Effect of IFN-ß therapy on the frequency and function of CD4+CD25+ regulatory T cells and Foxp3 gene expression in relapsing–remitting multiple sclerosis (RRMS): A preliminary study

Namdar, Afshin; Nikbin, Behroz; Ghabaee, Mojde; Bayati, Asghar; Izad, Maryam

doi:10.1016/j.jneuroim.2009.10.013

Cited by 57 publications

(48 citation statements)

References 48 publications

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“…Furthermore, by employing these collective suppressive mechanisms, Tregs are able to attenuate inflammation, despite being significantly less prevalent than are macrophages after MI injury (estimated 1 Treg for every 333 macrophages at 7 days after injury) (35). Interestingly, several studies have demonstrated an important role for IFN signaling in the activation and recruitment of Tregs to injured tissue (45,46,59,60). IFN-γ has been shown in prior studies to affect multiple pathways, including suppression of fibrosis in chronic myocarditis by reducing profibrotic cytokine secretion (61), as well as mediation of basic FGF-induced (bFGF-induced) fibroblast migration via CXCL10 (62).…”

Section: Discussionmentioning

confidence: 99%

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

Ramjee¹,

Li²,

Manderfield³

et al. 2017

Journal of Clinical Investigation

128

106

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Section: Discussionmentioning

confidence: 99%

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

Ramjee¹,

Li²,

Manderfield³

et al. 2017

Journal of Clinical Investigation

128

106

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“…IFNAR signaling has been shown to affect the development and recruitment of CD4 ϩ regulatory T (Treg) cells, but the data are unclear as to whether that effect is positive or negative (39)(40)(41)(42). Treg cells possess a myriad of anti-inflammatory properties, including suppression of virus-specific CTLs during LRI (43).…”

Section: Efficient Development Of a Functional Hmpv-specific Cd8mentioning

confidence: 99%

“…To date, there are conflicting studies on the impact of IFNAR signaling on Treg cells. Some groups have shown a negative impact of IFNAR signaling on the development of Treg cells (39,40), but others have shown that treatment with type I IFN can lead to higher Treg cell numbers (41,42). Treg cells can secrete suppressive cytokines, such as IL-10, to limit the functionality of CD4 Other inhibitory T cell receptors, including LAG-3 (60), 2B4 (61), and Tim-3 (62), contribute to CD8 ϩ T cell exhaustion during chronic infection, with the expression of multiple receptors increasing the exhaustion phenotype (63,64).…”

Section: Both Wt and Ifnarmentioning

confidence: 99%

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Hastings

Erickson

Schuster

et al. 2015

J Virol

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Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR ؊/؊ ) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8 ؉ T cell response. HMPV-infected IFNAR ؊/؊ mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR ؊/؊ mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8؉ T cells of IFNAR ؊/؊ mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8 ؉ T cells of IFNAR ؊/؊ mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1 low dendritic cells (DCs), but not PD-L1 high alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8 ؉ T cell impairment. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8 ؉ T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8؉ T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8 ؉ T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8 ؉ T cell impairment. H uman metapneumovirus (HMPV) is a leading cause of acute lower respiratory infection (LRI), with infants and elderly and immunocompromised persons at the highest risk of severe complications from viral infection (1-9). No licensed therapeutics or vaccines exist to combat or prevent HMPV infection. Nearly all individuals have been exposed to HMPV by the age of 5 years (10, 11). Infection with this virus results in a neutralizing antibody (n...

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“…Type I IFNs were reported to upregulate the Tregs numbers and suppressive capacity and promote FOXP3 mRNA expression in MS, Chronic Hepatitis C infection, experimental models of colitis and encephalomyelitis [124][125][126][127][128][129]. Inducers of type I…”

Section: Effect Of Type I Ifns On Tregsmentioning

confidence: 99%

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

Narendra¹

2017

Linköping University Medical Dissertations

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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 onl...

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Effect of IFN-ß therapy on the frequency and function of CD4+CD25+ regulatory T cells and Foxp3 gene expression in relapsing–remitting multiple sclerosis (RRMS): A preliminary study

Cited by 57 publications

References 48 publications

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction

Role of Type I Interferon Signaling in Human Metapneumovirus Pathogenesis and Control of Viral Replication

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

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