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A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [RNA-Seq]

ABSTRACT: The majority of common chronic human diseases remain incurable, impacting a significant portion of the population and necessitating lifelong treatments that impose a substantial burden on health, the economy, and society. Asthma, the most prevalent respiratory disease, exemplifies this challenge, affecting over 300 million people and causing more than 250,000 deaths annually. Here, we demonstrate the achievement of long-term remission of type 2-high asthma through a single infusion of engineered CAR T cells. By utilizing IL-5 as the targeting domain and depleting BCOR and ZC3H12A, we engineer long-lived CAR T cells designed to eradicate IL-5R+ eosinophils, termed Immortal-like and Functional IL-5 CAR T (5TIF) cells. Furthermore, we enhance 5TIF cells by engineering them to secrete an IL-4 mutein that blocks the signaling of both IL-4 and IL-13, two inflammatory cytokines driving asthma pathology, resulting in the creation of 5TIF4 cells. In multiple asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, leads to long-term depletion of pathological eosinophils and blockade of IL-4/IL-13 actions. This results in sustained repression of type 2 inflammation and alleviation of asthmatic symptoms. Additionally, 5TIF4 cells can be induced in human T cells in NSG mice. These findings demonstrate that asthma, a prevalent and incurable disease, can undergo durable remission through a single infusion of engineered CAR T cells. This breakthrough paves the way for the potential functional cure of chronic noncancerous diseases using long-lived CAR T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE262359 | GEO | 2024/04/04

REPOSITORIES: GEO

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Project description:Memory helper T cells provide long-lasting host defeMemory helper T cells provide long-lasting host defense against microbial pathogens, while distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes in allergic inflammation remain unknown. We found that Interleukin-33 (IL-33) enhanced Amphiregulin production by the IL-33 receptor, ST2hi memory T helper-2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of Osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and Amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of Amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and Osteopontin-producing eosinophils. Thus, the IL-33-Amphiregulin-Osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders. against microbial pathogens, while distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes in allergic inflammation remain unknown. We found that Interleukin-33 (IL-33) enhanced Amphiregulin production by the IL-33 receptor, ST2 hi memory T helper-2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of Osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and Amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of Amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and Osteopontin-producing eosinophils. Thus, the IL-33-Amphiregulin-Osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.

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A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [RNA-Seq]

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