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

Abstract

Antibody-secreting cells (ASCs), including short-lived plasmablasts and long-lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine-12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C-X-C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1 mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti-OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long-term (five-month) CXCR4 blockade with AMD3100 after effective short-term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4-CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival.

Computational Analysis of Multiparametric Flow Cytometric Data to Dissect B Cell Subsets in Vaccine Studies

“…). Multidimensional analysis of B cells was based on the expression of B220 (pan‐B cell marker in the mouse) , CD38 (highly expressed on mature and memory B cells, while it is reduced to an intermediate expression in germinal center B cells) , GL7 and CD95 (coexpressed by B cells involved in the GC reaction) , CD73 (memory B cells) , IgG1 and IgM (B cell receptors (BCR) in switched or unswitched B cells, respectively) , TACI and CD138 (coexpressed by terminally differentiated PCs) and CXCR4 (chemokine receptor involved in long‐lived PCs homing into bone marrow niches) . The flow of the process (Fig.…”

Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration

“…This combination holds great promise in the treatment of lupus as indicated by its efficacy in the NZB/W murine preclinical lupus model. 71…”

G‐protein coupled receptors and ligands that organize humoral immune responses

“…A study in the lupus-prone NZB/W mouse strain found that treatment with the CXCR4 antagonist, AMD3100, displaces PCs into blood and causes a reduction in numbers within BM and spleen. Combining the treatment with bortezomib, a proteasome inhibitor used to treat multiple myeloma, caused a more marked reduction in BM and spleen PCs and ameliorated disease in the mice (99). Further work is needed to understand the therapeutic potential of CXCR4 antagonism for the depletion of long-lived plasma cells.…”