Induction of oral tolerance and the effect of interleukin-4 on murine skin allograft rejection.

We studied the effect of oral and portal vein administration of alloantigens on mouse skin allograft survival. Graft receptor BALB/c mice received spleen cells (30, 90, 150 or 375 x 10(6)) from donor C57BL/6 mice intragastrically on three successive days, starting seven days before the skin graft. Allograft survival was significantly increased with the feeding of 150 x 10(6) allogeneic spleen cells by one gavage (median survival of 12 vs 14 days, P< or =0.005) or when 300 x 10(6) cells were given in six gavage (12 vs 14 days, P<0.04). A similar effect was observed when 150 x 10(6) spleen cells were injected into the portal vein (12 vs 14 days, P< or =0.03). Furthermore, prolonged allograft survival was observed with subcutaneous (12 vs 16 days, P< or =0.002) or systemic (12 vs 15 days, P< or =0.016) application of murine interleukin-4 (IL-4), alone or in combination with spleen cell injection into the portal vein (12 vs 18 days, P< or =0.0018). Taken together, these results showed that tolerance induction with spleen cells expressing fully incompatible antigens by oral administration or intraportal injection partially down-modulates skin allograft rejection. Furthermore, these findings demonstrated for the first time the effect of subcutaneous or systemic IL-4 application on allograft skin survival suggesting its use as a beneficial support therapy in combination with a tolerance induction protocol.