Trini Ochoa

"Newly-formed plasma cells are more sensitive than long-lived plasma cells to bortezomib treatment"

Trini Ochoa, Brian Gaudette, David Allman

Antibody-mediated diseases represent a problem in autoimmunity and transplantation and current therapeutic interventions fail to completely deplete the plasma cell pool.  Previous studies have been able to demonstrate that early treatment with proteasome inhibitors leads to substantial decreases in donor-specific alloantibodies, but such an impact is not achieved during late antibody-mediated rejection.  Along those lines, it is unknown if proteasome inhibition affects newly-formed or long-lived plasma cells differentially; or whether plasma cell precursors are depleted, or both.  In this study, we have utilized a hapten-protein conjugate immunization model to track antigen-specific numbers in the plasma cell and germinal-center B-cell pools after proteasome inhibition during early and late time points.  We find a strong association between longer-lived plasma cells and survival to bortezomib and observe substantial depletion of plasma cell precursors.  In addition, through in vitro modeling of plasma cell differentiation, we find a strong correlation between high division numbers in activated B-cells and sensitivity to bortezomib.  Mechanistically, it is unknown which transcription factors mediate plasma cell apoptosis after the induction of a terminal unfolded protein response.  Here, we elucidate a potential role for the transcription factor CHOP in promoting plasma cell apoptosis in response to proteasome inhibition. Unexpectedly, CHOP also appears to play a role in suppressing the number of activated B-cells in response to proteasomal inhibition.