DIFFERENTIAL INHIBITION OF B-CELL DEVELOPMENT AND XENOREACTIVE NATURAL ANTIBODY-PRODUCTION BY ADMINISTRATION OF ANTI-MU OR ANTI-DELTA MONOCLONAL-ANTIBODIES IN ADULT RATS

Background. Given the role of xenoreactive natural antibodies (XNA) in the pathogenesis of xenograft rejection, we tested whether the admini stration of anti-mu or anti-delta monoclonal antibodies (mAbs) in adul t rats would suppress the generation of XNA. Methods. Adult LOU/C (Ig kappa-1a) rats were treated with anti-mu or anti-delta mAbs after nonl ethal total body irradiation and bone marrow transplantation from cong enic LOU/C (Ig kappa-1b) rats. The differentiation of donor bone marro w (BM)-driven Ig kappa-1b(+) B cells and XNA production were analyzed. Results. Both anti-mu and anti-delta mAbs arrested B-cell differentia tion in the BM. In anti-mu-treated rats, there was a total depletion o f donor-driven, peripheral IgK1b(+) B cells, secreting cells, and circ ulating XNA of the Ig kappa-1b allotype, In anti-delta-treated rats, a significant number of Ig kappa-1b(+) B cells, which did not express m embrane IgD, ''escaped'' deletion and partially repopulated peripheral lymphoid organs. This B-cell population was active in the production of XNA, as revealed by the high serum levels of XNA in these animals. Conclusions. Anti-mu administration resulted in arrest of B-cell. diff erentiation and in down-regulation of IgM and IgG XNA production in ad ult rats. These data suggest that the use of anti-mu mAbs may be a use ful approach to suppress the production of XNA and prevent xenograft r ejection. Furthermore, we suggest that the B-cell population responsib le for the production of XNA in adult rats belongs to a B-cell lineage expressing low levels of membrane IgD and ''escaping'' deletion in th e BM upon anti-delta treatment.