Studies of pharmacological interventions and pathogenesis of rheumatoid arthritis
Author: Lampa, Jon
Date: 2002-11-22
Location: Nanna Svartz Auditorium, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
View/ Open:
thesis.pdf (615.6Kb)
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disease primarily
affecting the joints. The chronic inflammation frequently results in
joint destruction and various forms of physical impairment. T cells are
believed to be of importance for the propagation of many cases of RA due
to the association with certain types of HLA class 11, whose function is
to present antigen to the T cell receptor. There is, however, evidence
that also macrophages and B cells may be of prime importance in driving
the inflammatory process in RA
In this thesis, an approach has been made to study immune functions in RA
during treatment with two different anti-rheumatic drugs, intramuscular
gold and tumour necrosis factor-(TNF)alpha-blockade with etanercept (a
soluble TNFalpha-receptor), with the goal to learn more about RA
pathogenesis. The mechanism of action of intramuscular gold treatment is
not known but it has been suggested that gold may shift the immune system
towards production of anti-inflammatory cytokines, rather than inducing a
general immune suppression. We investigated the cytokine production in
vitro in response to gold sodium thiomalate (GSTM), and found a
stimulatory effect on monocyte dependent production of the and-
inflammatory cytokine interleukin (IL)-10 along with a decrease of
interferon-(IFN)gamma levels in corresponding supematants. In concordance
with these results, there was an increased IL-10 production during GSTM
treatment in RA patients. In addition, the in vitro effect of GSTM on
IL-10 production from peripheral blood mononuclear cells (PBMC) predicted
development of skin reactions during in vim treatment with GSTM, with low
IL-10 production being associated with appearance of skin reactions. From
these studies we conclude that intramuscular gold treatment has cytokine
stimulating properties, and the stimulation of IL-1 0 production might
have importance for the therapeutic effect of gold in RA- Moreover, the
ability of RA patients to produce IL-1 0 in response to gold may
influence the development of skin reactions.
RA T cells are hyporesponsive when stimulated with microbial antigens in
vitro compared to T cells from the blood of healthy subjects. Activated
monocytes/macrophages suppress T cell functions, possibly mediated
through pro-inflammatory cytokines such as TNFalpha We investigated
peripheral T cell reactivity in RA patients during etanercept therapy and
found an increased T cell reactivity against microbial antigens and
collagen type 11, an autoantigen. These findings indicate that T cell
hyporesponsiveness in RA is, at least partly, TNFalpha-mediated and that
TNFalpha-blockade may not only suppress but also stimulate certain
aspects of antimicrobial immune defence and autoimmunity. The findings
thus warrant further consideration of development of autoimmune reactions
during TNFalpha-blockade therapy.
TNFalpha is also known to stimulate production of matrix
metalloproteinases (MMPs), which are upregulated in the inflamed joint
and highly associated with development of synovial degradation and joint
erosions. During etanercept therapy, serum levels of both MMP-1 and MMP-3
were downregulated in parallel with the reduction of inflammatory
parameters. Moreover, pre-treatment MMP-3 serum levels correlated with
changes in disease activity during etanercept therapy.
Cytokine promoter polymorphisms are known to be associated with different
levels of production of the same cytokine. This observation indicates
that also intervention with a cytokine may differ in efficacy depending
on genetic variations. Although TNFalpha-blockade is very efficient in
ameliorating diseases activity in most of the treated patients with RA,
about one third of the patients do not respond appropriately to this
therapy and there are as yet no prognostic markers for clinical response.
We analysed whether promoter polymorphisms of pro- and anti-inflammatory
cytokine genes correlated with clinical response to etanercept. A
combination of alleles conferring a normal TNFalpha production (-308
T1/T1) and high IL-10 production (-1087 G/G) was associated with good
clinical responsiveness to etanercept. Another combination conferring
high inflammatory capacity (A2 allele in intron 2 of the IL1 RN gene and
rare C allele in codon 25 of the TGF131 gene) was associated with
nonresponsiveness. Thus, genetic polymorphisms that influence the balance
of cytokines that are of relevance for the course of RA seem to be
associated with clinical outcome of etanercept therapy. This finding may
be of value for further studies possibly promoting the use of cytokine
polymorphisms as predictors for response to various biological agents in
the future.
List of papers:
I. Lampa J, Klareskog L, Ronnelid J (2002). "Effects of gold on cytokine production in vitro; increase of monocyte dependent interleukin 10 production and decrease of interferon-gamma levels. " J Rheumatol 29(1): 21-8
Pubmed
II. Ernestam S, Lampa J, Rogberg S, Ronnelid S, Klareskog L, Hafstrom I (2002). "Evidence for immunostimulatory effects of intramuscular gold in rheumatoid arthritis; correlation with skin reactions." (Submitted)
III. Berg L, Lampa J, Rogberg S, van Vollenhoven R, Klareskog L (2001). "Increased peripheral T cell reactivity to microbial antigens and collagen type II in rheumatoid arthritis after treatment with soluble TNFalpha receptors. " Ann Rheum Dis 60(2): 133-9
Pubmed
IV. Catrina AI, Lampa J, Ernestam S, af Klint E, Bratt J, Klareskog L, Ulfgren AK (2002). "Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. " Rheumatology 41(5): 484-9
Pubmed
V. Padyukov L, Lampa J, Heimbürger M, Ernestam S, Cederholm T, Lundkvist I, Andersson P, Hermansson Y, Harju A, Klareskog L, Bratt J (2002). "Genetic markers for the efficacy of TNF blocking therapy in rheumatoid arthritis." (Submitted)
I. Lampa J, Klareskog L, Ronnelid J (2002). "Effects of gold on cytokine production in vitro; increase of monocyte dependent interleukin 10 production and decrease of interferon-gamma levels. " J Rheumatol 29(1): 21-8
Pubmed
II. Ernestam S, Lampa J, Rogberg S, Ronnelid S, Klareskog L, Hafstrom I (2002). "Evidence for immunostimulatory effects of intramuscular gold in rheumatoid arthritis; correlation with skin reactions." (Submitted)
III. Berg L, Lampa J, Rogberg S, van Vollenhoven R, Klareskog L (2001). "Increased peripheral T cell reactivity to microbial antigens and collagen type II in rheumatoid arthritis after treatment with soluble TNFalpha receptors. " Ann Rheum Dis 60(2): 133-9
Pubmed
IV. Catrina AI, Lampa J, Ernestam S, af Klint E, Bratt J, Klareskog L, Ulfgren AK (2002). "Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. " Rheumatology 41(5): 484-9
Pubmed
V. Padyukov L, Lampa J, Heimbürger M, Ernestam S, Cederholm T, Lundkvist I, Andersson P, Hermansson Y, Harju A, Klareskog L, Bratt J (2002). "Genetic markers for the efficacy of TNF blocking therapy in rheumatoid arthritis." (Submitted)
Issue date: 2002-11-01
Rights:
Publication year: 2002
ISBN: 91-7349-372-4
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