Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion.
The protective effects of immunosuppressants against ischemia/reperfusion (I/R) injury have been attributed to their non-specific anti-inflammatory effect. However, these effects may also depend on their effect on T lymphocytes, which are increasingly considered to be key players in I/R. Here, we studied the effects of tacrolimus and sirolimus on lymphocyte subpopulations in an I/R rat model. The animals were treated with tacrolimus, sirolimus or vehicle, before undergoing a 60-min ischemia event of the right hepatic lobe, followed by excision of the remaining liver. After 2 h, I/R rats showed increased mortality, plasma lactate dehydrogenase (LDH) levels, hepatocyte apoptosis, liver histological injury and parenchymal infiltration by neutrophils, macrophages, NK cells and T lymphocytes. Most of the changes were antagonized by both immunosuppressants. Tacrolimus augmented the proportion of cycling cells in I/R rats, whereas sirolimus showed the opposite effect. The increased Th1/Th2 ratio found in I/R livers after 2 h was reverted by immunosuppressants, which also amplified the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T lymphocytes at 24 h. The protective effects of both tacrolimus and sirolimus correlated well with a decreased ratio of proinflammatory to anti-inflammatory T lymphocytes, and with an increase in the Treg proportion. This suggests a new mechanism to explain the known beneficial effect shown by immunosuppressants early after I/R.
Arias-Diaz
Javier
J
Department of Surgery, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain. javardi@gmail.com
Ildefonso
José A
JA
Muñoz
Juan J
JJ
Zapata
Agustín
A
Jiménez
Eva
E
D000818:Animals; D017209:Apoptosis; D006498:Hepatectomy; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus