Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

Baowei Peng, Peiqing Ye, Bruce R. Blazar, Gordon J. Freeman, David J. Rawlings, Hans D. Ochs, Carol H. Miao

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII(hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that shortterm therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS+CD4+ T cells and activation of CD25 +Foxp3+ Tregs in the peripheral blood, spleen, and lymph nodes. CD4+ T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-β. Moreover, CD4+CD25+ Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Φx 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.

Original languageEnglish (US)
Pages (from-to)1662-1672
Number of pages11
JournalBlood
Volume112
Issue number5
DOIs
StatePublished - Sep 1 2008

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