The PI3K p110δ Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function.

Aged Cell Proliferation / drug effects Dose-Response Relationship, Drug Humans Isoenzymes / antagonists & inhibitors Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy Male Middle Aged Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors / pharmacology Purines / pharmacology Quinazolinones / pharmacology Structure-Activity Relationship T-Lymphocytes, Regulatory / drug effects

Journal

Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R

Informations de publication

Date de publication:
01 03 2019
Historique:
received: 07 12 2017
accepted: 19 12 2018
pubmed: 30 1 2019
medline: 13 11 2019
entrez: 30 1 2019
Statut: ppublish

Résumé

In chronic lymphocytic leukemia (CLL), signaling through several prosurvival B cell surface receptors activates the PI3K signaling pathway. Idelalisib is a highly selective PI3K (PI3Kδ) isoform-specific inhibitor effective in relapsed/refractory CLL and follicular lymphoma. However, severe autoimmune adverse effects in association with the use of idelalisib in the treatment of CLL, particularly as a first-line therapy, gave indications that idelalisib may preferentially target the suppressive function of regulatory T cells (Tregs). On this background, we examined the effect of idelalisib on the function of human Tregs ex vivo with respect to proliferation, TCR signaling, phenotype, and suppressive function. Our results show that human Tregs are highly susceptible to PI3Kδ inactivation using idelalisib compared with CD4

Identifiants

DOI: 10.4049/jimmunol.1701703 PMID: 30692213
pubmed: 30692213
pii: jimmunol.1701703
doi: 10.4049/jimmunol.1701703
doi:

Substances chimiques

Isoenzymes 0
Phosphoinositide-3 Kinase Inhibitors 0
Protein Kinase Inhibitors 0
Purines 0
Quinazolinones 0
idelalisib YG57I8T5M0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1397-1405

Subventions

Organisme : Biotechnology and Biological Sciences Research Council
ID : BBS/E/B/000C0407
Pays : United Kingdom

Informations de copyright

Copyright © 2019 by The American Association of Immunologists, Inc.

Auteurs

Stalin Chellappa (S)

Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, N-0424 Oslo, Norway.
K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0318 Oslo, Norway.

Kushi Kushekhar (K)

Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, N-0424 Oslo, Norway.
K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0318 Oslo, Norway.
ORCID: 0000-0003-2380-6309

Ludvig A Munthe (LA)

K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
Department of Immunology and Transfusion Medicine, Oslo University Hospital, N-0424 Oslo, Norway.

Geir E Tjønnfjord (GE)

K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
Department of Haematology, Oslo University Hospital, N-0424 Oslo, Norway.

Einar M Aandahl (EM)

Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, N-0424 Oslo, Norway.
K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0318 Oslo, Norway.
Section for Transplantation Surgery, Oslo University Hospital, N-0424 Oslo, Norway; and.
ORCID: 0000-0002-0115-8382

Klaus Okkenhaug (K)

Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
ORCID: 0000-0002-9432-4051

Kjetil Taskén (K)

Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, N-0424 Oslo, Norway; kjetil.tasken@medisin.uio.no.
K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway.
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0318 Oslo, Norway.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › Isoenzymes › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Leucémie chronique lymphocytaire à cellules B › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Purines › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinazolines › Quinazolinones › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › The PI3K p110δ Isoform Inhibitor Idelalisib...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Sous-populations de lymphocytes T › Lymphocytes T régulateurs › The PI3K p110δ Isoform Inhibitor Idelalisib...