Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo
N Moore1, M Moreno Gonzales2, K Bonner2
1Department of Surgery, Division of Transplant Surgery and Department of Immunology, Mayo Clinic, Rochester, MN.
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.
Insights
Plerixafor mobilizes plasma cells (PCs) from the spleen but does not deplete them or enhance bortezomib therapy. CXCR4/CXCL12 interactions retain PCs in the spleen, but other factors drive drug resistance in transplant patients.
Area of Science:
- Immunology
- Hematology
- Pharmacology
Background:
- Plasma cells (PCs) are crucial for alloantibody production in transplant recipients and exhibit resistance to current therapies.
- Stromal microenvironments influence normal PC localization, development, and survival through receptor-ligand interactions.
- CXCR4/CXCL12 signaling is implicated in PC homing and retention within specific niches.
Purpose of the Study:
- To investigate the role of CXCR4/CXCL12 interactions in PC retention and sensitivity to bortezomib.
- To determine if plerixafor, a CXCR4 antagonist, can deplete PCs or sensitize them to proteasome inhibitor therapy.
Main Methods:
- Mice were treated with plerixafor at various doses to assess PC mobilization and distribution.
- CXCR4 expression was analyzed on PCs in spleen, bone marrow, and peripheral blood.
- Bortezomib was administered alone and in combination with plerixafor to evaluate synergistic effects on PC depletion.
Main Results:
- Plerixafor treatment led to significant mobilization of PCs from the spleen into peripheral blood, an effect abrogated by splenectomy.
- The total number of PCs in the spleen and bone marrow remained unchanged after plerixafor administration.
- Bortezomib reduced PC numbers, but the addition of plerixafor did not enhance this cytotoxic effect.
Conclusions:
- CXCR4/CXCL12 interactions are vital for retaining a specific subpopulation of PCs within the spleen.
- Plerixafor-mediated CXCR4/CXCL12 blockade does not deplete PCs nor improve bortezomib efficacy.
- PC resistance to bortezomib is likely mediated by factors independent of CXCR4/CXCL12 interactions.
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