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Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo
Author(s) -
Moore N.,
Moreno Gonzales M.,
Bonner K.,
Smith B.,
Park W.,
Stegall M.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14236
Subject(s) - plerixafor , bortezomib , cxcr4 , medicine , bone marrow , spleen , stromal cell , in vivo , pharmacology , stromal cell derived factor 1 , blockade , cancer research , multiple myeloma , immunology , receptor , biology , chemokine , microbiology and biotechnology
Plasma cells ( PC s) 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 PC s, we hypothesized that interfering with CXCR 4/ CXCL 12 interactions with plerixafor might cause PC depletion and enhance the efficacy of the proteasome inhibitor bortezomib. PC s in mouse spleen, bone marrow, and peripheral blood demonstrated CXCR 4 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. CXCR 4/ CXCL 12 blockade with plerixafor resulted in increased mobilization of PC s into the peripheral blood. Splenectomy completely abrogated this effect, suggesting that all plerixafor‐mobilized cells were from the spleen. The total number of PC s in the spleen and marrow remained constant despite treatment with plerixafor. Bortezomib caused a reduction in PC s, but adding plerixafor did not increase killing. We conclude that CXCR 4/ CXCL 12 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 CXCR 4/ CXCL 12 interactions are responsible for drug resistance.

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