Article
Antigen-specific depletion of autoantibody-secreting plasma cells
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Published: | September 12, 2014 |
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Background: Long-lived memory plasma cells (PCs) are an unmet therapeutic target in autoimmune diseases. Researchers have expanded their effort to develop new therapies to eliminate these cells. However, the current therapeutic options target the whole long-lived memory PC pool, depleting also PCs secreting protective antibodies. The challenge for the future is to develop therapeutic tools for the selective depletion of memory PCs expressing pathogenic antibodies. For this reason, we developed an innovative method for the depletion of PCs secreting a specific antibody/autoantibody.
Methods: We generated an antigen-affinity matrix consisting of an antibody that selectively binds to PCs coupled to the antigen/autoantigen specific to the antibodies/autoantibodies secreted by the PCs. The capacity of the affinity matrix (anti-CD138-ovalbumin-construct) to eliminate selectively the PCs secreting the antibody-of-interest was tested in vitro using 1) anti-ovalbumin secreting hybridoma cells, and 2) spleen cells from ovalbumin-immunized mice. Moreover, by using an affinity matrix consisting of anti-CD138-Acetylcholine-Receptor (AChR), we tested the efficiency of our method for the depletion of PCs secreting pathogenic autoantibodies against the AChR ex-vivo in a model of experimental autoimmune myasthenia gravis (EAMG).
Results: The anti-ovalbumin-specific hybridoma cells and the anti-ovalbumin-PCs from the spleen of immunized mice were specifically lysed when the cells were coated with the affinity matrix and cultured ex-vivo in presence of complement (P=0.0001, P=0.0002, respectively). Conversely, CD138-positive myeloma cells and PCs secreting antibodies against other antigens were not affected confirming the specificity of the method. Notably, PCs secreting pathogenic autoantibodies from the spleen of mice with EAMG can be eliminated using an anti-CD138-AChR-construct (P=0.0102), suggesting that the AM technology is a valid method for the autoantigen-specific depletion of PCs.
Conclusion: The affinity matrix technology achieves the antigen/autoantigen-specific depletion of pathogenic memory plasma cells while leaving protective plasma cell memory intact. Its therapeutic efficacy is currently under investigation in murine models of autoimmune disease.