Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.
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 short-term 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-beta. 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 Phix 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.
Peng
Baowei
B
Department of Pediatrics, Seattle Children's Hospital Research Institute and University of Washington, Seattle, WA 98101, USA.
Ye
Peiqing
P
Blazar
Bruce R
BR
Freeman
Gordon J
GJ
Rawlings
David J
DJ
Ochs
Hans D
HD
Miao
Carol H
CH
D019264:Adoptive Transfer; D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D010584:Bacteriophage phi X 174 / Q000276:immunology; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006467:Hemophilia A / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors
D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins; D011994:Recombinant Proteins; D005169:Factor VIII