Blockade of the integrin alpha L beta 2 but not of integrins alpha 4 and/or beta 7 significantly prolongs intestinal allograft survival in mice

Background-Small bowel transplantation remains a difficult therapeutic opti on endangered by a high rate of rejection and infectious complications. To improve these clinical results, it is mandatory to set up animal models to test alternative immunosuppressive regimens which may lead to immunotoleran ce. Aims-To determine the value of blockade of alpha L beta 2 (LFA-1) and alpha 3 and beta 7 integrins (alpha 4 beta 1, alpha 4 beta 7, and alpha E beta 7 ) in the prevention of rejection of fetal small bowel grafts in mice and th e effect of the association of calcineurin dependent drugs in anti-LFA-1 tr eated mice. Methods-Adult recipient mice engrafted with allogeneic fetal small bowel re ceived a short course of anti-alpha 4 and/or anti-LFA-1 monoclonal antibodi es (mAb) with or without FK506 or cyclosporin A. In addition, in a set of e xperiment, beta 7(-/-) mice were used as recipients. Graft biopsies were pe rformed and processed for standard histology. Results-Blockade of the pathways of the integrins alpha 4 and beta 7 had a modest or no effect on intestinal graft survival. In contrast, transitory, short administration of anti-LFA-1 monoclonal antibody alone, when started before engraftment (day-1), allowed long term survival of intestinal grafts , even when associated with calcineurin dependent drugs. However, early wit hdrawal of FK506 reversed the immunosuppressive effect of anti-LFA-1 treatm ent. Conclusions-These results suggest that firstly, anti-LFA-1, but not anti-al pha 4 mAb treatment, may be useful in improving the results of intestinal t ransplantation, and secondly, that this treatment is not incompatible with long term administration of tacrolimus currently used in the prevention of small bowel graft rejection in humans.