Descripción del proyecto
Detener a los traidores antes de que actúen podría proporcionar nuevos tratamientos para la aterosclerosis
La aterosclerosis es una enfermedad arterial crónica que se caracteriza por la acumulación de materiales lipídicos (placas) que pueden obstruir las arterias. Durante las últimas décadas, se ha observado que la inflamación crónica asociada a la inmunidad puede desencadenar acontecimientos que den lugar a una enfermedad cardiovascular aterosclerótica grave. Algunas células del sistema inmunitario reconocen una proteína en el colesterol de las lipoproteínas de baja densidad (LDL). Parece que normalmente tienen una función protectora contra la aterosclerosis, pero pueden volverse patógenas durante el curso de la enfermedad. ANIMATE está buscando pruebas de este proceso a través de diversas técnicas y sistemas. La caracterización de las funciones de cambio de las células inmunitarias en el tiempo y el espacio podría señalar nuevos mecanismos para impedir que los grupos de células protectoras varíen su enfoque.
Objetivo
Atherosclerosis is a chronic immune disease of arteries that causes vessel-narrowing atherosclerotic plaques. Its acute complications, myocardial infarction and stroke, are the leading causes of death worldwide. Atherosclerosis is accompanied by an inflammatory and autoimmune response with CD4+ T-helper cells that recognize self-antigens, including ApoB-100 (ApoB), the main protein in low-density lipoprotein (LDL) cholesterol. Although their existence has been inferred from indirect evidence, the existence and function of atherosclerosis-specific, self-reactive CD4+ T cells on a single-cell level remains elusive. In particular, it is unclear whether these are pro- or anti-inflammatory.
Preliminary data suggest the existence of a natural pool of ApoB-reactive T-helper cells that share properties with atheroprotective T-regulatory cells but transform into pathogenic T-effector cells in the natural course of disease. This proposal aims to explore this loss of protective immunity on a cellular and function level. It employs novel tools to detect antigen-specific T cells in vivo by MHC-II multimers, mass cytometry (CyTOF), single cell RNA-sequencing (scRNA-seq), lineage-tracing mouse models, and live cell imaging. Based on the anticipated findings, this study will define a map of auto-reactive T-helper cell phenotypes in a temporal, spatial, and functional dimension. These insights will be used to identify novel immunomodulatory strategies to therapeutically stabilize the population of protective ApoB-specific T-helper cells, or to prevent their transformation into pathogenic T cell phenotypes by adoptive cells transfers, vaccination, or cytokine-blockade. In clinical association studies, a direct correlation of auto-immunity and clinical atherosclerosis will be tested.
This proposal will decipher traits of protective immunity in atherosclerosis and help to build the conceptual framework to define novel therapeutic strategies for patients.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
79106 Freiburg
Alemania