Enhancement of immune tolerance via induction of NK1.1 positive liver-associated-lymphocytes under immunosuppressive conditions.

BACKGROUND/AIMS: The liver was previously shown to play a critical role in oral tolerance induction. A subset of liver-associated-lymphocytes expressing NK1.1 marker (NK1.1+ LAL) have killing activities and it has been suggested that they play a role in immune modulation. FK506 is a powerful immunosuppressive agent affecting T-cell differentiation and function. The exact pathway involved in peripheral tolerance induction using this drug remains unknown. The aim of the present study was to determine the interaction between FK506 and NK1.1+ LAL in induction of peripheral immune tolerance in the experimental colitis model.

METHODS

Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall with and without FK506 treatment. The effect of FK506 treatment on NK1.1+ LAL was tested by cell-sorting and cytotoxicity assay. Colitis was assessed by standard clinical, macroscopic and histologic scores.

RESULTS

Both FK506 treatment and oral tolerance induced a significant increase in NK1.1+ LAL number and cytotoxicity function. FK506 treatment enhanced the effect of oral tolerance on amelioration of disease activity. Orally tolerized mice treated with FK506 had no mortality nor increase in body weight, and manifested significant improvement in disease macroscopic and microscopic scores.

CONCLUSIONS

This study shows for the first time that immune tolerance induced by both oral administration of an antigen and by FK506 treatment may be mediated via enhancement of NK1.1+ LAL. This subset of lymphocytes may play an immunoregulatory role in immune tolerance induction.