IP-10 Can Be Measured in Dried Plasma Spots in Patients with Chronic Hepatitis C Infection

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Abstract

The chemokine IP-10 (CXCL10) is a candidate marker for hepatitis C virus (HCV) fibrosis monitoring. The aim of this proof-of-concept study is to assess if IP-10 measurements from dried plasma spots (DPS) are accurate in HCV-infected patients with either minimal or significant fibrosis. We measured IP-10 levels in plasma and DPS of 21 HCV-infected patients with cirrhosis and 19 patients with no/little fibrosis (determined with FibroScan). Cirrhotic patients had significantly higher levels of IP-10 compared to patients with minimal fibrosis. DPS and plasma measurements of IP-10 are comparable and the correlation was excellent (r ² = 0.97, p<0.0001). The DPS based method for IP-10 detection performs well in HCV-infected patients with either minimal or significant fibrosis.

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Most cited references 6

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Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.

Lawrence Pfeffer, Meiyun Fan, Susan R. Pfeffer … (2012)

Chemokines and inflammatory cytokines are key regulators of immunity and inflammation during viral infections. Hepatitis C virus (HCV) is a hepatotropic RNA virus frequently associated with chronic liver inflammation and hepatocellular carcinoma. Intrahepatic levels of chemokines and cytokines are elevated in chronic HCV infections, but the underlying mechanisms remain unclear. We found that Toll-like receptor-3 (TLR3) senses HCV infection in cultured hepatoma cells, leading to nuclear factor kappa B (NF-κB) activation and the production of numerous chemokines and inflammatory cytokines, such as regulated on activation normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α, MIP-1β, IP-10, and interleukin-6. The chemokine/cytokine induction occurred late in HCV infection and was abrogated when HCV was ultraviolet-inactivated before infection, indicating a dependence on the cellular recognition of HCV replication products. Gel-shift and chromatin immunoprecipitation assays revealed that NF-κB plays a pivotal role in HCV-induced chemokine/cytokine transcription. Mutations specifically disrupting the double-stranded RNA (dsRNA)-binding activity of TLR3 ablated the chemokine/cytokine response to HCV infection, indicating that HCV dsRNA was the pathogen-associated molecular pattern triggering TLR3 signaling. In vitro synthesized HCV dsRNAs, with a minimal length of ∼80-100 base pairs, activated TLR3-dependent chemokine expression, regardless of the genome position from which they derived. In contrast, HCV single-stranded RNAs, including those derived from the structured 3'nontranslated region highly potent for RIG-I activation, failed to do so. Moreover, robust production of chemokines and inflammatory cytokines was also observed in primary human hepatocytes after stimulation with extracellular poly-I:C, a TLR3 ligand. Our data suggest that TLR3-mediated chemokine and inflammatory cytokine responses may play an important role in host immune responses to HCV and the pathogenesis of HCV-associated liver diseases. Copyright © 2011 American Association for the Study of Liver Diseases.

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Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology.

Poul Thorsen, Kristin Skogstrand, David Hougaard … (2005)

Inflammatory reactions and other events in early life may be part of the etiology of late-onset diseases, including cerebral palsy, autism, and type 1 diabetes. Most neonatal screening programs for congenital disorders are based on analysis of dried blood spot samples (DBSS), and stored residual DBSS constitute a valuable resource for research into the etiology of these diseases. The small amount of blood available, however, limits the number of analytes that can be determined by traditional immunoassay methodologies. We used new multiplexed sandwich immunoassays based on flowmetric Luminex xMAP technology to measure inflammatory markers and neutrophins in DBSS. The high-capacity 25-plex multianalyte method measured 23 inflammatory and trophic cytokines, triggering receptor expressed on myeloid cells-1 (TREM-1), and C-reactive protein in two 3.2-mm punches from DBSS. It also measured 26 cytokines and TREM-1 in serum. Standards Recovery in the 25-plex method were 90%-161% (mean, 105%). The low end of the working range for all 25 analytes covered concentrations found in DBSS from healthy newborns. Mean recovery of exogenous analytes added at physiologic concentrations in DBSS models was 174%, mean intra- and interassay CVs were 6.2% and 16%, respectively, and the mean correlation between added and measured analytes was r2 = 0.91. In DBSS routinely collected on days 5-7 from 8 newborns with documented inflammatory reactions at birth, the method detected significantly changed concentrations of inflammatory cytokines. Measurements on DBSS stored at -24 degrees C for >20 years showed that most cytokines are detectable in equal concentrations over time. The method can reliably measure 25 inflammatory markers and growth factors in DBSS. It has a large potential for high-capacity analysis of DBSS in epidemiologic case-control studies and, with further refinements, in neonatal screening.

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Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response.

Jama Darling, Jeroen Aerssens, Gregory Fanning … (2011)

Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P 600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. Copyright © 2010 American Association for the Study of Liver Diseases.

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: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 14 September 2012

Volume: 7

Issue: 9

Electronic Location Identifier: e45181

Affiliations

[1 ]Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark

[2 ]Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark

[3 ]Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

[4 ]Department of Infectious Diseases, Odense University Hospital, Odense, Denmark

[5 ]Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark

Institut Pasteur, France

Author notes

* E-mail: mruhwald@ 123456gmail.com

Competing Interests: Nina Weis and Morten Ruhwald are employed at Copenhagen University Hospitals, Hvidovre, which is the proprietor of a pending patent disclosing the use of IP-10 and filter paper for the monitoring of liver fibrosis (PCT/DK/11162289.0). Morten Ruhwald is registered as inventor. This potential competing interest does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. Ellen Sloth Andersen, Peer Brehm Christensen, and Belinda Klemmensen Moessner have no conflicts of interest to disclose.

Conceived and designed the experiments: MR ESA NW BKM PBC. Performed the experiments: MR ESA BKM. Analyzed the data: MR. Contributed reagents/materials/analysis tools: MR. Wrote the paper: MR.

Article

Publisher ID: PONE-D-12-11517

DOI: 10.1371/journal.pone.0045181

PMC ID: 3443225

PubMed ID: 23024806

SO-VID: c2f3a16d-9f16-4dda-87dd-a9bbd84f55ac

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 12 April 2012

Date accepted : 15 August 2012

Page count

Pages: 4

Funding

The work was supported by the Danish National Advanced Technology Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

IP-10 Can Be Measured in Dried Plasma Spots in Patients with Chronic Hepatitis C Infection

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Abstract

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Most cited references 6

Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.

Simultaneous measurement of 25 inflammatory markers and neurotrophins in neonatal dried blood spots by immunoassay with xMAP technology.

Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response.

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