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

N. Moore, M. Moreno Gonzales, K. Bonner, B. Smith, W. Park, Mark D Stegall

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Transplantation
DOIs
StateAccepted/In press - 2017

Fingerprint

Plasma Cells
Spleen
Bone Marrow
Isoantibodies
Proteasome Inhibitors
Splenectomy
Drug Resistance
JM 3100
Ligands
Transplants
Therapeutics

Keywords

  • Basic (laboratory) research/science
  • Cellular biology
  • Chemokines/chemokine receptors
  • Immunosuppression/immune modulation
  • Plasma cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo. / Moore, N.; Moreno Gonzales, M.; Bonner, K.; Smith, B.; Park, W.; Stegall, Mark D.

In: American Journal of Transplantation, 2017.

Research output: Contribution to journalArticle

Moore, N. ; Moreno Gonzales, M. ; Bonner, K. ; Smith, B. ; Park, W. ; Stegall, Mark D. / Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo. In: American Journal of Transplantation. 2017.
@article{41da102d89144c6ca698f74acca0020d,
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.",
keywords = "Basic (laboratory) research/science, Cellular biology, Chemokines/chemokine receptors, Immunosuppression/immune modulation, Plasma cells",
author = "N. Moore and {Moreno Gonzales}, M. and K. Bonner and B. Smith and W. Park and Stegall, {Mark D}",
year = "2017",
doi = "10.1111/ajt.14236",
language = "English (US)",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo

AU - Moore, N.

AU - Moreno Gonzales, M.

AU - Bonner, K.

AU - Smith, B.

AU - Park, W.

AU - Stegall, Mark D

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Basic (laboratory) research/science

KW - Cellular biology

KW - Chemokines/chemokine receptors

KW - Immunosuppression/immune modulation

KW - Plasma cells

UR - http://www.scopus.com/inward/record.url?scp=85016083233&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016083233&partnerID=8YFLogxK

U2 - 10.1111/ajt.14236

DO - 10.1111/ajt.14236

M3 - Article

C2 - 28235241

AN - SCOPUS:85016083233

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

ER -