Studies on immunological mechanisms of induced arthritis in the rat
Author: Svelander, Lena
Date: 2002-12-13
Location: Hörsalen, Centrum för Molekylär Medicin (CMM) L8:00, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
Abstract
Experimental arthritis induced with adjuvants shares many features with
the human autoimmune disorder rheumatoid arthritis (RA). The use of
arthritis models is therefore a relevant approach in the search for
pathogenic mechanisms in human disease.
This thesis has focused on investigation of the mechanisms underlying
arthritis induced with adjuvants in rats. The experimental models we have
utilized were oil-induced arthritis (OIA), squalene-induced arthritis
(SIA) and a new model, denominated CpG-induced arthritis.
OIA and SIA are both induced with non-immunogenic adjuvants, OIA with
incomplete Freund's adjuvant and SIA with the cholesterol precursor
squalene. They are both T cell dependent diseases, affecting only the
peripheral joints with subsequent erosions of bone and cartilage. The
influence of MHC as well as non-MHC genes has been demonstrated in both
these models.
In the first paper we evaluated the contribution of CD4+ and CD8+ T cells
respectively, to development of disease. This was performed using
adoptive transfer to irradiated recipients. To further characterise the
pathogenic cells we blocked receptors on the transferred population,
determined their TCR VP usage and analysed their cytokine expression. We
demonstrated that CD4+, but not CD8+ T cells were pathogenic and could
transfer OIA to irradiated recipients. These cells were polyclonal and
Th1-biased. Blocking of cell surface molecules (CD4, ICAM1 or the IL-2
receptor) on the arthritis-transferring cell population before transfer
did not markedly influence passive OIA development.
One important feature with experimental models is the possibility to
characterise events before arthritis onset. In the second study we
utilised this possibility investigating systemic and local effects after
injection with IFA but before disease onset. In an attempt to
characterise differences underlying susceptibility we used the
susceptible DA strain as well as the MHCcongenic but resistant LEW.1AV1
and PVG.1AV1 strains. Of the selected phenotypes, an early systemic
response to the adjuvant exposure as well as lymph node hyperplasia, both
not regulated by MHC genes, could be demonstrated. In the susceptible
strain, the acute-phase reactant alpha1-acid glycoprotein and mRNA
expression of IL-1beta were demonstrated to be potential markers for
disease.
Since it is intriguing that non-immunogenic adjuvants can lead to an
organ-specific disease and both susceptible as well as resistant strains
express a systemic response to the adjuvant injection, we explored the
distribution of adjuvant. We demonstrated a high deposition of the 3 H-
labelled squalene at the injection site even after 15 days (i.e. when
animals are arthritic). Adjuvant was also deposited in draining inguinal
lymph nodes but not in affected joints or in non-draining lymph nodes
(axillary and brachial). All strains revealed the same distribution of
adjuvant regardless of susceptibility. Although no adjuvant could be
traced in the non-draining lymph nodes these cells were still pathogenic
and could transfer disease to irradiated recipients.
DNA sequences containing CpG motifs are common in bacteria but rare in
humans. This immunostimulatory DNA induces an innate immune response
through interaction with Tolllike receptor (TLR)-9. Intradermal.
administration of CpG-containing oligonucleotides together with IFA
induced arthritis in LEW.1AV1 rats, a strain which is resistant to
arthritis induced by IFA alone. In this arthritis model IL-1beta, AGP and
T cells also appeared to be of importance for the pathogenesis.
In conclusion, this thesis has added to the knowledge of immune responses
to diseaseinducing adjuvants as well as tissue distribution of injected
adjuvants. We have also taken genetic aspects into consideration when
investigating differences in distribution of and response to adjuvants
between disease-susceptible and -resistant rat strains.
List of papers:
I. Svelander L, Mussener A, Erlandsson-Harris H, Kleinau S (1997). "Polyclonal Th1 cells transfer oil-induced arthritis. " Immunology 91(2): 260-5
Pubmed
II. Svelander L, Holm BC, Buchtt A, Lorentzen JC (2001). "Responses of the rat immune system to arthritogenic adjuvant oil. " Scand J Immunol 54(6): 599-605
Pubmed
III. Holm BC, Svelander L, Bucht A, Lorentzen JC (2002). "The arthritogenic adjuvant squalene does not accumulate in joints, but gives rise to pathogenic cells in both draining and non-draining lymph nodes. " Clin Exp Immunol 127(3): 430-5
Pubmed
IV. Svelander L, Erlandersson-Harris H, Lorentzen JC, Klareskog L, Bucht A (2002). "Oligo-DNA containing CpG motifs can induce T cell dependent arthritis in rats." (Submitted)
I. Svelander L, Mussener A, Erlandsson-Harris H, Kleinau S (1997). "Polyclonal Th1 cells transfer oil-induced arthritis. " Immunology 91(2): 260-5
Pubmed
II. Svelander L, Holm BC, Buchtt A, Lorentzen JC (2001). "Responses of the rat immune system to arthritogenic adjuvant oil. " Scand J Immunol 54(6): 599-605
Pubmed
III. Holm BC, Svelander L, Bucht A, Lorentzen JC (2002). "The arthritogenic adjuvant squalene does not accumulate in joints, but gives rise to pathogenic cells in both draining and non-draining lymph nodes. " Clin Exp Immunol 127(3): 430-5
Pubmed
IV. Svelander L, Erlandersson-Harris H, Lorentzen JC, Klareskog L, Bucht A (2002). "Oligo-DNA containing CpG motifs can induce T cell dependent arthritis in rats." (Submitted)
Issue date: 2002-11-22
Publication year: 2002
ISBN: 91-7349-349-X
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