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Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance
Author(s) -
Lapierre Pascal,
Béland Kathie,
Yang Roland,
Alvarez Fernando
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26023
Subject(s) - autoimmune hepatitis , peripheral tolerance , immunology , adoptive cell transfer , central tolerance , medicine , t cell , immune tolerance , regulatory t cell , cxcr3 , ex vivo , hepatitis , biology , il 2 receptor , in vivo , antigen , immune system , chemokine receptor , chemokine , microbiology and biotechnology
Autoimmune hepatitis (AIH) is characterized by a loss of immunological tolerance to hepatocytes. Patients respond well to immunosuppression but progression to endstage liver disease occurs in 10%‐20% of cases, leading to liver transplantation. Using a murine model of type 2 AIH, we identified susceptibility factors for autoimmune hepatitis and attempted to restore immunological tolerance to liver autoantigens. An increased ectopic expression of a liver autoantigen (FTCD) in the thymus leading to reduced numbers of circulating autoreactive T cells was sufficient to prevent development of AIH in mice. However, in the presence of a reduced central tolerance to FTCD, a strong regulatory T‐cell response was able to inhibit proliferation of liver‐specific autoreactive T cells and prevent AIH. Development of a severe AIH stemmed from reduced numbers of functional regulatory T cell (Tregs) leading to an increased proliferation of FTCD‐specific autoreactive T and B cells. Adoptive transfer of ex vivo expanded CXCR3 + Tregs in mice with AIH efficiently targeted the inflamed liver, restored peripheral tolerance to FTCD, and induced remission of AIH. Conclusion : Peripheral tolerance to liver autoantigens in AIH is paramount. Autologous infusion of ex vivo expanded CXCR3 + Tregs in AIH patients could be an effective therapeutic approach to restore peripheral tolerance and induce remission of AIH. (H EPATOLOGY 2013)