Studies on the differentiation of inflammatory and regulatory T-cells

Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve T$_R$$_e$$_g$ and T$_h$17 dysregulation. Thus, understanding how vitamin D modifies CD4$^+$ T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH)$_2$D$_3$, the active form of vitamin D, upon human CD4$^+$ T-cell differentiation. 1,25(OH)$_2$D$_3$, acted directly upon human CD4$^+$ T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFN$_y$ and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH)$_2$D$_3$-treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH)$_2$D$_3$reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH)$_2$D$_3$modified immunity. Furthermore, pro-regulatory effects of 1,25(OH)$_2$D$_3$were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH)$_2$D$_3$ was observed, supporting ability of 1,25(OH)$_2$D$_3$to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D$_3$to drive 1,25(OH)$_2$D$_3$-modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH)$_2$D$_3$in serum. Whether dysregulation of the T$_R$$_e$$_g$/T17 balance or response to 1,25(OH)$_2$D$_3$ was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH)$_2$D$_3$ were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH)$_2$D$_3$might be useful in the treatment of synovitis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Vitamin D and rheumatoid arthritis

1,25-dihydroxyvitamin D (1,25(OH)2D) has potent immunomodulatory properties, and many immune cells express the vitamin D receptor (VDR) and the 1α-hydroxylase (1α-OHase) enzyme that synthesizes 1,25(OH)2D from precursor 25-hydroxyvitamin D (25(OH)D). Thus, the immune system is intimately linked to the vitamin D system, and insufficiency of vitamin D may impair both innate and adaptive immune function. Low serum levels of 25(OH)D have been associated with increased risk and severity of autoimmune diseases. This chapter focuses specifically on the relationship between vitamin D and the autoimmune disease rheumatoid arthritis (RA). In addition to describing the mechanisms that link 25(OH)D and 1,25(OH)2D with inflammatory immune responses, this chapter will also document the wide array of studies that have shown association between serum 25(OH)D and RA disease, and the vitamin D supplementation studies that have explored possible beneficial effects of vitamin D supplementation of RA.</p

Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management

BACKGROUND: Drug-induced colitis is a known complication of therapies that alter the immune balance, damage the intestinal barrier or disturb intestinal microbiota. Immune checkpoint inhibitors (ICI) directed against cancer cells may result in activated T lymphocyte-induced immune-related adverse events (AEs), including immune-related colitis and hepatitis. The aim of this review article is to summarize the incidence of gastrointestinal (GI) and hepatic AEs related to ICI therapy. We have also looked at the pathogenesis of immune-mediated AEs and propose management strategies based on current available evidence. METHODS: A literature search using PubMed and Medline databases was undertaken using relevant search terms pertaining to names of individual drugs, mechanism of action, related AEs and their management. RESULTS: ICI-related GI AEs are common, and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of both all-grade colitis and hepatitis were highest with combination therapy with anti-CTLA-4/PD-1; severity of colitis was dose-dependent (anti-CTLA-4). Early intervention is associated with better outcomes. CONCLUSION: ICI-related GI and hepatic AEs are common and clinicians need to be aware. Patients with GI AEs benefit from early diagnosis using endoscopy and computed tomography. Early intervention with oral steroids is effective in the majority of patients, and in steroid-refractory colitis infliximab and vedolizumab have been reported to be useful; mycophenolate has been used for steroid-refractory hepatitis

Plasma levels of the n-3 polyunsaturated fatty acid eicosapentaenoic acid are associated with anti-TNF responsiveness in rheumatoid arthritis, and inhibit the etanercept driven rise in Th17 cell differentiation <i>in vitro</i>

Objective. To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF–driven Th17 cell differentiation.Methods. Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25– T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid(EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry.Results. Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (–0.51, p = 0.007 and –0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28.Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequencies in vitro. Physiological concentrations of EPA, but not LA, prevented this.Conclusion. EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies

Serum and synovial fluid vitamin D metabolites and rheumatoid arthritis

Vitamin D-deficiency has been linked to inflammatory diseases including rheumatoid arthritis (RA). Studies to date have focused on the impact of serum 25-hydroxyvitamin D3 (25(OH)D3), an inactive form of vitamin D, on RA disease activity and progression. However, anti-inflammatory actions of vitamin D are likely to be mediated at sites of RA disease, namely the inflamed joint, and may involve other vitamin D metabolites notably the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). In the current study serum and synovial fluid samples from n = 20 patients with persistent RA and n = 7 patients with reactive arthritis (ReA) were analysed for multiple vitamin D metabolites. Serum data for RA and ReA patients were compared to healthy controls (HC). There was no significant difference between RA or ReA patients relative to HC for 25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3 or 25(OH)D2. However, 3-epi-25(OH)D3 was significantly lower in RA and ReA patients compared to HC (p &lt; 0.05). All vitamin D metabolites, apart from 25(OH)D2, were lower in SF compared to serum, and SF 1,25(OH)2D3 was unquantifiable in 13/20 RA and 4/7 ReA samples. SF 25(OH)D3, 3-epi-25(OH)D3 and DBP correlated inversely with swollen joint score, and serum 25(OH)D2 and SF DBP correlated directly with C-reactive protein levels. These data indicate that serum 25(OH)D3 provides only limited insight into the role of vitamin D in RA. Alternative serum metabolites such as 3-epi-25(OH)2D3, and SF metabolites, notably lack of SF 1,25(OH)2D3, may be more closely linked to RA disease severity and progress

1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept

Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell–mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment

Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using (13)C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of (13)C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids

Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses

1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D(3), is generally used as an indication of “vitamin D status”. However, utilization of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D(3)-1α-hydroxylase (CYP27B1) into active 1,25(OH)(2)D(3). Using human T cells, we now show that addition of inactive 25(OH)D(3) is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact resulting in the generation and release of 1,25(OH)(2)D(3) which subsequently affects T cell responses. In most tissues, vitamin D binding protein (DBP) acts as a carrier to enhance the utilization of vitamin D. However, we show that DBP modulates T cell responses by restricting the availability of inactive 25(OH)D(3) to DC. These data indicate that the level of “free” 25(OH)D(3) available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses