Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells.
Cristina SoléMaria RoyoSebastian SandovalTeresa MolinéAlejandra GabaldónJosefina Cortés-HernándezPublished in: International journal of molecular sciences (2024)
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.
Keyphrases
- nucleic acid
- end stage renal disease
- cell therapy
- newly diagnosed
- ejection fraction
- chronic kidney disease
- circulating tumor
- systemic lupus erythematosus
- single cell
- peritoneal dialysis
- prognostic factors
- stem cells
- cell free
- signaling pathway
- endoplasmic reticulum stress
- cell death
- dendritic cells
- drug delivery
- patient reported outcomes
- high resolution
- cell proliferation
- single molecule