Acute Phase Protein α1-Antitrypsin Reduces the Bacterial Burden in Mice by Selective Modulation of Innate Cell Responses

Kaner, Ziv; Ochayon, David E.; Shahaf, Galit; Baranovski, Boris M.; Bahar, N.; Mizrahi, Mark; Lewis, Eli C.

doi:10.1093/infdis/jiu620

Cited by 52 publications

(36 citation statements)

References 48 publications

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“…[21] Concomitantly, AAT has been demonstrated to directly bind IL-8, [22] and danger-associated molecular pattern molecules (DAMPs), such as extracellular heat shock protein (HSP) 70 [23] and gp96, [24] which otherwise act as adjuvants to the associated immune responses. [25,26] Surprisingly, the anti-inflammatory qualities of AAT still allow innate immune cells to respond to authentic threats; macrophages readily phagocytose bacteria, neutrophils decontaminate infected sites, [27] and antigen-loaded dendritic cells migrate to draining lymph nodes. [18] T lymphocytes, on the other hand, respond to AAT-rich environment indirectly, pending stimulation from innate immunocytes.…”

Section: Aat Modulates Inflammation and Immune Responsesmentioning

confidence: 99%

“…[25,30] Indeed, it has been suggested that the reduction in bacterial burden, as depicted in CF patients for instance, [31] during treatment with AAT may relate to enhanced anti-pathogen immune responses; at the same time, local tissues are spared from inappropriate excessive injury that might promote deleterious adaptive responses by elevating the levels of local DAMPs. [27,32,33] 1.4. The biochemical activities of AAT extend beyond serine-protease inhibition As our appreciation of these multiple functions of AAT grew, it became apparent that we may have to consider the possibility that AAT exerts at least some of its attributes irrespective of its capacity to inhibit serine-proteases.…”

Section: Aat Modulates Inflammation and Immune Responsesmentioning

confidence: 99%

“…[70][71][72] This apparent contradiction was further explored in several pulmonary and extra-pulmonary animal models, all of which suggested an anti-bacterial property of AAT in vivo. [27,31,73] The first patent to describe the use of AAT for the treatment of bacterial infection was published in 2005, [74] describing the administration of AAT as a means of protection from and treatment of mycobacterial infection. On this ground, one patent application was published in 2012 and two in 2014, all of which describe the construct of an AAT-Fc fusion molecule, already known to be anti-inflammatory and cytoprotective, [43,44,54] to treat and prevent mycobacterial infection.…”

Section: Patents On Reduction Of Bacterial Burdenmentioning

confidence: 99%

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Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Lior

Geyra²,

Lewis

2016

Expert Opinion on Therapeutic Patents

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A molecule no longer patentable per se, presents with novel clinical applications; its mechanism still unfolding. While modified protein sequences are patentable and potentially superior, they are burdened by regulatory setbacks. Thus, recent approaches in the context of AAT appear in patents that describe combinations with other drugs, redefined clinical subclasses, and unique recombinant entities, carefully skirting saturated areas of AAT patentology. It will be fascinating to follow technologies and creative patenting as AAT navigates the trying trades of pharmaceutical industry towards an increasing lineup of unmet clinical needs.

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Section: Aat Modulates Inflammation and Immune Responsesmentioning

confidence: 99%

Section: Aat Modulates Inflammation and Immune Responsesmentioning

confidence: 99%

Section: Patents On Reduction Of Bacterial Burdenmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Lior

Geyra²,

Lewis

2016

Expert Opinion on Therapeutic Patents

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“…AAT may also be expressed by macrophages under particular conditions [12]. Interestingly, inflammatory oxidative bursts neutralize the antiproteolytic function of AAT, allowing activated neutrophils and macrophages to migrate and to exert bacteriocidic functions [13]. Indeed, in the past thirty years, life-long weekly infusions of plasmaderived affinity-purified AAT have become the treatment of choice for AAT deficient individuals [14] and, despite prolonged exposure to excessive circulating AAT and its renowned anti-inflammatory profile, long-term studies indicate that treated patients exhibit an unexpected reduction in bacterial infection rates [1,15].…”

Section: Introductionmentioning

confidence: 99%

Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology

Guttman¹,

Freixo-Lima²,

Lewis³

2016

Integr Cancer Sci Therap

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The acute-phase protein α1-antirypsin (AAT) has recently been suggested to exert beneficial effects in various immune-associated pathologies, such as graftversus-host disease, rheumatoid arthritis, multiple sclerosis and allogeneic transplantation. These effects have been demonstrated to take place through direct immunomodulation of dendritic cells, macrophages, neutrophils and B cells, while allowing, in a yet inexplicable distinction, intact isolated functions of T cells and NK cells. With such a unique discriminatory targeting of immunocytes, AAT drives immune responses simultaneously towards regulation of inflammation and expansion of antigen-specific regulatory T cells (Tregs). Based on this intriguing activity profile, a concern was raised regarding the impact of chronic treatment with human AAT with respect to susceptibility to tumors and to metastatic spread. Tumor development is linked to inflammatory responses in a manner which largely promotes immune evasion. Local innate immunocytes, such as tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs) and the recently appreciated tumor-associated neutrophils (TANs), are considered instrumental in primary tumor survival. This is accomplished in part by the release of growth factors and cytokines, including VEGF, TGFβ, IL-10 and IL-1 receptor antagonist (IL-1Ra), all of which have been demonstrated to be elevated in inflammatory conditions during AAT therapy. While clinical studies report heightened serum AAT levels in patients with a variety of advanced tumors, there is no evidence to point to a particular pro-tumor effect of AAT, and the possibility that its elevation in the blood might represent a meresystemic marker-rather than an accessory to tumor development-is grossly overlooked. Indeed, preclinical studies reveal significant inhibition of tumor development during treatment with AAT, and prolonged follow-up studies of individuals who receive life-long excessive doses of intravenous AAT do not depict a rise in tumor occurrence. Considering the prospect of AAT being indicated for medical indications to individuals with normal levels of the protein, its relation to tumor immunology is of immense importance. We hereby review the current knowledge regarding some possible roles that AAT may play, both locally and systemically, in the delicate and detrimental arena of tumor immunology.

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“…In addition to its role in regulating NE, AAT inhibits the activity of other neutrophilreleased proteases, including proteinase 3, a-defensins, and cathepsin G, and has antiinflammatory and immunomodulatory properties (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Serum deficiency of AAT is associated with an imbalance between proteases and AAT in the lung, leading to slow destruction of the lung parenchyma, a process accelerated by cigarette smoking (1,(3)(4)(5)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

Chiuchiolo

Crystal

2016

Annals ATS

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Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, gene therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs. The focus of this review is to describe the various strategies for AAT gene therapy for the pulmonary manifestations of AAT deficiency and the state of the art in bringing AAT gene therapy to the bedside.

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Acute Phase Protein α1-Antitrypsin Reduces the Bacterial Burden in Mice by Selective Modulation of Innate Cell Responses

Cited by 52 publications

References 48 publications

Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease

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