Tecnologías e investigación de trasplantes

Dysfunction of Selective Suppression of Auto-Antibody Production in SLE Mouse and Reconstruction of this Mechanism by Induction of Bone-Marrow Chimerism

Abstract

Emiko Takeuchi and Yasuo Takeuchi

Background: Mixed chimerism induced by hematopoietic stem cell transplantation is useful in the treatment of autoimmune diseases, but the details of the mechanism by which mixed chimerism reverses the autoimmune state have not been determined. Here, we propose a potential mechanism in which newly developed T cells positively selected by the recipient’s thymus are able to regulate auto-reactive B cells. To test this hypothesis, we investigated whether major histocompatibility complex (MHC)/T cell receptor (TCR) cognate interaction was important for the regulation of auto-reactive B cells. We induced an auto-cross-reactive Antibody (Ab) by immunization using a foreign antigen with a homolog to an auto-antigen in a BXSB lupus mouse strain and achieved MHC-matched or mismatched mixed chimerism.

Methods: Stable multi-lineage mixed chimeric BXSB mice were established with non-lymphoablative conditioning. In order to induce auto-cross-reactive Ab, a foreign antigen Pigeon Cytochrome C (PCC) was immunized in these chimeric BXSB mice with various MHC combinations. Anti-PCC and anti-Mouse Cytochrome C (MCC: cross-reactive with PCC) Abs were measured by ELISA.

Results: In normal mice and MHC-matched/haplo-identical chimeric mice, the titer of the anti-MCC Ab reached plateau at low levels. In BXSB and fully MHC-mismatched chimeric mice, however, both anti-PCC and MCC Ab levels were higher.

Conclusion: These results suggest that the regulatory mechanism selectively suppresses auto-reactive Ab production through cognate interaction. Dysfunction of this suppression system is one possible cause of lupus; the induction of BM mixed chimerism may allow us to reconstruct the system.