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Regulatory T cells control toxicity in a humanized model of IL-2 therapy.

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Li, Yan Strick-Marchand, Helene Lim, Ai Ing Ren, Jiazi Masse-Ranson, Guillemette Lucas, Sophie [UCL] Di Santo, James P

While patient selection and clinical management have reduced high-dose IL-2 (HDIL2) immunotherapy toxicities, the immune mechanisms that underlie HDIL2-induced morbidity remain unclear. Here we show that dose-dependent morbidity and mortality of IL-2 immunotherapy can be modeled in human immune system (HIS) mice. Depletion of human T cell subsets during the HDIL2 treatment reduces toxicity, pointing to the central function of T cells. Preferential expansion of effector T cells secondary to defective suppressive capacity of regulatory T (Treg) cells after HDIL2 therapy further underscores the importance of Treg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of Treg after LDIL2 therapy, and is ameliorated in HDIL2-treated HIS mice receiving the PIM-1 kinase inhibitor, Kaempferol. Modeling IL-2 pathophysiology in HIS mice offers a means to understand the functions of effector and regulatory T cells in immune-mediated toxicities associated with cancer immunotherapy.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2017
Language Anglais
Journal information "Nature Communications" - Vol. 8, p. 1762 (2017)
Peer reviewed yes
Publisher Nature Publishing Group (London)
issn 2041-1723
e-issn 2041-1723
Publication status Publié
Affiliation UCL - SSS/DDUV/GECE - Génétique cellulaire
Links
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Bibliographic reference Li, Yan ; Strick-Marchand, Helene ; Lim, Ai Ing ; Ren, Jiazi ; Masse-Ranson, Guillemette ; et. al. Regulatory T cells control toxicity in a humanized model of IL-2 therapy.. In: Nature Communications, Vol. 8, p. 1762 (2017)
Permanent URL http://hdl.handle.net/2078.1/193849