Biology subjects

Mazuz, K.

Publications and source records attributed to Mazuz, K..

2 recordsLinked to original sources

bioRxiv2026

Synovium-Restricted Armored PD-1-Targeted CAR-T Cells Reprogram Immunity and Resolve Experimental Arthritis

Despite major therapeutic advances, a substantial fraction of patients with autoimmune disease remains refractory to treatment. While B cell-targeted CAR-T therapies have shown considerable efficacy, the central contribution of pathogenic T cells to rheumatoid arthritis (RA) suggests that complementary T cell-directed strategies may enable deeper disease control. Using single-cell multi-omics of human RA and experimental models, PDCD1 was identified as a selective marker of synovial disease-associated T cells. We developed PD-1-directed CAR-T cells that potently eliminate these cells in vitro and in vivo, leading to marked attenuation of synovitis in RA models. To limit off-target activity, we engineered NR4A2-driven CAR-responsive biosensors to restrict CAR activity to inflamed synovium. To couple anti-PD-1 CAR-mediated cytotoxicity with microenvironmental modulation, we further engineered these CAR-T cells to secrete soluble TNF receptor II (sTNFRii), counteracting baseline inflammation and CAR-induced IFN response and promoting a tissue-reparative myeloid state. PD-1-targeted CAR-T therapy thus represents a promising, specific, and safe strategy for autoimmune diseases involving disease-associated T cells.

immunology↗

bioRxiv2026

A framework for reparative CAR T engineering in the CNS

Chimeric antigen receptor (CAR) T cells have shown remarkable therapeutic promise in hematological malignancies and, more recently, in autoimmunity. They also hold considerable potential for neurodegenerative diseases and CNS injury, where the therapeutic objective shifts from cell depletion to immune modulation and tissue repair. Using ischemic stroke as proof-of-concept, we engineered MOG-targeting CAR T cells to dissect how distinct CAR designs shape the CNS microenvironment. CD4/CD8 CAR T cells (a mixture of CD4 and CD8 subsets) proliferated robustly and efficiently infiltrated the ischemic hemisphere, but induced broad immune recruitment and exacerbated neuroinflammation. In contrast, CD4 restricted CAR T cells markedly reduced immune infiltration, reprogrammed microglia, and minimized inflammatory activation. We engineered CD4 CAR T cells to secrete brain-derived neurotrophic factor (BDNF) to determine whether they could be redirected toward a reparative, non-cytotoxic phenotype. CD4 BDNF-CAR T cells further attenuated inflammation, reduced immune infiltration, and promoted the expansion of regulatory T cells. CD4 BDNF-CAR T treated mice showed significantly improved gait performance following stroke. Together, these findings establish a cellular framework and outline principles for engineering reparative CAR T platforms for neurological diseases.

immunology↗