title: Hepatic stellate cell-conditioned myeloid cells provide a novel therapy for prevention of factor VIII antibody formation in mice.
abstract: A major complication of factor VIII (F.VIII) infusion therapies for the treatment of hemophilia A is the formation of antibodies (inhibitors) against F.VIII, a T-cell-dependent, B-cell-mediated process. To date, attempts to inhibit formation of the inhibitors have been limited in success. We have shown that hepatic stellate cells (HSCs) promote the development of myeloid-derived suppressor cells (MDSCs). The HSC-induced MDSCs are potent regulators of T-cell and B-cell responses. Here we show that MDSCs can be propagated from hemophilia A mouse bone marrow cells in coculture with HSCs. These cells exhibit a suppressive phenotype and display a marked ability to inhibit T-cell proliferation induced by dendritic cells in response to F.VIII. MDSCs can also inhibit proliferation and activation of B cells stimulated by immunoglobulin M and interleukin 4. Administration of HSC-induced MDSCs induces CD4(+) T cell and B220(+) B-cell hyporesponsiveness to F.VIII and reduces inhibitor formation in hemophilia A mice. These results suggest that MDSCs could serve as a form of immunotherapy for preventing inhibitor formation via induction of immune tolerance.
authors.affiliation: Department of Molecular Medicine, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Sumantha
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Gong-Qing
authors.initials: GQ
authors.lastname: Shen
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Medicine, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, United States.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Qian
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, United States. Electronic address: ragni@pitt.edu.
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Ragni
authors.affiliation: Department of Molecular Medicine, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States; Department of General Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, United States. Electronic address: lul2@ccf.org.
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001483:Base Sequence; D017931:DNA Primers; D005169:Factor VIII / Q000276:immunology*; D006467:Hemophilia A / Q000276:immunology*; D055166:Hepatic Stellate Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D016133:Polymerase Chain Reaction
chemical_list: D001323:Autoantibodies; D017931:DNA Primers; D005169:Factor VIII