Both tacrolimus and sirolimus decrease Th1Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemiareperfusion

Abstract

The protective effects of immunosuppressants against ischemiareperfusion (IR) 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 IR. Here, we studied the effects of tacrolimus and sirolimus on lymphocyte subpopulations in an IR 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 2h, IR 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 IR rats, whereas sirolimus showed the opposite effect. The increased Th1Th2 ratio found in IR livers after 2h was reverted by immunosuppressants, which also amplified the proportion of CD4CD25Foxp3 regulatory T lymphocytes at 24h. 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 IR.