Massaro, G. | Search bioRxiv

bioRxiv2025

ANTIGEN-SPECIFIC CD8+ T-CELLS ARE INVOLVED IN HUMAN CAROTID ATHEROSCLEROTIC PLAQUES DESTABILIZATION

Immunization of ApoE-/- mice expressing human HLA-A 02:01 with p210, an apoB100-derived peptide, reduces atherosclerotic plaque development by inducing a p210-specific CD8+ T cell population. Studying Class-I MHC/CD8+ T cell signaling offers a promising approach to understanding the mechanism behind the athero-protective effects of p210 immunization. We aimed to identify a p210-specific CD8+ T cell population in human carotid atherosclerotic plaques from blood-positive HLA-A 02:01 patients undergoing surgical carotid endarterectomy (CEA). The study included 22 consecutive patients who were HLA-A 02:01 (+) out of 49 enrolled (reflecting an estimated prevalence of about 30% HLA-A02:01(+) in the Caucasian population). Immunohistochemistry staining used a PE-marked A 02:01-KTTKQSFDL Pentamer on fixed endarterectomy plaques. Both HLA-A 02:01 (+) and (-) patient plaques were used, with the latter serving as an internal negative control. Presence of pentamer (+) CD8 T cells indicated a p210-specific CD8+ T cell population. Patients positive for HLA-A 02:01 showed an average of 3.40 {+/-} 2.17 x 10^3 HPF p210-specific CD8+ T cells (61.80%, 3% of total CD3+) in the shoulders of atherosclerotic plaques post-CEA, significantly higher than in controls (p < 0.0001). The proportion of p210-specific CD8+ T cells was lower in plaques displaying morphological features of instability. This study, for the first time, identifies a p210-specific CD8+ T cell population in human carotid atherosclerotic plaques from HLA-A02:01(+) patients, suggesting a role for autoimmunity in atherosclerosis development and supporting the potential efficacy of p210 immunization in HLA-A02:01 (+) individuals to reduce atherosclerosis. The variation in this specific T cell population within human plaques correlates with plaque vulnerability, highlighting p210-specific CD8+ T cells as a potential target for future therapies.

immunology↗

bioRxiv2019

Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

neuroscience↗