Blunting specific T-dependent antibody responses with engineered "decoy" B cells.

Autor:	Pitner RA; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA., Chao JL; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA., Dahl NP; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA., Fan MN; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA., Cai X; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA., Avery NG; Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA., Roe K; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA., Spiegel PC Jr; Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA., Miao CH; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA., Gerner MY; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA., James RG; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA., Rawlings DJ; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: drawling@uw.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Oct 02; Vol. 32 (10), pp. 3453-3469. Date of Electronic Publication: 2024 Aug 26.
DOI:	10.1016/j.ymthe.2024.08.023
Abstrakt:	Antibody inhibitors pose an ongoing challenge to the treatment of subjects with inherited protein deficiency disorders, limiting the efficacy of both protein replacement therapy and corrective gene therapy. Beyond their central role as producers of serum antibody, B cells also exhibit many unique properties that could be exploited in cell therapy applications, notably including antigen-specific recognition and the linked capacity for antigen presentation. Here we employed CRISPR-Cas9 to demonstrate that ex vivo antigen-primed Blimp1-knockout "decoy" B cells, incapable of differentiation into plasma cells, participated in and downregulated host antigen-specific humoral responses after adoptive transfer. Following ex vivo antigen pulse, adoptively transferred high-affinity antigen-specific decoy B cells were diverted into germinal centers en masse, thereby reducing participation by endogenous antigen-specific B cells in T-dependent humoral responses and suppressing both cognate and linked antigen-specific immunoglobulin (Ig)G following immunization with conjugated antigen. This effect was dose-dependent and, importantly, did not impact concurrent unrelated antibody responses. We demonstrated the therapeutic potential of this approach by treating factor VIII (FVIII)-knockout mice with antigen-pulsed decoy B cells prior to immunization with an FVIII conjugate protein, thereby blunting the production of serum FVIII-specific IgG by an order of magnitude as well as reducing the proportion of animals exhibiting functional FVIII inhibition by 6-fold. Competing Interests: Declaration of interests R.A.P., R.G.J., and D.J.R. are credited as inventors on a provisional patent application (Application No. 63/584,432) filed by Seattle Children’s Research Institute with the United States Patent and Trademark Office regarding the materials described in this article. This patent application covers aspects of the synthesis, characterization, and applications of the materials discussed herein. C.H.M. is a member of the Editorial Board for Molecular Therapy. (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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