Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells
Solé Marcé, Cristina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Royo, Maria (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sandoval, Sebastian (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Moliné, Teresa (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Gabaldón, Alejandra (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Cortés Hernández, Josefina (Hospital Universitari Vall d'Hebron. Institut de Recerca)

Date:	2024
Abstract:	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.
Grants:	Instituto de Salud Carlos III PI19/01817
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Lupus nephritis ; CAART ; Anti-dsdna ; B cell
Published in:	International journal of molecular sciences, Vol. 25 (april 2024) , ISSN 1422-0067

DOI: 10.3390/ijms25084226
PMID: 38673811

19 p, 5.0 MB

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