Elimination of autoreactive B cells in humanized SCID mouse model of SLE.

Although the exact etiology of systemic lupus erythematosus (SLE) remains elusive, B-cell hyperactivity and production of autoantibodies directed to components of the cell nucleus are a well-established pathogenetic mechanism of the disease. Therefore, the targeted inhibition of DNA-specific B cells is a logical therapeutic approach. The complement receptor type 1 (CR1, CD35) has been shown to suppress human B-cell activation and proliferation after co-cross-linking with the BCR, and may serve as a mediator for negative signal delivery. In order to evaluate this therapeutic approach in a human-like system, we used immune-restricted SCID mice transferred with PBMCs from SLE patients. The tolerance of these humanized SCID mice to native DNA was re-established after administration of a chimeric molecule consisting of a CR1-specific mAb coupled to the decapeptide DWEYSVWLSN that mimics dsDNA. The generated protein-engineered chimera was able to co-cross-link selectively native DNA-specific BCR with the B-cell inhibitory receptor CR1, thus delivering a strong inhibitory signal.