gms | German Medical Science

Background: Since both short-lived and long-lived plasma cells are demonstrated to contribute to the pathogenesis of antibody-mediated diseases, they should be considered as a promising therapeutic target. Short-lived plasma cells respond to immunosuppressive drug treatments and B-cell targeted therapies, but long-lived plasma cells do not. So far, long-lived plasma cells can be only depleted by immunoablative protocols in the setting of autologous stem cell transplantation and by proteasome inhibitors such as bortezomib. However, these treatments result in the unselective depletion of all plasma cells. The fact that they do not distinguish between plasma cells secreting protective antibodies and those secreting pathogenic autoantibodies can lead to the impairment of protective humoral memory. Therefore, there is a need for the selective depletion of pathogenic plasma cells in autoimmune diseases. We have developed a method to target plasma cells in an (auto)antigen-specific manner by using an affinity matrix consisting of an antibody against plasma cell marker Syndecan-1 (CD138) coupled with the (auto)antigen of interest. After successful in vitro experiments, we aimed to show antigen-specific plasma cell depletion in a murine model with anti-ovalbumin-secreting plasma cells as target cells.

Methods: Balb/c mice were treated by secondary immunization with ovalbumin (OVA) and chicken gamma globulin (CGG) so that they could develop long-lived plasma cells secreting antibodies against these antigens. To avoid sequestration of the OVA-anti-CD138 affinity matrix due to circulating anti-OVA antibodies in immunized mice, the anti-OVA antibody levels were substantially reduced by intraperitoneal OVA administration. Afterwards, the OVA-anti-CD138 affinity matrix was administered in a single dose to label all plasma cells in the bone marrow.

Results: The OVA-matrix administration resulted in 47% depletion of anti-OVA secreting plasma cells in the bone marrow, but did not affect anti-CGG secreting plasma cells. The analysis of genuine long-lived anti-OVA-specific plasma cells in the bone marrow, characterized by the absence of BrdU incorporation during a two-week BrdU feeding period, showed 75% reduction of these cells.

Conclusion: This is the first proof-of-principle of an affinity matrix for antigen-specific in vivo depletion of plasma cells. This unique platform opens the door to the development of novel strategies for targeting plasma cells secreting pathogenic antibodies.