title: 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.
authors.affiliation: Department of Surgery, Division of Transplant Surgery and Department of Immunology, Mayo Clinic, Rochester, MN.
authors.forename: N
authors.initials: N
authors.lastname: Moore
authors.affiliation: Division of Transplant Surgery, Mayo Clinic, Rochester, MN.
authors.forename: M
authors.identifier: http://orcid.org/0000-0001-6971-3971
authors.initials: M
authors.lastname: Moreno Gonzales
authors.affiliation: Division of Transplant Surgery, Mayo Clinic, Rochester, MN.
authors.forename: K
authors.initials: K
authors.lastname: Bonner
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN.
authors.forename: B
authors.initials: B
authors.lastname: Smith
authors.affiliation: Department of Surgery, Division of Transplant Surgery and Department of Immunology, Mayo Clinic, Rochester, MN.
authors.forename: W
authors.initials: W
authors.lastname: Park
authors.affiliation: Department of Surgery, Division of Transplant Surgery and Department of Immunology, Mayo Clinic, Rochester, MN.
authors.forename: M
authors.initials: M
authors.lastname: Stegall
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors*; D002633:Chemotaxis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D000069286:Bortezomib
keywords: basic (laboratory) research/science; cellular biology; chemokines/chemokine receptors; immunosuppression/immune modulation; plasma cells