Platelet Gene Therapy Promotes Targeted Peripheral Tolerance by Clonal Deletion and Induction of Antigen-Specific Regulatory T Cells

Frontiers in Immunology
Xiaofeng LuoQizhen Shi

Abstract

Delivery of gene therapy as well as of biologic therapeutics is often hampered by the immune response of the subject receiving the therapy. We have reported that effective gene therapy for hemophilia utilizing platelets as a delivery vehicle engenders profound tolerance to the therapeutic product. In this study, we investigated whether this strategy can be applied to induce immune tolerance to a non-coagulant protein and explored the fundamental mechanism of immune tolerance induced by platelet-targeted gene delivery. We used ovalbumin (OVA) as a surrogate non-coagulant protein and constructed a lentiviral vector in which OVA is driven by the platelet-specific αIIb promoter. Platelet-specific OVA expression was introduced by bone marrow transduction and transplantation. Greater than 95% of OVA was stored in platelet α-granules. Control mice immunized with OVA generated OVA-specific IgG antibodies; however, mice expressing OVA in platelets did not. Furthermore, OVA expression in platelets was sufficient to prevent the rejection of skin grafts from CAG-OVA mice, demonstrating that immune tolerance developed in platelet-specific OVA-transduced recipients. To assess the mechanism(s) involved in this tolerance we used OTII mice that...Continue Reading

References

May 20, 1998·Proceedings of the National Academy of Sciences of the United States of America·G L Evans, R A Morgan
Mar 3, 2001·The New England Journal of Medicine·T Kamradt, N A Mitchison
May 23, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Thomas A FergusonDouglas R Green
Jun 18, 2002·Arteriosclerosis, Thrombosis, and Vascular Biology·Sandra L HaberichterRobert R Montgomery
Oct 23, 2002·ILAR Journal·Michael F W Festing, Douglas G Altman
Mar 11, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dipica HaribhaiCalvin B Williams
Apr 30, 2003·Molecular Therapy : the Journal of the American Society of Gene Therapy·Neeltje A KootstraInder M Verma
Oct 4, 2003·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Benjamin D EhstMarc K Jenkins
Jul 6, 2004·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lingfei XuKatherine Parker Ponder
Jul 6, 2004·Molecular Therapy : the Journal of the American Society of Gene Therapy·Peiqing YeCarol H Miao
Jul 11, 2006·The Journal of Clinical Investigation·Qizhen ShiRobert R Montgomery
Feb 3, 2007·Journal of Thrombosis and Haemostasis : JTH·Q ShiR R Montgomery
Mar 28, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Christopher B DoeringH Trent Spencer
Jun 16, 2007·Cell Death and Differentiation·L-P Erwig, P M Henson
Jul 14, 2010·Advanced Drug Delivery Reviews·Qizhen Shi, Robert R Montgomery
Feb 3, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Hideto MatsuiDavid Lillicrap
May 19, 2011·Journal of Thrombosis and Haemostasis : JTH·B MoghimiR W Herzog
May 29, 2012·Journal of Thrombosis and Haemostasis : JTH·E L KuetherQ Shi
Jun 5, 2012·Cold Spring Harbor Perspectives in Biology·Yan Xing, Kristin A Hogquist
Sep 18, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yingyu ChenQizhen Shi
Nov 20, 2013·Journal of Pharmacology & Pharmacotherapeutics·Jaykaran Charan, N D Kantharia
Apr 20, 2017·Journal of Clinical Medicine·Angiola RocinoAntonio Coppola

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Methods Mentioned

BETA
transgenic
flow cytometry
electron microscopy
PCR
ELISA
protein replacement therapy
transfection

Software Mentioned

FlowJo

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