Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ai-Hong ZhangDavid W Scott

Abstract

Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell-targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3ζ transmembrane and signaling domains. We termed these "BAR" for B cell-targeting Ab receptors. CD4+CD25hiCD127low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 or A2 domains (C2- and A2-BAR). Such BAR-Tregs specifically suppressed the recall Ab response of spleen cultures from FVIII-immunized mice in vitro and completely prevented anti-FVIII Ab development in response to FVIII immunization. Mechanistic studies with purified B cells and T cells from tolerized or control recipients demonstrated that the FVIII-specific B cells were directly suppressed or anergized, whereas the T cell response remained intact. Taken together, we report in this study a successful proof-of-principle strategy using Ag-expressing Tregs t...Continue Reading

References

Aug 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·D ScandellaC A Fulcher
Sep 30, 1998·British Journal of Haematology·D C ReesD M Keeling
Nov 10, 2001·Nature Immunology·R S BystryA G Betz
Jul 15, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ludger KleinHarald von Boehmer
Jun 29, 2004·Journal of Thrombosis and Haemostasis : JTH·P Lollar
Feb 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·David C GondekRandolph J Noelle
Feb 25, 2005·Blood·Karin C StraathofCliona M Rooney
Mar 19, 2005·Nature Reviews. Immunology·Jeffrey A Bluestone
Jan 19, 2006·Blood·Dong-Mei ZhaoEthan M Shevach
Jun 21, 2008·Nature Reviews. Immunology·Dario A A VignaliCreg J Workman
Feb 24, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dat Q TranEthan M Shevach
Oct 6, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Charles W Ashley, Clare Baecher-Allan
May 19, 2011·Journal of Thrombosis and Haemostasis : JTH·B MoghimiR W Herzog
Dec 16, 2011·Journal of Molecular Cell Biology·Qizhi TangSang-Mo Kang
Jun 13, 2012·Proceedings of the National Academy of Sciences of the United States of America·Janine GototIsis Ludwig-Portugall
Jun 29, 2013·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Claudio G BrunsteinJohn E Wagner
Nov 5, 2014·Molecular Therapy. Methods & Clinical Development·Debalina SarkarRoland W Herzog
Dec 31, 2014·Proceedings of the National Academy of Sciences of the United States of America·Roberto A MaldonadoTakashi Kei Kishimoto
Nov 27, 2015·Science Translational Medicine·Jeffrey A BluestoneQizhi Tang
Mar 22, 2016·The Journal of Clinical Investigation·Katherine G MacDonaldMegan K Levings
May 22, 2016·Blood·Jennifer N Brudno, James N Kochenderfer
Jul 13, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Aaron E FosterDavid M Spencer

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Citations

Mar 19, 2019·Annual Review of Cell and Developmental Biology·Andrew Getahun, John C Cambier
Sep 22, 2019·Nature Reviews. Drug Discovery·Leonardo M R FerreiraQizhi Tang
May 7, 2020·Frontiers in Immunology·Alessandra De Paula PohlDavid W Scott
Jan 31, 2020·Frontiers in Immunology·Sebastien Lacroix-DesmazesKathleen P Pratt
Aug 15, 2020·Frontiers in Immunology·Yasmin R MohseniGiovanna Lombardi
Apr 7, 2019·Nature Biomedical Engineering·Dominic A Boardman, Megan K Levings
Jan 21, 2021·Biomedicines·Zachary C StenslandMia J Smith
Jul 22, 2019·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Maha AbdeladhimDavid W Scott
Jun 1, 2021·Frontiers in Immunology·Claudia Selck, Margarita Dominguez-Villar
Feb 20, 2020·Molecular Therapy. Methods & Clinical Development·Jenni FirrmanWeidong Xiao

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