Hepatic stellate cell–conditioned myeloid cells provide a novel therapy for prevention of factor VIII antibody formation in mice

• Administration of myeloid-derived suppressor cells (MDSCs) inhibits factor VIII inhibitor formation
• MDSCs are potent regulators of T- and B-cell responses
• MDSCs could serve as an immunotherapeutic approach

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.