title: Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.
abstract: Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. Here, we show that in the antibody-mediated autoimmune disease pemphigus vulgaris (PV), autoantigen-based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR). We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains. Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo. CAAR-T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody-mediated autoimmune disease.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Ellebrecht
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Bhoj
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Arben
authors.initials: A
authors.lastname: Nace
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xuming
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael Jeffrey
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Laboratory of Molecular and Cellular Biology, Istituto Dermopatico dell'Immacolata (IDI-IRCCS), 00167 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Zenzo
authors.affiliation: Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Seykora
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: George
authors.initials: G
authors.lastname: Cotsarelis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. aimee.payne@uphs.upenn.edu milone@mail.med.upenn.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Milone
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA. aimee.payne@uphs.upenn.edu milone@mail.med.upenn.edu.
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Payne
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D017252:CD3 Complex / Q000737:chemistry / Q000276:immunology; D060846:Cell Engineering; D003602:Cytotoxicity, Immunologic; D051184:Desmoglein 3 / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy / Q000379:methods*; D051379:Mice; D010392:Pemphigus / Q000276:immunology / Q000628:therapy*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000737:chemistry / Q000276:immunology
chemical_list: D001323:Autoantibodies; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D051184:Desmoglein 3; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9