Interplay between TNF and Regulatory T Cells in a TNF-Driven Murine Model of Arthritis (original) (raw)
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The role of TNF-α in rheumatoid arthritis: a focus on regulatory T cells
Journal of Clinical and Translational Research, 2016
The autoimmune disorder rheumatoid arthritis (RA) causes chronic inflammation and destruction of joints. T cells are a predominant component of the synovial environment in RA, however the functional role of these cells is not yet fully understood. This is in part due to the fact that the balance and importance of the relation of T regs with T-effector cells in RA is still under investigation.The current treatment regimen for this debilitating disease focuses on controlling symptoms and preventing further joint damage through the use of therapies which affect different areas of the immune system at the synovium. One of the main therapies involves Tumor Necrosis Factor alpha (TNF-α) inhibitors. In the RA immune-environment, TNF-α has been shown to have an influential and extensive but as yet poorly understood effect on T reg function in vivo, and undoubtably an important role in the treatment of RA. Interestingly, the high levels of TNF-α found in RA patients appear to interfere with the mechanisms controlling the suppressive function of T regs. Relevance for patients: This review focuses on the conflicting literature available regarding the role played by T regs in RA and the impact of TNF-α and anti-TNF-α therapies on T regs in this scenario. Individuals suffering from RA can benefit from better insight of the treatment mechanisms of the immunologic processes which occur throughout this disease, as current treatments for RA focus on several different areas of the immune system at the synovial compartment.
Experimental Models of Arthritis in Which Pathogenesis Is Dependent on TNF Expression
Biochemistry. Biokhimii͡a, 2014
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by joint damage as well as systemic manifestations. The exact cause of RA is not known. Both genetic and environmental factors are believed to contribute to the development of this disease. Increased expression of tumor necrosis factor (TNF) has been implicated in the pathogenesis of RA. Currently, the use of anti-TNF drugs is one of the most effective strategies for the treatment of RA, although therapeutic response is not observed in all patients. Furthermore, due to non-redundant protective functions of TNF, systemic anti-TNF therapy is often associated with unwanted side effects such as increased frequency of infectious diseases. Development of experimental models of arthritis in mice is necessary for studies on the mechanisms of pathogenesis of this disease and can be useful for comparative evaluation of various anti-TNF drugs. Here we provide an overview of the field and present our own data with two...
Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis
Autoimmunity Highlights, 2010
Regulatory T cells (Treg) are a CD4 + lymphocyte subset involved in self-tolerance and autoimmunity prevention. There is evidence for a phenotypic and/or functional impairment of this cell subset during the natural history of several chronic autoimmune/inflammatory diseases, including rheumatoid arthritis (RA). Although the intracellular transcription factor FoxP3 is thought to be the master regulator of Treg cell function, a number of other molecules expressed on the cell surface have been proposed for the identification of Treg cells. This is important in order to favour their possible selective isolation and in the development of new therapeutic strategies. In the present paper, available data on phenotypic and functional characterization of Treg cells in both peripheral blood and synovial fluid from RA patients are reviewed and their possible pathogenic role in triggering and perpetuating rheumatoid joint inflammation is discussed.
Increased number and function of FoxP3 regulatory T cells during experimental arthritis
Arthritis & Rheumatism, 2008
draining lymph nodes, indicating selective tropism to sites of disease. In contrast to the in vitro unresponsiveness of Treg cells when cultured alone, substantial proportions of Treg cells proliferated in both nonarthritic and arthritic mice. However, they also underwent greater apoptosis, thereby maintaining equilibrium with Teff cells. Similarly, enhanced Treg cell-suppressive activity during arthritis was offset by greater resistance by their Teff cell counterparts and antigen-presenting cells.
TNF blockade in rheumatoid arthritis: Implications for therapy and pathogenesis
APMIS, 1997
The role of the immune response in rheumatoid arthritis (RA) is a subject of debate, although it is widely believed to be a T-cell-driven disease. Progress is being hindered by lack of convincing evidence of a defined specific antigen initiating or perpetuating the response. Clinical trials using monoclonal antibodies directed against T-cell surface molecules such as CD4, CD5, and CD7 have thus far not provided evidence of efficacy. The negative data may reflect inadequate dosing or could suggest that indiscriminate depletion of T cells is insufficient by itself as a therapeutic strategy. Blocking proinflammatory cytokines (e.g. TNFa, IL-1) or augmenting anti-inflammatory cytokines (e.g. IL-10) offers an alternative approach to therapy. Clinical trials using monoclonal anti-TNFa have been particularly successful in controlling inflammation and markedly reducing acute phase proteins and cellular ingress. However, because disease invariably relapses, repeated therapy is necessary. Preliminary experience suggests that this is possible. Anti-TNF therapy for RA has defined a molecular target and new approach for treating immuno-inflammatory disorders.
Suppressive activity of human regulatory T cells is maintained in the presence of TNF
Nature medicine, 2016
Drugs that block tumor necrosis factor (TNF) have been used with success in the treatment of different autoimmune and inflammatory diseases, such as rheumatoid arthritis, Crohn's disease and psoriasis. However, some patients do not respond to these treatments, and a few develop autoimmune responses for unknown reasons. Given that regulatory T (T reg) cells expressing forkhead box P3 (FOXP3) have a major role in regulating autoimmune diseases, and that the production of TNF is increased in these diseases, the effect of TNF on T reg cells is of interest. In previous studies, we looked at different conditions both in vitro and in vivo and observed that TNF promoted proliferation of T reg cells while maintaining the cells' suppressive activity in mice 1-3. However, experiments performed using human cells reported that TNF inhibited the suppressive activity of T reg cells in vitro, which was associated with either decreased expression or inactivation of FOXP3 (refs. 4-7). Recently, it was shown that TNF, which is produced in the synovial fluid of individuals with rheumatoid arthritis, reduced T reg cell suppressive function 7 .
Arthritis Research Therapy, 2001
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA). An indirect immunofluorescence test and rat oesophagus substrate was used for the detection and quantification of AKA antibodies in patients´ sera. Overall 33/60 patients with JIA had sera positive for AKA (55 %, P = 0,0001) ranging from 1:10 to 1:160 dilutions. Following idiopathic arthritis of childhood classification criteria AKA occurred in 2/7 patients with systemic disease (28,6 %), in 13/30 patients with RF negative polyarthritis (43,3 %, P = 0,008) and in 15/18 RF positive polyarthritis (83,3 %, P = 0,000002). AKA were also found in a small cohort of patients with oligoarthritis (1/3) and psoriatic arthritis (2/2). AKA positivity occurred in 3/26 healthy controls at a 1:20 dilution. The presence of AKA was correlated as well as with the severity of the disease. Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, however this did not reach statistical significance (P = 0,18). We also observed that AKA remained positive regardless of disease activity. AKA were detectable in 55,6 % patients with active JIA and in 48,6 % patients in the complete or near remission. Acknowledgement: This research was supported by a European Commission (Acronym: EUROBANK, contract no: QOL-2000-14.1), web site http://www.ncl.ac.uk and by grant of 2nd Medical Faculty, Charles University in Prague, VZ no. 111300003. P2 The significance of antibodies to cyclic citrullinated peptide, antikeratin antibodies, antiperinuclear factor, rheumatoid factor isotypes and HLA shared epitope in prediction of erosive disease in early rheumatoid arthritis patients