Tolerance Induction in Response to Liver Inflammation

Iobadze

BioMed Research International

et al. 2014

Background. T cell-mediated immune responses contribute to the hepatocellular injury during autoimmune hepatitis, viral infection, and hepatotoxins. Pharmacological compounds regulating immune responses are suitable candidates for prevention/treatment of this pathology. Therefore, the main aim of this study was to define the effects of antioxidant, anti-inflammatory mixture of citrus peel extract (CPE) on the immune-mediated liver injury. Methods. The influence of CPE on liver injury was determined by the activity of transaminases in plasma and the histological changes. Anti-inflammatory and antioxidant effects were studied by measuring frequency of T regulatory cells (Tregs), cytokines (TNF-α, IL-10, and IFN-γ), and nitric oxide levels. Results. The CPE application notably prevents development of liver injury through decreasing levels of both cytokines (TNF-alpha, INF) and regulatory T cells and increasing levels of IL-10. CPE injection also diminished the serum NO, which in turn resulted in evident reduction of the liver damage. Conclusion. Our findings represent the primary preclinical data indicating that the CPE in vivo could ameliorate Con A induced hepatitis. The low dose of CPE most likely can be used for the treatment of the T cell-mediated liver injury as in autoimmune hepatitis, alcoholic hepatitis, and chronic viral hepatitis.

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Effect of Citrus Peel Extracts on Cytokines Levels and T Regulatory Cells in Acute Liver Injury

Iobadze

BioMed Research International

et al. 2014

The Journal of Immunology

“…Moreover, in an in vivo migration experiment, we clearly demonstrated that CXCR3-deficient Tregs were less frequent in the liver of congenic mice upon Con A challenge compared with wt Tregs, verifying an impaired migration capacity of Tregs lacking CXCR3. It has to be remembered that non-lymphoid tissue-homing Tregs also express further chemokine receptors beside CXCR3 (e.g., CCR5 and CCR6), which might also account for Treg recruitment to the inflamed site (27)(28)(29)(30). Hence, we did not expect a complete lack of Tregs in the liver of CXCR3 2/2 mice, and, moreover, a total loss of Treg recruitment to target tissue might have resulted in an even more pronounced phenotype of naive CXCR3 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

Self Cite

The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ–mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10–producing CD4+CD25+Foxp3+ regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11. CXCR3−/− mice developed a more severe liver injury with higher plasma transaminase activities and a more pronounced Th1/Th17 response compared with wild-type (wt) animals upon Con A injection. Moreover, CXCR3−/− mice did not establish tolerance upon Con A restimulation, although Tregs from CXCR3−/− mice were still suppressive in an in vitro suppression assay. Instead, Tregs failed to accumulate in livers of CXCR3−/− mice upon Con A restimulation in contrast to those from wt animals. Con A-tolerant wt mice harbored significantly increased numbers of intrahepatic CXCR3+T-bet+ Tregs that produced IL-10 compared with nontolerant animals. IFN-γ deficiency or anti–IFN-γ Ab treatment demonstrated that conversion to CXCR3+T-bet+ Tregs depended on a Th1 response. Accordingly, in an immunotherapeutic approach, CD4+CD25+Foxp3+ Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis, whereas Tregs from Con A-tolerant wt mice allowed CXCR3-deficient mice to recover from Con A hepatitis. In summary, CXCR3+T-bet+IL-10+ Tregs are generated in the liver in dependence of IFN-γ, then disseminated into the organism and specifically migrate into the liver, where they limit immune-mediated liver damage.

The Journal of Immunology

“…8), probably because these Tregs migrated into the ear. Peripheral-homing Tregs also express further chemokine receptors, including CCR5 and CCR6 beside CXCR3, which might account for Treg recruitment into the inflamed sites (50)(51)(52)(53). Treg migration may be compensated by these chemokine receptors in CXCR3 2/2 mice, which may explain no obvious developmental abnormalities in these mice (26).…”

Section: Cxcr3 Deficiency Attenuates Migration Of Tregs Into the Chalmentioning

confidence: 99%

CXCR3 Deficiency Prolongs Th1-Type Contact Hypersensitivity

Suga

Sugaya

Miyagaki

et al. 2013

Sensitization and challenge using dinitrofluorobenzene (DNFB) induce contact hypersensitivity (CHS) with Th1 cell infiltration, whereas those using FITC generate CHS with Th2 cell infiltration. In this study, we attempted to determine the role of CXCR3, a chemokine receptor, in Th1- and Th2-type CHS induced by DNFB or FITC using CXCR3-deficient (CXCR3−/−) mice. Ear swelling was prolonged after DNFB challenge in CXCR3−/− mice, which was accompanied by increased Th1 cytokines and decreased TGF-β and IL-10 expression at a late time point of CHS, whereas there was no significant difference between wild-type and CXCR3−/− mice in FITC-induced CHS. In Th1-type CHS, the number of regulatory T cells (Tregs) was decreased in the challenged ear of CXCR3−/− mice compared with that of wild-type mice, suggesting that CXCR3 would be important in migration of Tregs into the site of inflammation. Moreover, we examined the characteristics of CXCR3+ Tregs both in vitro and in vivo, revealing that CXCR3+ Tregs expressed high levels of TGF-β and IL-10 as well as IFN-γ compared with CXCR3− Tregs. When CXCR3−/− mice were injected with CXCR3+ Tregs, the prolonged ear swelling induced by DNFB was normalized. Taken together, our results suggest that CXCR3+ Tregs play a key role for quenching Th1-type CHS.