La cytokine BAFF et les cellules T CD4+ sont des facteurs de survie majeurs pour les plasmocytes spléniques dans le contexte de déplétion B chez la souris : implications thérapeutiques pour les maladies auto-immunes

Abstract : Previous data suggested that the monoclonal anti-CD20 antibody induced paradoxically the settlement of autoreactive splenic long-lived plasma cells (LLPC) in the spleen of patients with auto-immune cytopenia, explaining the treatment failure. To investigate whether this process had a general relevance and decipher its mechanism, we used the AID-CreERT2-EYFP mouse model, which allows the irreversible expression of EYFP in B cells engaged in an immune response after tamoxifen regimen to follow plasma cells at different times after immunization. When analyzed by multiplex PCR at the single-cell level, while the splenic EYFP+B220-PC of untreated mice displayed an intermediate profile between short-lived and long-lived PC, the PC from anti-CD20 treated mice composed a more mature homogeneous population, similar to the long-lived bone marrow PC. The absolute number of splenic EYFP+B220-PC did not change significantly upon anti-CD20 treatment indicating that B-cell depletion promoted PC differentiation rather than a long-lived PC selection. BAFF (B-cell activating factor) and CD4+ T-cells played a major role in plasma cell survival since combination of anti-CD20 with anti-BAFF or anti-CD4 antibodies dramatically reduced the number of splenic EYFP+B220- LLPC. Anti-CD20 treatment also promoted the differentiation of LLPC in the spleen in the lupus prone NZB/W model, while a treatment combining anti-CD20 with anti-BAFF induced a marked reduction in total splenic PC numbers. These results suggest that the process of PC maturation upon anti-CD20 treatment is a general mechanism and that interfering with anti-BAFF antibody at the time of B-cell depletion might greatly improve the response rate in auto-immune disease.
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Lan-Huong Thai. La cytokine BAFF et les cellules T CD4+ sont des facteurs de survie majeurs pour les plasmocytes spléniques dans le contexte de déplétion B chez la souris : implications thérapeutiques pour les maladies auto-immunes. Immunologie. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB069⟩. ⟨tel-02143023⟩

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