[Role of calcineurin-dependent drugs on the immunosuppressive effect induced by the anti-LFA-1 antibody in a fetal intestinal transplantation model in mice].
OBJECTIVE
We have previously demonstrated that anti-LFA-1 monoclonal antibody (mAb) can efficiently protect against rejection of small bowel allograft in a mouse model. The aim of the present work was to determine, in the same model, the optimum conditions for utilisation of anti-LFA-1 mAb and the effects of calcineurin-dependent drugs on the immunosuppression induced by anti-LFA-1 mAb treatment.


METHODS
Foetal small intestines of C57Bl/6 (H-2b) mice were transplanted into adult C3H/He (H-2k) mice. Recipients were treated with anti-LFA-1 mAb alone (with or without day-1 injection), or combined to cyclosporin (20 mg.kg-1.j-1 for 14 days), or to tacrolimus (1 mg.kg-1.j-1 from day 0 to day 7). Biopsies were performed after engraftment from day 5 to day 30.


RESULTS
Administration of anti-LFA-1 mAb alone is sufficient to induce significant prolongation of intestinal allograft survival, provided that the treatment starts one day before engraftment. This tolerogenic effect is reversed by the transitory administration of tacrolimus (p = 0.008).


CONCLUSIONS
Treatment with anti-LFA-1 mAb has to be started before the allogeneic response has begun. Calcineurin-dependent drugs can modulate the tolerogenic effect induced by anti-LFA-1. A transgenic mice model should give precise details about underlying mechanisms of these interactions, before a possible utilisation of anti-LFA-1 mAb in intestinal transplantation in humans.
Crétolle-Vastel
C
C
Service de chirurgie pédiatrique, hôpital Necker-Enfants-Malades, Paris, France.
Camby
C
C
Cerf-Bensussan
N
N
Cavazzana-Calvo
M
M
Fischer
A
A
Révillon
Y
Y
Sarnacki
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D001706:Biopsy; D019703:Calcineurin / Q000187:drug effects*; D016572:Cyclosporine / Q000276:immunology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005333:Fetus; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000627:therapeutic use*; D007421:Intestine, Small / Q000637:transplantation*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016559:Tacrolimus / Q000276:immunology* / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; C114320:anti-LFA-1 monoclonal antibody; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus