Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine [Elektronisk resurs] / Sudeep Chenna Narendra
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- Chenna Narendra, Sudeep, 1982- (författare)
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Alternativt namn: Narendra, Sudeep Chenna, 1982-
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Magnusson, Mattias (preses)
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Uppugunduri, Srinivas (preses)
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Kastbom, Alf (preses)
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Bessis, Natacha (opponent)
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- Linköpings universitet. Institutionen för klinisk och experimentell medicin (utgivare)
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Alternativt namn: IKE
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Alternativt namn: Linköping University. Department of Clinical and Experimental Medicine
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Alternativt namn: Linköping University. Faculty of Health Sciences. Department of Clinical and Experimental Medicine
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Linköpings universitet Medicinska fakulteten (utgivare)
- Linköping Department of Clinical and Experimental Medicine, Linköping University, 2017
- Engelska 75 s. (PDF)
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Serie: Linköping University Medical Dissertations, 0345-0082 ; 1572
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Läs hela texten (Sammanfattning och ramberättelse från Linköping University Electronic Press)
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Sammanfattning
Ämnesord
Stäng
- In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future. Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis. Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.
Ämnesord
- Arthritis -- immunology (MeSH)
- Uridine (MeSH)
- Interferon-alpha (MeSH)
- Medical and Health Sciences (hsv)
- Basic Medicine (hsv)
- Immunology in the medical area (hsv)
- Medicin och hälsovetenskap (hsv)
- Medicinska grundvetenskaper (hsv)
- Immunologi inom det medicinska området (hsv)
- Natural Sciences (hsv)
- Biological Sciences (hsv)
- Immunology (hsv)
- Naturvetenskap (hsv)
- Biologiska vetenskaper (hsv)
- Immunologi (hsv)
- Medical and Health Sciences (hsv)
- Basic Medicine (hsv)
- Pharmacology and Toxicology (hsv)
- Medicin och hälsovetenskap (hsv)
- Medicinska grundvetenskaper (hsv)
- Farmakologi och toxikologi (hsv)
- Medical and Health Sciences (hsv)
- Basic Medicine (hsv)
- Microbiology in the medical area (hsv)
- Medicin och hälsovetenskap (hsv)
- Medicinska grundvetenskaper (hsv)
- Mikrobiologi inom det medicinska området (hsv)
Klassifikation
- 616.722 (DDC)
- Ven (kssb/8 (machine generated))
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