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| Name | Class |
|---|---|
| Arthritis Research UK | OTHER |
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Neutrophils emerge as key immune cells in the initiation and perpetuation of immune responses in autoimmune diseases. They display marked abnormalities in phenotype and function in various autoimmune diseases, including systemic vasculitis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
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).
Expression of Interferon lambda receptor 1 (IFNLR1)/interleukin 28 Receptor Alpha (IL28RA) in human neutrophils.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy controls | Staff or patients attending hospital or visitors attending with patients. They should not have vasculitis or inflammatory arthritis | ||
| Early rheumatoid arthritis | Newly diagnosed patients with rheumatoid arthritis attending hospital, prior to use of biologic therapies | ||
| New or relapsing ANCA vasculitis | Newly diagnosed or flaring patients with anti-neutrophil cytoplasm antibody associated systemic vasculitis attending hospital | ||
| Newly diagnosed giant cell arteritis | Newly diagnosed patients with giant cell arteritis attending hospital |
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| Measure | Description | Time Frame |
|---|---|---|
| Expression of IFNLR1/IL28Ra in human neutrophils, by laboratory measurement of blood neutrophils | This will be tested on samples of blood taken from patients | Within one month of diagnosis (or flare of vasculitis) |
| Measure | Description | Time Frame |
|---|---|---|
| Vasculitis disease activity, based on a scale of disease activity in vasculitis (Birmingham Vasculitis Activity Score version 3.0, BVAS 3.0) | This will be assessed using the patient using the Birmingham Vasculitis Activity Score (version 3.0), a questionnaire completed by the clinician. A numeric score can be calculated (range 0-63) | Within one month of diagnosis (or flare of vasculitis) |
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Inclusion Criteria:
Exclusion Criteria:
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Healthy volunteers will be recruited as staff or patients attending secondary care or accompanying patients but who do not have vasculitis or any form of inflammatory arthritis Patients with vasculitis or arthritis who are attending secondary care will be invited to participate if they fulfill eligibility criteria.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Raashid A Luqmani, DM FRCP | Contact | 01865227971 | jana.vaskova@ndorms.ox.ac.uk | |
| Jana Vaskova | Contact | 01865227971 | jana.vaskova@ndorms.ox.ac.uk |
| Name | Affiliation | Role |
|---|---|---|
| Raashid A Luqmani, DM FRCP | Professor of Rheumatology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Oxford University Hospitals NHS Foundation Trust | Recruiting | Oxford | OX3 7HE | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25941255 | Background | 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. | |
| 12483210 | Background |
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| ID | Term |
|---|---|
| D001168 | Arthritis |
| D014657 | Vasculitis |
| ID | Term |
|---|---|
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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Blood samples
| Vasculitis damage, based on a scale of disease damage in vasculitis (Vasculitis Damage Index version 1.0, VDI 1.0) | This will be assessed using the Vasculitis Damage Index (Version 1.0), a questionnaire completed by the clinician. A numeric score can be calculated (0-64) | Within one month of diagnosis (or flare of vasculitis) |
| Disease activity assessment score for arthritis, based on a scale (Disease activity score for 28 joints, DAS-28) | This will be assessed using a score of the number of painful and tender joints, results of the test of inflammatory markers (usually the C-reactive protein) and a patient's estimate of disease on a visual analogue scale. The data is recorded in a specifically designed calculator, providing a numerical score from 0 to 10 | Within one month of diagnosis (or flare of vasculitis) |
| Expression of Toll like receptors, adhesion molecules and chemokine receptors in human neutrophils, by laboratory measurement of blood neutrophils | This will be tested on samples of blood taken from patients. | Within one month of diagnosis (or flare of vasculitis) |
| STAT1 signalling by neutrophils | This will be tested on samples of blood taken from patients. | Within one month of diagnosis (or flare of vasculitis) |
| 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. |
| 12469119 | Background | 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. |