Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells

• Published in: International journal of molecular sciences Vol. 25; no. 8; p. 4226
• Main Authors: Solé, Cristina, Royo, Maria, Sandoval, Sebastian, Moliné, Teresa, Gabaldón, Alejandra, Cortés-Hernández, Josefina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2024
• Subjects: Adult; anti-dsDNA; Antibodies; Antibodies, Antinuclear - immunology; Antigens; Autoantibodies; Autoantibodies - immunology; Autoantigens - immunology; Autoimmune diseases; Autoimmunity; B cell; B cells; B-Lymphocytes - immunology; Belimumab; CAART; Cells; Chronic kidney failure; Cytokines; Cytokines - metabolism; Cytotoxicity; Disease; Female; Health aspects; Humans; Inflammation; Lupus; lupus nephritis; Lupus Nephritis - immunology; Lupus Nephritis - pathology; Lupus Nephritis - therapy; Lymphocytes; Male; Nephritis; Pathogenesis; Proteins; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Remission (Medicine); Resveratrol; T cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Canada; Massachusetts; Spain; B cell; lupus nephritis; CAART; anti-dsDNA
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25084226

Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the challenges of chronic immunosuppression associated with current therapies, we have engineered T cells to express chimeric autoantibody receptors (DNA-CAART) for the precise targeting of B cells expressing anti-dsDNA autoantibodies. T cells from LN patients were transduced using six different CAAR vectors based on their antigen specificity, including alpha-actinin, histone-1, heparan sulphate, or C1q. The cytotoxicity, cytokine production, and cell-cell contact of DNA-CAART were thoroughly investigated in co-culture experiments with B cells isolated from patients, both with and without anti-dsDNA positivity. The therapeutic effects were further evaluated using an in vitro immune kidney LN organoid. Among the six proposed DNA-CAART, DNA4 and DNA6 demonstrated superior selectively cytotoxic activity against anti-dsDNA B cells. Notably, DNA4-CAART exhibited improvements in organoid morphology, apoptosis, and the inflammatory process in the presence of IFNα-stimulated anti-dsDNA B cells. Based on these findings, DNA4-CAART emerge as promising candidates for modulating autoimmunity and represent a novel approach for the treatment of LN.