α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

Ozeri, Eyal; Mizrahi, Mark; Shahaf, Galit; Lewis, Eli C.

doi:10.4049/jimmunol.1101340

Cited by 68 publications

(69 citation statements)

References 56 publications

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“…Animal experiments were approved by the German authority for animal protection (33.9-42502-04-09/1766). The intranasal administrations were performed as previously described (40)(41)(42).…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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215

148

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The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastasedeficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastasedeficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40-to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.is the prototypic member of the serpin superfamily and one of the most abundant serine protease inhibitors in the circulation (1). As an acute-phase protein, AAT is thought to play an important role in limiting host-tissue injury triggered by proteases, particularly neutrophil elastase (NE). The clinical relevance of AAT is highlighted in individuals with inherited deficiency in circulating AAT, who have increased susceptibility to early-onset pulmonary emphysema, liver and pancreatic diseases, and in rare cases to panniculitis and vasculitis (2). It has been assumed that in AAT-deficiency the protease/antiprotease balance is shifted toward NE, which leads to extensive tissue damage, particularly in causing emphysema. Therefore, augmentation of circulating AAT was introduced 25 y ago to treat emphysema patients with severe PiZZ (Glu342Lys) AAT deficiency (3). Because clinical trials of AAT augmentation therapy use historical data as controls, the benefit of AAT therapy for PiZZ patients remains under debate (4-6), although in most cases therapy offers disease stabilization. The uncertainty surrounding the efficacy of augmentation therapy also reflects the incomplete understanding of the properties of the AAT protein, which can be affected by the isolation methods from plasma.Although the a...

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“…Animal experiments were approved by the German authority for animal protection (33.9-42502-04-09/1766). The intranasal administrations were performed as previously described (40)(41)(42).…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

215

148

View full text Add to dashboard Cite

show abstract

“…Dendritic cells and macrophages are modified; dendritic cells become semi-mature (9), a state associated with reduced co-stimulatory abilities, excess IL-10 production and facilitation of antigen-specific Treg expansion (8). Interestingly, Ozeri et al (9) demonstrated that AAT promotes semimature IL-10-producing and readily migrating dendritic cells, allowing the cells to reach the draining lymph nodes and exert their tolerogenic functions. In this study, an intriguing uncoupling of inflammation-mediated elevation in the dendritic cell chemoattractant receptor (CCR7) was observed, whereby AAT appears to have allowed for persistent CCR7 surface expression but had downregulated other dendritic cell inflammatory markers (9).…”

Section: How Are T Cells Affected By Aat Without Being Direct Cellulamentioning

confidence: 99%

“…Interestingly, Ozeri et al (9) demonstrated that AAT promotes semimature IL-10-producing and readily migrating dendritic cells, allowing the cells to reach the draining lymph nodes and exert their tolerogenic functions. In this study, an intriguing uncoupling of inflammation-mediated elevation in the dendritic cell chemoattractant receptor (CCR7) was observed, whereby AAT appears to have allowed for persistent CCR7 surface expression but had downregulated other dendritic cell inflammatory markers (9). Indeed, in the whole animal and, specifically, in lymph nodes during an antigenic event, IL-10 production rises as a consequence of AAT therapy (6-9).…”

Section: How Are T Cells Affected By Aat Without Being Direct Cellulamentioning

confidence: 99%

“…There is a need to develop immune modulating agents that can allow T-cell-mediated graft-versus-leukemia responses while sparing the recipient from an injurious inflammatory and immunological assault. Given the ability of AAT to modify dendritic cells toward a tolerogenic phenotype and to facilitate the expansion of Tregs (6,8,9), together with its potent antiinflammatory profile and outstanding safety record, AAT is an attractive candidate to address acute GVHD. Several lines of evidence support this approach.…”

Section: Graft Versus Host Diseasementioning

confidence: 99%

“…The endogenous inhibitor of IL-1 activity, IL-1 receptor antagonist, is upregulated by AAT in human blood cells (5). Similarly, IL-10 levels have been shown to increase by AAT in various experimental conditions (4,(6)(7)(8)(9). When examining the cellular targets of AAT, one finds that these primarily include members of the innate immune system, such as macrophages and neutrophils, as well as B lymphocytes and dendritic cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

142

108

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α 1 -Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/mL circulating levels. During acute-phase responses, circulating AAT levels increase more than fourfold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema. These individuals are treated with lifelong weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient individuals may interfere with disease progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV), and is currently evaluated in clinical trials for type 1 diabetes, cystic fibrosis and graft versus host disease. Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.

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Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory

et al. 2020

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Regulation of immune function continues to be one of the most well-recognized extraskeletal actions of vitamin D. This stemmed initially from the discovery that antigen presenting cells such as macrophages could actively metabolize precursor 25-hydroxyvitamin D (25D) to active 1,25-dihydroxyvitamin D (1,25D). Parallel observation that activated cells from the immune system expressed the intracellular vitamin D receptor (VDR) for 1,25D suggested a potential role for vitamin D as a localized endogenous modulator of immune function. Subsequent studies have expanded our understanding of how vitamin D exerts effects on both the innate and adaptive arms of the immune system. At an innate level, intracrine synthesis of 1,25D by macrophages and dendritic cells stimulates expression of antimicrobial proteins such as cathelicidin, as well as lowering intracellular iron concentrations via suppression of hepcidin. By potently enhancing autophagy, 1,25D may also play an important role in combatting intracellular pathogens such as M. tuberculosis and viral infections. Local synthesis of 1,25D by macrophages and dendritic cells also appears to play a pivotal role in mediating T-cell responses to vitamin D, leading to suppression of inflammatory T helper (Th)1 and Th17 cells, and concomitant induction of immunotolerogenic Tregulatory responses. The aim of this review is to provide an update on our current understanding of these prominent immune actions of vitamin D, as well as highlighting new, less well-recognized immune effects of vitamin D. The review also aims to place this mechanistic basis for the link between vitamin D and immunity with studies in vivo that have explored a role for vitamin D supplementation as a strategy for improved immune health. This has gained prominence in recent months with the global coronavirus disease 2019 health crisis and highlights important new objectives for future studies of vitamin D and immune function.

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α-1 Antitrypsin Promotes Semimature, IL-10–Producing and Readily Migrating Tolerogenic Dendritic Cells

Cited by 68 publications

References 56 publications

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory

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