Prevention of fetal bowel allograft rejection by combined treatment with anti-ICAM-1 and anti-LFA-1 antibodies

Abstract

Prevention and treatment of allograft rejection remain the major issues in clinical small bowel transplantation. New strategies for manipulating immune responses using more powerful immunosuppressive agents continue to be evaluated. The fetal small bowel from BALB c (H-2 d) or C3H He (H-2 k) mice was transplanted into the space between the peritoneum and rectus abdominis of adult C3H He (H-2 k) recipient mice. Syngeneic (n = 6) and allogeneic transplant groups were made. In the allogeneic group, the recipient mice were subdivided into three groups, depending on the duration of combined treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies (MAbs): untreated (n = 10), 7-day course (n = 10), and 4-week course (n = 14). A dose of 50 μg/mouse/d each of both MAbs was given intraperitoneally, immediately after transplantation and on the consecutive days. All mice were killed 4 weeks after transplantation, and the graft as well as the recipient spleen were taken for histological examination, graft survival ratio, mixed lymphocyte reaction (MLR) assay and cytotoxic T lymphocyte (CTL) assay. All grafts in the syngeneic group survived with normal villi, whereas all grafts in the allogeneic group without treatment disappeared within 4 weeks. All grafts in the allogeneic group with a 7-day course of MAb treatment showed marked disruption of the mucosa with massive cellular infiltration. However, in the allogeneic group treated for 4 weeks, all allografts had adequate growth and demonstrated normal villi with minimal cellular infiltration. Splenocytes from allografted recipient mice without MAb treatment showed markedly increased MLR and CTL activity, compared with the activity seen in the syngeneic MLR and CTL. The spleen cells from allografted recipients treated with the MAbs for 7 days resulted in a moderate inhibition of the CTL and MLR activity. No enhanced CTL and MLR activity was observed in the allografted recipients treated with MAbs for 4 weeks. These findings suggest that in the small bowel transplantation model of fetal mice, allograft rejection could be suppressed by combined treatment with MAbs to ICAM-1 and LFA-1. This mode of immunosuppression might be applicable to humans undergoing small bowel transplantation.