than immune activation (1)(2)(3). It was reported 40 y ago that primary liver transplant induced a recipient pig to accept other allograft organs from the same donor (4), which suggested that the liver not only maintained the selftolerance, but also induced systemic tolerance in an antigenspecific manner.…”

mentioning

confidence: 99%

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Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The liver plays a critical role in inducing systemic immune tolerance, for example, during limiting hypersensitivity to food allergy and in rendering acceptance of allotransplant or even hepatotropic pathogens. We investigated the unknown mechanisms of liver tolerance by using an established hepatitis B virus (HBV)-carrier mouse model, and found that these mice exhibited an antigen-specific tolerance toward peripheral HBsAg vaccination, showing unenlarged draining lymph node (DLN), lower number of germinal centers (GC), and inactivation of GC B cells and follicular T helper (Tfh) cells. Both in vivo and in vitro immune responses toward HBsAg were suppressed by mononuclear cells from HBV-carrier mice, which were CD4 + Foxp3 − type 1 regulatory T (Tr1)-like cells producing IL-10. Using recipient Rag1 −/− mice, hepatic Tr1-like cells from day 7 of HBV-persistent mice acquired the ability to inhibit anti-HBV immunity 3 d earlier than splenic Tr1-like cells, implying that hepatic Tr1-like cells were generated before those in spleen. Kupffer cell depletion or IL-10 deficiency led to impairment of Tr1-like cell generation, along with breaking HBV persistence. The purified EGFP + CD4 + T cells (containing Tr1-like cells) from HBV-carrier mice trafficked in higher numbers to DLN in recipient mice after HBsAg vaccination, and subsequently inactivated both Tfh cells and GC B cells via secreting IL-10, resulting in impaired GC formation and anti-HB antibody production. Thus, our results indicate Tr1-like cells migrate from the liver to the DLN and inhibit peripheral anti-HBV immunity by negatively regulating GC B cells and Tfh cells.peripheral tolerance | unresponsive

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Section: Resultsmentioning

confidence: 88%

mentioning

confidence: 99%

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…160,161 Alternatively, as NKT cells play a major role in liver-mediated tolerance, GC may exert it effects in the liver. 102,[162][163][164] Finally, as CD1d molecules are highly expressed in the bowel, and as both DCs and NKT cells play a role in mucosal immunity in the bowel, GC may exert its effect on the gutassociated lymphoid tissue. [165][166][167] GC AS A THERAPEUTIC AGENT IN HUMANS An altered number or function of NKT cells has also been described in several human autoimmune diseases.…”

Section: Sites For Action Of Gcmentioning

confidence: 99%

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

2009

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Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with lowdose ERT and re-evaluating the use of ERT in asymptomatic patients.

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“…In addition, Kupffer cells constitutively express many proinflammatory cytokines including IL-10,TGF-β, IL-1, IL-6, IL-12, IL-18, tumor necrosis factor α, and indoleamine 2,3-dioxygenase, and may modulate differentiation and proliferation of other immune cells in the liver. 18,38,39 This suggests that Kupffer cells maybe important in regulating immunoreactions in the liver and contributing to liver-mediated systemic immune tolerance. 40 The liver hosts several other important cell types including hepatic stellate cells, liver sinusoidal endothelial cells, and radiation-resistant sessile Kupffer cells.…”

Section: Liver Nonparenchymal Cells and Tolerance Inductionmentioning

confidence: 99%

“…17 Furthermore, the liver is the site of persistent viral infections such as hepatitis B and hepatitis C, possibly because of an ongoing immune response that fails to clear the virus. 18,19 Therefore, the liver has the unique immunologic property of inducing tolerance to alloantigens.…”

Section: Establishment Of Liver Tolerancementioning

confidence: 99%