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Impact of cellular therapies on autoreactive, long-lived plasma cells in autoimmune diseases (AID)

According to the current view, chronic AID are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs, these patients exhibit continued autoantibody production, which often contributes to progression of the AID. To elucidate this problem, we analyzed the lifespan of cells secreting (auto)antibodies (Ab) in NZB/W mice. The number of Ab-secreting cells in splenic tissue increased from ages 1 to 5 months and became stable thereafter. Later, some 60% of the total Ab-secreting cell compartment consisted of dividing, short-lived plasmablasts (SLPB), whereas 40% consisted of nondividing, long-lived plasma cells (LLPC) with a half-life of more than 6 months. Although high-dose cyclophosphamide eliminated SLPB, LLPC survived and continued to produce (auto)Ab. This explains why treatment with cyclophosphamide (CY) does not result in the complete disappearance of antinuclear Ab. Pathogenic anti-dsDNA Ab usually vanish after this treatment, indicating that they are generated by proliferating SLPB. However, anti-dsDNA Ab can be resistant to CY in refractory SLE.

We treated six refractory SLE patients by autologous stem cell transplantation (ASCT) using CY and ATG as the mobilization regimen. ASCT was performed using purified CD34+ stem cells. The patients have now been followed for 5–70 months. Initially, persistent anti-dsDNA disappeared within 3 months. Likewise, the ANA became negative except in one case. That patient continued to exhibit anti-Ro/SSA and anti-La/SSB, the titers of which decreased continuously and were undetectable after 17 months. This emphasizes the enormous lifespan of residual plasma cells after interrupting the supply of new cells from the dividing SLPB compartment.

In conclusion, the aforementioned ASCT protocol can lead to depletion of autoreactive LLPC. Since ASCT may not always be able to eliminate autoreactive LLPC, these cells are potential targets for autoimmune disease therapy.

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Hiepe, F., Manz, R., Hoyer, B. et al. Impact of cellular therapies on autoreactive, long-lived plasma cells in autoimmune diseases (AID). Arthritis Res Ther 6 (Suppl 1), 88 (2004).

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