Arthritis Clinical Trial
Official title:
Interferon-lambda: Novel Biologics for Controlling Neutrophil-mediated Pathology in Rheumatic Diseases?
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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