Betriu Mendez, SergiRovira Juárez, JordiArana Aliaga, CaroltGarcia Busquets, AinhoaMartinez Florensa, MarioRamirez Bajo, Maria JoseBañon Maneus, ElisendaLazo Rodriguez, MartaBartoló-Ibars AClaas FHJMulder AHeidt SJuan Otero, ManelBayés Genís, Beatriz EnriquetaCampistol Plana, Josep M.Palou Ribera, EduardDiekmann, Fritz2025-11-142025-11-142023-10-01Betriu, Sergi; Rovira, Jordi; Arana, Carolt; Garcia-Busquets, Ainhoa; Matilla-Martinez, Marina; Ramirez-Bajo, Maria J; Banon-Maneus, Elisenda; Lazo-Ro (2023). Chimeric HLA antibody receptor T cells for targeted therapy of antibody-mediated rejection in transplantation. Hla, 102(4), 449-463. DOI: 10.1111/tan.15156https://hdl.handle.net/2445/224369The presence of donor-specific antibodies (DSA), mainly against HLA, increases the risk of allograft rejection. Moreover, antibody-mediated rejection (ABMR) remains an important barrier to optimal long-term outcomes after solid organ transplantation. The development of chimeric autoantibody receptor T lymphocytes has been postulated for targeted therapy of autoimmune diseases. We aimed to develop a targeted therapy for DSA desensitization and ABMR, generating T cells with a chimeric HLA antibody receptor (CHAR) that specifically eliminates DSA-producing B cells. We have genetically engineered an HLA-A2-specific CHAR (A2-CHAR) and transduced it into human T cells. Then, we have performed in vitro experiments such as cytokine measurement, effector cell activation, and cytotoxicity against anti-HLA-A2 antibody-expressing target cells. In addition, we have performed A2-CHAR-Tc cytotoxic assays in an immunodeficient mouse model. A2-CHAR expressing T cells could selectively eliminate HLA-A2 antibody-producing B cells in vitro. The cytotoxic capacity of A2-CHAR expressing T cells mainly depended on Granzyme B release. In the NSG mouse model, A2-CHAR-T cells could identify and eradicate HLA-A2 antibody-producing B cells even when those cells are localized in the bone marrow. This ability is effector:target ratio dependent. CHAR technology generates potent and functional human cytotoxic T cells to target alloreactive HLA class I antibody-producing B cells. Thus, we consider that CHAR technology may be used as a selective desensitization protocol or an ABMR therapy in transplantation.© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.15application/pdfEnglishCell biologyCiências biológicas iCiências biológicas iiCiências biológicas iiiGeneticsImmunologyImmunology and allergyMedicina iMedicina iiMedicina iiiPathologyAbmr therapyAbmr therapy,antibody-producing b cells,chimeric hla antibody receptor t cells (char-tc),desensitization protocol,donor-specific antibodies,hla-sensitized patientAdultAlleleAllelesAlloantibodyAlloreactive t cellAnimalAnimal experimentAnimalsAntibodiesAntibodyAntibody mediated rejectionAntibody-producing b cellsArticleB lymphocyteCell activationChimeric hla antibody receptor t cellChimeric hla antibody receptor t cells (char-tc)Controlled studyCytotoxic t lymphocyteDesensitizationDesensitization protocolDonor specific antibodyDonor-specific antibodiesEffector cellEnzyme releaseGenetic engineeringGenetic transductionGeneticsGraft rejectionGranzyme bHla a2 antigenHla antibodyHla antigenHla antigensHla-a2 antigenHla-sensitized patientsHumanHuman cellHumansImmunosuppressive agentImmunosuppressive drugs,antigen receptor,class-i,survival benefit,kidney,failure,impact,risk,hemodialysis,activatioIn vitro studyIsoantibodiesLymphocyte antigen receptorMaleMiceMolecularly targeted therapyMouseNonhumanOrgan transplantationProtein expressionReceptors, antigen, t-cellT lymphocyte activationTarget cellUnclassified druginfo:eu-repo/semantics/article2025-10-309377394