BLOCKADE OF INDUCED XENOANTIGEN EXPRESSION PREVENTS REJECTION AFTER RETRANSPLANTATION OF ACCOMMODATED HAMSTER-TO-RAT HEART XENOGRAFTS

Background. We have shown previously that a 2-week course of leflunomi de (LF) together with a maintenance therapy of cyclosporine (CsA) rend ered hamster-to-rat heart xenografts (Xg) resistant against anti-hamst er IgM xenoantibody (XAb)-mediated rejection, a state compatible with the notion of accommodation, Our aim in this study was to investigate the mechanism underlying this Xg accommodation. Methods, ''Accommodate d'' Xgs were retransplanted to CsA-treated naive rats in the presence or absence of additional LF treatment or anti-hamster IgM serum inject ion, Immunohistopathology and fluorescence-activated cell sorting was performed to detect IgM and complement (C) deposition in Xgs, and endo thelial cell (EC) expression of P- and E-selectin, ICAM-1, and VCAM-1 in vivo and in vitro, Results, Retransplanted accommodated Xgs were re jected in CsA-treated naive rats and elicited IgM XAbs, Passive transf er of IgM XAbs provoked hyperacute rejection) of both control and retr ansplanted Xgs, Addition of a 5-day course of LF prevented the rejecti on of only accommodated Xgs, Adoptively transferred IgM XAbs were depo sited in rejected control and accommodated Xgs, but not in accommodate d Xgs accepted by LF-treated rats, LF blocked the EC induction of P-an d E-selectins in both control fresh and accommodated Xgs, Hence, after retransplantation accommodated Xgs express mainly induced xenoantigen s (XAgs), such as P-and E-selectins, that can entirely be suppressed b y LF, In contrast, control hamster Xgs express additional XAgs and rem ain susceptible to XAb-mediated rejection, These findings are in agree ment with in vitro studies showing that LF totally suppressed induced EC antigens (e.g., P-selectin and E-selectin), but not constitutively expressed antigens (e.g., ICAM-1). Conclusion. Accommodated Xgs show a down-regulation of constitutive XAgs, but may be rejected after retra nsplantation by a mechanism involving EC expression of inducible XAgs, LF is able to block this latter XAg induction.