Adoptive transfer of<i>ex vivo</i>expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance

Lapierre, Pascal; Béland, Kathie; Yang, Roland; Alvarez, Fernando

doi:10.1002/hep.26023

Cited by 98 publications

(86 citation statements)

References 33 publications

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“…Differences in Treg numbers have recently been described to account for the sex bias observed in a murine model of AIH (22,32). In our model, Treg numbers were similar between female and male livers.…”

Section: Discussionsupporting

confidence: 56%

Testosterone Suppresses Hepatic Inflammation by the Downregulation of IL-17, CXCL-9, and CXCL-10 in a Mouse Model of Experimental Acute Cholangitis

Schwinge

Carambia

Quaas

et al. 2015

The Journal of Immunology

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Autoimmune liver diseases predominantly affect women. In this study, we aimed to elucidate how sex affects autoimmune hepatic inflammation. Acute experimental cholangitis was induced by adoptive transfer of OVA-specific CD8+ T cells into mice, which express the cognate Ag on cholangiocytes. In contrast to previous mouse models of cholangitis, this model displayed a strong sexual dimorphism: female mice developed marked cholangitis, whereas male mice were resistant to cholangitis induction. The recruitment of endogenous CD4+ T cells, but not transferred CD8+ T cells into female livers was strongly increased. These cells expressed higher amounts of the proinflammatory cytokine IL-17, which was at least in part responsible for the liver inflammation observed. The recruitment of endogenous CD4+ T cells was associated with increased expression of the chemokines CXCL-9 and CXCL-10 in female livers. The sex-specific factor responsible for the observed differences was found to be testosterone: male mice could be rendered susceptible to liver inflammation by castration, and testosterone treatment was sufficient to completely suppress liver inflammation in female mice. Accordingly, testosterone treatment of female mice significantly reduced the expression of IL-17A, CXCL-9, and CXCL-10 within the liver. Serum testosterone levels of untreated mice negatively correlated with the IL-17, CXCL-9, and CXCL-10 expression in the liver, further supporting a role for testosterone in hepatic immune homeostasis. In conclusion, testosterone was found to be the major determinant of the observed sexual dimorphism. Further study into the role of testosterone for liver inflammation could lead to novel treatment targets in human autoimmune liver diseases.

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Section: Discussionsupporting

confidence: 56%

Testosterone Suppresses Hepatic Inflammation by the Downregulation of IL-17, CXCL-9, and CXCL-10 in a Mouse Model of Experimental Acute Cholangitis

Schwinge

Carambia

Quaas

et al. 2015

The Journal of Immunology

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“…In a mouse model of type 2 AIH, transferred antigen-specific Treg were able to restore peripheral tolerance [41]. This was confirmed in humans by Longhi et al [42] who generated CYP2D6-specific Treg that efficiently suppressed in vitro autoreactive CD4+ T cells derived from type 2 AIH patients.…”

Section: Immunomodulatory Therapy For Aihsupporting

confidence: 54%

Future Perspective: Immunomodulatory Therapy for Autoimmune Hepatitis

Sebode

Lohse²

2014

Dig Dis

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In the last two decades, more and more light has been shed on the immunologic pathogenesis of autoimmune liver diseases, notably autoimmune hepatitis (AIH). An immunologic dysbalance with proinflammatory immune responses dominating over hepatic tolerance seems to be part of AIH pathogenesis. In detail, an impairment of regulatory T cells (Treg) is suspected. If this holds true and reduced Treg numbers or their function are pathogenic for AIH, this offers the option of cellular or immunomodulatory therapy. However, the exact immunological role of Treg in AIH still needs to be clarified before cellular therapy is promising for patients.

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“…In pre-clinical studies, transfer of ex vivo-expanded CD4 + Tregs was shown to both preserve and restore immune tolerance in several mouse models of autoimmunity, such as type 1 diabetes [36], lupus [37], and autoimmune hepatitis [38]. Motivated by these promising results, Treg immunotherapy has been further investigated in the clinic in the context of type 1 diabetes.…”

Section: Treg Immunotherapymentioning

confidence: 97%