ACCOMMODATION AND T-INDEPENDENT B-CELL TOLERANCE IN RATS WITH LONG-TERM SURVIVING HAMSTER HEART XENOGRAFTS

It was previously reported that treatment with leflunomide (LF; 10 mg/ kg/day) together with cyclosporine (CsA; 10 mg/kg/day) resulted in lon g term survival of hamster heart xenografts (Xg) in rats and that LF c ould be withdrawn 2 to 4 wk after transplantation. To study the mechan isms allowing withdrawal of LF, second hamster heart Xgs were transpla nted 6 wk after the first xenograft. Only the rats that received LF fo r 4 wk accepted second Xgs (>30 days; n = 5). Hence, after 4 wk of LF, the rats developed partial B cell tolerance, as they were unable to p roduce T-independent (CsA-resistant) XAbs. Rejection of second Xgs (2- 4 days; n = 5) in the 2-wk LF group resulted in the formation of IgM x enoantibodies (XAbs) localizing together with complement within reject ed grafts. However, these XAbs did not affect first Xgs, suggesting th at the latter Xgs became resistant to this IgM XAb-mediated rejection, a phenomenon referred to as accommodation. Accommodation was further confirmed as adoptive transfer of IgM XAbs, which resulted in hyperacu te Xg rejection in naive rats (<1 h; n = 5), did not cause rejection i n long term survivors (>30 days; n = 4). This was associated with a do wn-regulation of the expression on the graft endothelial cells of adhe sion molecules (believed to be important expressers of xenogeneic epit opes), such as P- and E-selectins. Interestingly, these adhesion molec ules reappeared after retransplanting the accommodated Xgs to naive re cipients. In conclusion, depending on the duration of the LF treatment , long term survival of hamster hearts in CsA-treated rats is based in part on accommodation and in part on T-independent B cell tolerance.