Monocyte NOTCH2 expression predicts IFN-beta immunogenicity in multiple sclerosis patients

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F18%3A10376736" target="_blank" >RIV/00216208:11110/18:10376736 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064165:_____/18:10376736

Výsledek na webu

<a href="https://doi.org/10.1172/jci.insight.99274" target="_blank" >https://doi.org/10.1172/jci.insight.99274</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1172/jci.insight.99274" target="_blank" >10.1172/jci.insight.99274</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Monocyte NOTCH2 expression predicts IFN-beta immunogenicity in multiple sclerosis patients

Popis výsledku v původním jazyce

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-beta is an established treatment for MS; however, up to 30% of IFN-beta-treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14(+) monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-beta. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-beta administration. Reduced monocyte NOTCH2 expression in nADA(+) MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA(+) patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-beta administration.

Název v anglickém jazyce

Monocyte NOTCH2 expression predicts IFN-beta immunogenicity in multiple sclerosis patients

Popis výsledku anglicky

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-beta is an established treatment for MS; however, up to 30% of IFN-beta-treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14(+) monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-beta. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-beta administration. Reduced monocyte NOTCH2 expression in nADA(+) MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA(+) patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-beta administration.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/7H12016" target="_blank" >7H12016: Anti-Biopharmaceutical Immunization: Prediction and analysis of clinical relevance to minimize the risk</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JCI Insight [online]

ISSN

2379-3708

e-ISSN

—

Svazek periodika

3

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

—

Kód UT WoS článku

000434866600010

EID výsledku v databázi Scopus

2-s2.0-85062250225