FcγRI is required for TGFβ2-treated macrophage-induced tolerance

Gu, Zelin; Chhabra, Arvind; Alard, Pascale; Warner, Dennis R.; Kosiewicz, Michele M

doi:10.1016/j.imbio.2013.04.003

Cited by 5 publications

(7 citation statements)

References 29 publications

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“…Previous studies have shown that ligation of FcγRI on macrophages could promote the production of the anti-inflammatory cytokine IL-10 and dampen the responses to IFN-γ [19, 38]. In addition, FcγRI is critical for TGFβ2-treated macrophage-induced tolerance and plays an important role in IgG4-induced M2 macrophage generation [20, 39]. In a comparative study on the activation of IL-10 production in macrophages, IgG4 has shown similar potency as IgG1 [40].…”

Section: Discussionmentioning

confidence: 99%

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Zhang

Song

et al. 2018

Cancer Immunol Immunother

191

179

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Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4S228P). The functional impact by the interaction of anti-PD-1 IgG4S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4S228P and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4S228P binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI+ macrophages to phagocytose PD-1+ T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4S228P had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI+ murine macrophage infiltration and the density of CD8+PD-1+ human T cells within tumors in the BGB-A317/IgG4S228P-treated group. These evidences suggested that FcγRI+ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2160-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Zhang

Song

et al. 2018

Cancer Immunol Immunother

191

179

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“…TLR4 upregulation was reported to modulate VILI; therefore, we evaluated TLR4 expression to investigate the role of the TLR4 pathway in our VIDD model ( Fig. 6c, d) [37]. Western blot analyses revealed increased TLR4 expression in mice subjected to V T 10 mL/kg compared with those subjected to V T 6 mL/kg and the nonventilated control mice.…”

Section: Sn50 and Tlr4 Homozygous Knockout Suppress The Effects Of MVmentioning

confidence: 96%

“…Total RNA (1 μg) was reverse transcribed by using a GeneAmp PCR system 9600 (PerkinElmer, Life Sciences, Inc., Boston, MA, USA), as previously described [35]. The following primers were used for real-time PCR: TRL4, forward primer 5′-CGCTTTCACCTCTGCCTTCACTACAG-3′ and reverse primer 5′-ACACTACCACAATAACCTTC CGGCTC-3′ and GAPDH as internal control, forward primer 5′-GGAGCGAGACCCCACTAACA-3′ and reverse primer 5′-ACATACTCAGCACCGGCCTC-3′ (Protech Technology Enterprise Co. Ltd., Taipei, Taiwan) [36,37]. All quantitative PCR reactions using SYBR Master Mix were performed on a CFX96 Touch Real-Time PCR Detection system (Bio-Rad Laboratories, Inc., Hercules, CA, USA).…”

Section: Real-time Pcrmentioning

confidence: 99%

Attenuation of ventilation-induced diaphragm dysfunction through toll-like receptor 4 and nuclear factor-κB in a murine endotoxemia model

Liu

Chen

et al. 2018

Laboratory Investigation

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Mechanical ventilation (MV) is often used to maintain life in patients with sepsis and sepsis-related acute lung injury. However, controlled MV may cause diaphragm weakness due to muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) signaling pathways may elicit sepsis-related acute inflammatory responses and muscle protein degradation and mediate the pathogenic mechanisms of VIDD. However, the mechanisms regulating the interactions between VIDD and endotoxemia are unclear. We hypothesized that mechanical stretch with or without endotoxin treatment would augment diaphragmatic structural damage, the production of free radicals, muscle proteolysis, mitochondrial dysfunction, and autophagy of the diaphragm via the TLR4/NF-κB pathway. Male C57BL/6 mice, either wild-type or TLR4-deficient, aged between 6 and 8 weeks were exposed to MV (6 mL/kg or 10 mL/kg) with or without endotoxemia for 8 h. Nonventilated mice were used as controls. MV with endotoxemia aggravated VIDD, as demonstrated by the increases in the expression levels of TLR4, caspase-3, atrogin-1, muscle ring finger-1, and microtubule-associated protein light chain 3-II. In addition, increased NF-κB phosphorylation and oxidative loads, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis were also observed. Furthermore, MV with endotoxemia reduced P62 levels and diaphragm muscle fiber size (P < 0.05). Endotoxin-exacerbated VIDD was attenuated by pharmacologic inhibition with a NF-κB inhibitor or in TLR4-deficient mice (P < 0.05). Our data indicate that endotoxin-augmented MV-induced diaphragmatic injury occurs through the activation of the TLR4/NF-κB signaling pathway.

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“…This infiltration of circulating monocytes controls the process of ACAID induction. F4/80 + monocytes eventually migrate to the thymus and spleen where they produce Tregs that impair the induction of cell-mediated immune responses in a systemic manner (Gu et al, 2013;Hsu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Examples of these cells include F4/80 + peritoneal exudate cells cultured with antigen and TGF-b as well as cells recovered from the iris/ciliary body of AC-injected mice (Ashour and Niederkorn, 2006b;Ashour, 2013, 2014). TGF-b in aqueous humor confers immunoregulatory properties and thus could be used in the in vitro model of ACAID instead of using the whole aqueous humor (Gu et al, 2013). The infiltration of the AC by F4/80 + cells causes these cells to be subject to the regulatory effects of TGF-b produced by iris cells or already present in the aqueous humor of the eye.…”

Section: Discussionmentioning

confidence: 99%

The in vivo and in vitro induction of anterior chamber associated immune deviation to myelin antigens in C57BL/6 mice

Farooq

Elkhatib

2014

Brain, Behavior, and Immunity

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FcγRI is required for TGFβ2-treated macrophage-induced tolerance

Cited by 5 publications

References 29 publications

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Attenuation of ventilation-induced diaphragm dysfunction through toll-like receptor 4 and nuclear factor-κB in a murine endotoxemia model

The in vivo and in vitro induction of anterior chamber associated immune deviation to myelin antigens in C57BL/6 mice

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