IL-7 in Rheumatoid Arthritis: Pathogenesis, Biomarker and Rationale for Anti-IL-7 Therapy (pp. 31-64)
Authors: (Frederique Ponchel, Agata Burska, Effie Myrthianou, George Goulielmos, Leeds Institute of Rheumatic and Musculoskeletal Medicine & Leeds Musculoskeletal Biomedical Research Unit, The University of Leeds, Leeds, UK, and others)
Abstract: Rheumatoid arthritis (RA) is a chronic disease primarily affecting the joints and
producing marked inflammatory changes in the synovial membrane and adjacent
structures. Although any joint can be affected the disease normally affects the hands, feet,
knees and wrists. Disease activity and the rate of progression to involve new joints are
variable. The pain and disability associated represent a real burden both for the patients
and society and the disease is also associated with premature mortality [1, 2].
There is currently no cure for RA. Historically, treatments which deplete T-cells led
to reduction of symptoms supporting the notion of a T cell mediated disease. Today, the
pathology is thought to be the product of a series of complex cellular interactions where
synovial T-cells orchestrate disease through their interaction with fibroblasts, B-cells,
dendritic cells, and macrophages. Modern treatment options include the use of
“biological” drugs, which block cytokines such as TNF alpha, IL-1, IL-6, limit costimulation
between B and T-cells or deplete B-cells. Although their use bring great
benefit, a wide range of adverse events have been reported (including infections, cancer,
vasculitis, lupus-like and multiple sclerosis, liver disease, hematologic abnormalities
(such as aplastic anemia, lymphoma) and aseptic meningitis). In addition resistance to
these agents or loss of response, relapse on cessation of treatment, side effects occurs in
more than 40% of patients. The cost of these therapies is also major pitfall.
The complex cellular interactions in the synovium between stromal cells, T-cells and
their subsequent effect on B-cells, macrophages and endothelial cells provide a large
panel of alternative targets, both cellular and molecular, for therapeutic intervention in
RA. Inhibiting cytokines signalling has proven successful and we (and others)
hypothesise that IL-7 may be an appropriate therapeutic target in RA as well as in several
other autoimmune diseases. The main rational for targeting IL-7 is that it is (i) over
expressed specifically at the disease site, however only in active disease, (ii) not capable
of exiting the joint (due to its retention and presentation by extra-cellular matrix) (iii)
produced by local resident cells with no mobility (i.e. fibroblasts). In addition, low levels
of circulating IL-7 in RA patients suggest that efficient inhibition of IL-7 signalling may
only take place in the joint. The role of IL-7 in the disease itself is slowly being dissected
and will be reviewed to support this statement.
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