Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the generation of pathogenic antibodies directed against a variety of autoantigens. We have previously shown that long-lived plasma cells can contribute to autoimmune pathology by secreting pathogenic autoantibodies. These cells are resistant to conventional immunosuppressive drugs, irradiation and B cell depletion. So far, immunoablation using antithymocyte globulin (ATG) followed by autologous hematopoietic stem cell transplantation and the proteasome inhibitor bortezomib are able to deplete long-lived plasma cells.
Objectives This study is aimed to test strategies for selective depletion of autoreactive long-lived plasma cells and to prevent their new generation in NZB/W mice representing a model of SLE.
Methods We studied immunoablative abilities of mixture of monoclonal antibodies in young (2 month-old) and old (6 month-old) NZB/W mice. We used double i.p coinjection of 200μg anti-LFA-1 and 200μg anti-VLA-4 in a 2-d interval, three times i.v injection of 0,75mg/kg bortezomib in 36-h intervals to achieve ablation of long-lived plasma cells. Furthermore, as B cells will contribute to the repopulation of plasma cells, we also co-treated mice with intravenous injections of 10mg/kg anti-CD20 and 250μg anti-B220 to deplete those plasma cell precursors. All injections were performed within one week. BrdU-feeding was started one week prior to treatment and continued for the whole treatment period (total 2 weeks) to analyze the therapeutic effect on the long-lived plasma cell compartment. The effect of this therapeutic regimen on B cells and plasma cells was analyzed 12 hour, 3 and 7 days after the last injection of Bortezomib by flow cytometry.
Results Flowcytometric analysis at hour 12 shows that the mixture of anti-CD20 and anti-B220 (targeting B cells), anti-VLA-4, anti-LFA-1 and bortezomib (targeting Plasma cells) was able to deplete all subsets of B cells, short-lived and long-lived plasma cells in spleen and bone barrow of young and old NZB/W mice. However FACS analysis on days 3 and 7 indicates a repopulation process by the graduate increase of short-lived and long-lived plasma cells. Long-lived plasma cells reached up to 7% and 41% of controls on day 7 in spleen and bone marrow respectively. These Results demonstrate the fast kinetics of plasma cell recovery after plasma cell depletion in the lupus-prone NZB/W mouse model.
Conclusions The combination treatment with the targeting of adhesion molecules and the use of the proteasome inhibitor (bortezomib) can deplete almost all long-lived plasma cells in bone marrow and spleen but their repopulation is fast. Therefore we will have to to find better ways to target the plasma cell precursors for longlasting depletion.
Neubert, K., et al., The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med, 2008. 14(7): p. 748-55
DiLillo, D.J., et al., Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J Immunol, 2008. 180(1): p. 361-71.
Bekar, K.W., et al., Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum, 2010. 62(8): p. 2443-57.
Disclosure of Interest None Declared
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