title: Strategies to target long-lived plasma cells for treating hemophilia A inhibitors.
abstract: Long-lived plasma cells (LLPCs) can persistently produce anti-factor VIII (FVIII) antibodies which disrupt therapeutic effect of FVIII in hemophilia A patients with inhibitors. The migration of plasma cells to BM where they become LLPCs is largely controlled by an interaction between the chemokine ligand CXCL12 and its receptor CXCR4. AMD3100 combined with G-CSF inhibit their interactions, thus facilitating the mobilization of CD34(+) cells and blocking the homing of LLPCs. These reagents were combined with anti-CD20 to reduce B-cells and the specific IL-2/IL-2mAb (JES6-1) complexes to induce Treg expansion for targeting anti-FVIII immune responses. Groups of mice primed with FVIII plasmid and protein respectively were treated with the combined regimen for six weeks, and a significant reduction of anti-FVIII inhibitor titers was observed, associated with the dramatic decrease of circulating and bone marrow CXCR4(+) plasma cells. The combination regimens are highly promising in modulating pre-existing anti-FVIII antibodies in FVIII primed subjects.
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA; School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chao Lien
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Lyle
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Shin
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA. Electronic address: miao@u.washington.edu.
authors.forename: Carol H
authors.initials: CH
authors.lastname: Miao
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001596:Benzylamines; D000080027:Cyclams; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006467:Hemophilia A / Q000276:immunology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D010950:Plasma Cells / Q000187:drug effects*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007166:Immunosuppressive Agents; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor
keywords: AMD3100; Factor VIII; G-CSF; Hemophilia A; Immune tolerance; Immunomodulation; Inhibitors; Plasma cells