Function of the Th17/Interleukin‐17A Immune Response in Murine Lupus Nephritis

Schmidt, Tilman; Paust, Hans‐Joachim; Krebs, Christian; Turner, Jan-Eric; Kaffke, Anna; Bennstein, Sabrina Bianca; Koyro, Tobias; Peters, Anett; Velden, Joachim; Hünemörder, Stefanie; Haag, Friedrich; Steinmetz, Oliver M.; Mittrücker, Hans‐Willi; Stahl, Rolf A.K.; Panzer, Ulf

doi:10.1002/art.38955

Cited by 85 publications

(48 citation statements)

References 46 publications

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“…In previous studies, despite the fact that MDSCs from arthritic mice retain an immunosuppressive activity, the mobilized MDSCs fail to limit the immunopathology, and these cells are highly efficient in facilitating Th17 cell differentiation via IL-1β, indicating their proinflammatory nature [8,39,40]. In the present study, M-MDSCs from diseased MRL/lpr mice expressed higher levels of inflammatory cytokines (e.g.…”

Section: Discussioncontrasting

confidence: 42%

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

Zhao

et al. 2016

Clinical Science

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Although major advancements have made in investigating the aetiology of SLE (systemic lupus erythaematosus), the role of MDSCs (myeloid-derived suppressor cells) in SLE progression remains confused. Recently, some studies have revealed that MDSCs play an important role in lupus mice. However, the proportion and function of MDSCs in lupus mice and SLE patients are still poorly understood. In the present study, we investigated the proportion and function of MDSCs using different stages of MRL/lpr lupus mice and specimens from SLE patients with different activity. Results showed that splenic granulocytic (G-)MDSCs were significantly expanded by increasing the expression of CCR1 (CC chemokine receptor 1) in diseased MRL/lpr lupus mice and in high-disease-activity SLE patients. However, the proportion of monocytic (M-)MDSCs remains similar in MRL/lpr lupus mice and SLE patients. G-MDSCs produce high levels of ROS (reactive oxygen species) through increasing gp91(phox) expression, and activated TLR2 (Toll-like receptor 2) and AIM2 (absent in melanoma 2) inflammasome in M-MDSCs lead to IL-1β (interleukin 1β) expression in diseased MRL/lpr mice and high-disease-activity SLE patients. Previous study has revealed that MDSCs could alter the plasticity of Th17 (T helper 17) cells and Tregs (regulatory T-cells) via ROS and IL-1β. Co-culture experiments showed that G-MDSCs impaired Treg differentiation via ROS and M-MDSCs promoted Th17 cell polarization by IL-1β in vitro Furthermore, adoptive transfer or antibody depletion of MDSCs in MRL/lpr mice confirmed that MDSCs influenced the imbalance of Tregs and Th17 cells in vivo Our results indicate that MDSCs with the capacity to regulate Th17 cell/Treg balance may be a critical pathogenic factor in SLE.

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Section: Discussioncontrasting

confidence: 42%

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

Zhao

et al. 2016

Clinical Science

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“…A recent study by Schmidt et al showed that IL-17A deficiency did not affect the morphological or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of nephritis in NZB/NZW mice, suggesting that the Th17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. 19 In vitro, both autologous and allogeneic Treg cells can be satisfactorily isolated, expanded, and successfully adoptively transfused into patients with chronic GVHD. 20 However, the long-term follow-up revealed some adverse events, such as malignant melanoma or skin cancer.…”

Section: Discussionmentioning

confidence: 99%

The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus

et al. 2015

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“…7 Similarly, in New Zealand Black (NZB)/New Zealand White (NZW) F1 mice, blockade or reduction of IFN-γ was beneficial. 8 Deletion of a regulatory element in the 3′ untranslated region of the IFN-γ gene in mice leads to congenital overexpression of IFN-γ and development of serological and cellular features characteristic of SLE. 9 Individuals treated with IFN-γ for several disorders (eg, bladder cancer, myeloproliferative disorders) developed or had potentiated autoimmune responses including SLE-like syndromes.…”

Section: Introductionmentioning

confidence: 99%

Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis

et al. 2017

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ObjectiveTo evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN).MethodsIn this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement).ResultsFifty-six subjects enrolled (28 SLE without LN; 28 with LN). Baseline mean SELENA-SLEDAI scores were 2.2 and 12.0 for SLE subjects without and with LN, respectively. Most subjects reported an AE; no meaningful imbalances were observed between AMG 811 and placebo. Pharmacokinetic profiles were similar and mostly dose-proportional in subjects without or with LN. AMG 811 treatment reduced CXCL-10 protein levels and blood-based RNA IFN-γ Blockade Signature compared with placebo. Reductions were less pronounced and not sustained in subjects with LN, even at the highest dose tested, compared with subjects without LN. No effect on SELENA-SLEDAI scores, proteinuria, C3 or C4 complement levels, or anti-dsDNA antibodies was observed.ConclusionAMG 811 demonstrated favourable pharmacokinetics and acceptable safety profile but no evidence of clinical impact. IFN-γ-associated biomarkers decreased with AMG 811; effects were less pronounced and not sustained in LN subjects.Trial registration numberNCT00818948; results.

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Function of the Th17/Interleukin‐17A Immune Response in Murine Lupus Nephritis

Cited by 85 publications

References 46 publications

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

The regulation of the Treg/Th17 balance by mesenchymal stem cells in human systemic lupus erythematosus

Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis

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