Interferon-lambda: Novel Biologics for Controlling Neutrophil-mediated Pathology in Rheumatic Diseases?
NCT ID: NCT02498808
Last Updated: 2017-08-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
85 participants
OBSERVATIONAL
2015-09-30
2018-12-31
Brief Summary
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These neutrophils are characterised by an extended life span, increased capacity to produce reactive oxygen species, active gene expression and release of extracellular traps. Consequently, there is a need for better understanding of neutrophil phenotype and functions in these conditions, as well as for identifying molecules capable of specifically manipulating neutrophil function. The investigators have recently discovered that interferon lambdas (IFN-λs), also known as interleukin 28 (IL28) and interleukin 29 (IL29), class II cytokines with previously studied anti-viral biological functions, specifically suppress neutrophil infiltration and interleukin-1β production and thereby, halt and reverse the development of collagen induced arthritis (CIA). The investigators propose to further investigate the cellular and molecular mechanisms behind this suppression and examine the translational potential of the investigators' finding by examining the IFN-λ receptor expression and function in neutrophils isolated from the blood of healthy donors and rheumatic patients (early rheumatoid arthritis and vasculitis).
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Detailed Description
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Neutrophils will be isolated from freshly drawn human blood with subsequent removal of red blood cells with dextran and/or magnetic-activated cell sorting (MACS). The investigators' preliminary results show that neutrophils isolated from the blood of a healthy donor express higher level of IL28RA messenger Ribonucleic Acid (mRNA) compared to Cluster of Differentiation-14 (CD14) negative or CD14 positive lymphocytes. To better understand the relative spread of IL28RA mRNA levels due to human heterogeneity, the investigators will compare the levels of IL28RA expression in neutrophils isolated from blood of 20 healthy donors. The investigators will examine whether treatment of human neutrophils ex vivo with recombinant human IL29 (Bristol- Meyers Squibb, BMS) induces Signal Transducer and Activators of Transcription 1 (STAT1) signalling. The investigators will also test newly generated antibodies to human IL28RA which have shown some specificity in IL28RA detection in cell lines, on neutrophil isolated from blood.
Expression of IFNLR1/IL28RA in neutrophils isolated from blood of rheumatic patients.
The investigators will then compare the levels of IL28RA expression on neutrophils isolated from blood of (1) 15 patients in the early phases of rheumatoid arthritis (RA) and while naïve to biologic therapeutic intervention; (2) 15 vasculitis patients with giant cell arteritis (GCA) (within one week of commencing high dose glucocorticoid) and (3) 15 vasculitis patients with granulomatosis with polyangitis (GPA; Wegener's) at presentation or during a relapse, prior to initiation of immunosuppressive therapy with either cyclophosphamide or rituximab. All patients will undergo standardised assessment of disease activity and damage, i.e. the Birmingham Vasculitis Activity Score version 3.0 (BVAS 3.0) and the Vasculitis Damage Index version 1.0 (VDI) for vasculitis or the disease activity score for 28 joints (DAS-28) for RA. This will allow the investigators to predict whether rheumatic patients are likely to respond to IL29 treatment.
Functional characterisation of human neutrophils treated with IL29.
The investigators will conduct a selective evaluation of the expression of adhesion molecules, the migratory responses and functional properties of human neutrophils treated with IL29 ex vivo. These selected activities will be examined in the IL29 treated neutrophils from blood of healthy donors, with or without stimulation with lipopolysaccharide (LPS), phorbol myristate acetate (PMA) or serum from RA and vasculitis patients. The investigators will assess the impact of IL29 treatment on neutrophils isolated from the blood of patients with RA and vasculitis.
Conditions
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Study Design
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CASE_CONTROL
PROSPECTIVE
Study Groups
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Healthy controls
Staff or patients attending hospital or visitors attending with patients. They should not have vasculitis or inflammatory arthritis
No interventions assigned to this group
Early rheumatoid arthritis
Newly diagnosed patients with rheumatoid arthritis attending hospital, prior to use of biologic therapies
No interventions assigned to this group
New or relapsing ANCA vasculitis
Newly diagnosed or flaring patients with anti-neutrophil cytoplasm antibody associated systemic vasculitis attending hospital
No interventions assigned to this group
Newly diagnosed giant cell arteritis
Newly diagnosed patients with giant cell arteritis attending hospital
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* Recent diagnosis of rheumatoid arthritis within 1 month or
* New diagnosis of giant cell arteritis within 1 month or
* New diagnosis of anti-neutrophil cytoplasm antibody associated vasculitis within 1 month or
* Flare of anti-neutrophil cytoplasm antibody associated vasculitis within one month
Exclusion Criteria
18 Years
ALL
Yes
Sponsors
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Arthritis Research UK
OTHER
University of Oxford
OTHER
Responsible Party
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Raashid Luqmani
Professor of Rheumatology
Principal Investigators
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Raashid A Luqmani, DM FRCP
Role: PRINCIPAL_INVESTIGATOR
Professor of Rheumatology
Locations
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Oxford University Hospitals NHS Foundation Trust
Oxford, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Jana Vaskova
Role: primary
References
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Blazek K, Eames HL, Weiss M, Byrne AJ, Perocheau D, Pease JE, Doyle S, McCann F, Williams RO, Udalova IA. IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1beta production. J Exp Med. 2015 Jun 1;212(6):845-53. doi: 10.1084/jem.20140995. Epub 2015 May 4.
Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003 Jan;4(1):69-77. doi: 10.1038/ni875. Epub 2002 Dec 16.
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003 Jan;4(1):63-8. doi: 10.1038/ni873. Epub 2002 Dec 2.
Other Identifiers
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20892
Identifier Type: -
Identifier Source: org_study_id
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