Formation of inhibitory antibodies is the most crucial and difficult problem for therapeutic treatment in hemophilia A patients, which requires great efforts for an effective solution. Molecular studies have shown that long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies due to the insufficient immunosuppessants and B cell depletion therapies. It is also believed that long-lived plasma cells play the essential roles in anti-FVIII antibody (Ab) production in hemophilia A (HemA) inhibitor patient. Recent studies showed that the migration of plasmablasts to the bone marrow is a crucial differentiation step for the generation of long-lived plasma cells through the chemokine CXCL12 and it’s receptor CXCR4 interaction. By the CXCL12/CXCR4 pathway, the BM CXCL12-expressing stromal cells are essential for CXCR4-expressing plasmablast cells homing back to BM to become the long-lived plasma cells. Therefore, we propose that the depletion of pathogenic long-lived plasma cells in BM by limiting CXCL12/CXCR4 activities is the key to the development of curative therapies in patients with pre-existing antibody-mediated diseases. We will first investigate if inhibitory antibody response is regulated in a conditional HemA/Cxcl12 KO mouse lacking Cxcl12 expressing stromal cells in BM. In addition, we will verify how the CXCL12/CXCR4 pathway is involved in the long-lived plasma cells trafficking. Next, we will block Cxcl12 expression in stromal cells by siRNA silencing or antagonist (e.g., G-CSF) treatment or eliminate the receptor Cxcr4 expressing plasmablast cells by treatment of Cxcr4 antagonist (e.g., AMD3100) in PB in order to prevent the plasmablast cells homing back to BM to become the long-lived plasma cells as promising new strategies for treating hemophilia A inhibitors.
|Effective start/end date||9/1/14 → 7/31/15|