Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance.
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.


CONCLUSIONS
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.
Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Quebec, Canada. Pascal.Lapierre@iaf.inrs.ca
Pascal
P
Lapierre
Kathie
K
Béland
Roland
R
Yang
Fernando
F
Alvarez
D019264:Adoptive Transfer; D000642:Ammonia-Lyases; D000818:Animals; D049109:Cell Proliferation; D061167:Central Tolerance; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051042:Glutamate Formimidoyltransferase; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000628:therapy*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000276:immunology; D064251:Multifunctional Enzymes; D061166:Peripheral Tolerance; D054367:Receptors, CXCR3 / Q000378:metabolism; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation*
C515188:Cxcr3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; D054367:Receptors, CXCR3; C494850:Ftcd protein, mouse; D051042:Glutamate Formimidoyltransferase; D000642:Ammonia-Lyases