Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo

Abstract

Plasma cells (PCs) are a major source of alloantibody in transplant patients and are resistant to current therapy. Because receptor-ligand interactions in stromal microenvironments play important roles in the localization, development, and survival of normal PCs, we hypothesized that interfering with CXCR4/CXCL12 interactions with plerixafor might cause PC depletion and enhance the efficacy of the proteasome inhibitor bortezomib. PCs in mouse spleen, bone marrow, and peripheral blood demonstrated CXCR4 expression. We then treated with plerixafor in doses ranging from 240 μg/kg in a single dose to a 1-mg/kg daily dose for 10 days. CXCR4/CXCL12 blockade with plerixafor resulted in increased mobilization of PCs into the peripheral blood. Splenectomy completely abrogated this effect, suggesting that all plerixafor-mobilized cells were from the spleen. The total number of PCs in the spleen and marrow remained constant despite treatment with plerixafor. Bortezomib caused a reduction in PCs, but adding plerixafor did not increase killing. We conclude that CXCR4/CXCL12 interactions are important for the retention of a subpopulation of PCs in the spleen, but this interaction has minimal effect on PCs in the marrow. The lack of enhancement of bortezomib-mediated depletion suggests that factors other than CXCR4/CXCL12 interactions are responsible for drug resistance.

CXCR4–CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice

“…The fact that we detected significantly higher numbers of Ki‐67 negative ASCs in the peripheral blood of treated NZB/W mice than in the controls suggests a mobilization effect on plasma cells (Supporting Information Fig. S1), which was described previously . This could be one mechanism of depletion observed by AMD3100 treatment, since ASCs mobilized from their survival niches die due to apoptosis within few days .…”

“…In contrast to our data, Moore et al. could not show any effect of AMD3100 on plasma cell depletion in spleen and bone marrow, which can be explained by the substantially lower dose of AMD3100 that was administered. Previously, we demonstrated in SLE patients and NZB/W mice that ASCs regenerated quickly after their efficient depletion with bortezomib , which can be interrupted by targeting the precursor B cells .…”

Plasma cell biology: Foundations for targeted therapeutic development in transplantation

“…Our data stand somewhat in contrast to a 2017 mouse study by Moore et al which failed to show a robust effect of plerixafor on plasma cell mobilization or sensitization to proteasome inhibitors 136 . The authors found maximal mobilization of plasma cells into the peripheral blood 1 hour after treatment with return to baseline by 24 hours.…”

Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle

“…They have high expression of CXCL12, the ligand for CXCR4 expressed on PC, which is responsible for their trafficking into the BM (18, 103). However, even though initial studies demonstrated these stromal cells supported PC survival in vitro , this survival was not sustained—and in vivo , they did not appear to have an essential role in supporting LLPC survival (48, 104). Furthermore, the PC-survival factors like APRIL, BAFF, and IL-6 are not secreted by these cells.…”