α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation

Abecassis, Avishag; Schuster, Ronen; Shahaf, Galit; Ozeri, Eyal; Green, Ross; Ochayon, David E.; Rider, Peleg; Lewis, Eli C.

doi:10.1038/cmi.2014.17

Cited by 40 publications

(35 citation statements)

References 54 publications

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“…In clinical practice, islets are transplanted into the liver by portal vein infusion. The major difference between these two methods is that in portal vein infusion, islets are directly exposed to blood after transplantation, which leads to IBMIR, a thrombotic/inflammatory reaction mediated by the innate immune system (17–19). IBMIR involves activation of the coagulation cascade and the inflammatory pathway and eventually leads to clot formation and infiltration of leukocytes into the islets that cause islet destruction and failure of engraftment (20).…”

Section: Introductionmentioning

confidence: 99%

“…Although the protective effect of AAT in the kidney capsule islet transplantation model has been reported (13,14,16,17,27), whether AAT protects intrahepatic islet grafts that mimic the clinical islet transplantation setting remains unknown. The focus of this study was to evaluate the effect of AAT on IBMIR-induced islet death and understand the molecular mechanisms of the anti-inflammatory effects of AAT.…”

Section: Introductionmentioning

confidence: 99%

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α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

et al. 2017

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Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β-cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline. AAT suppressed blood-mediated coagulation pathways by diminishing tissue factor production, reducing plasma thrombin-antithrombin complex levels and fibrinogen deposition on islet grafts, which correlated with less graft damage and apoptosis. AAT-treated mice showed reduced serum tumor necrosis factor-α levels, decreased lymphocytic infiltration, and decreased nuclear factor (NF)-κB activation compared with controls. The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-terminal kinase (JNK) phosphorylation. Blocking JNK activation failed to further reduce cytokine-induced apoptosis in β-cells. Taken together, AAT significantly improves islet graft survival after intraportal islet transplantation by mitigation of coagulation in IBMIR and suppression of cytokine-induced JNK and NF-κB activation. AAT-based therapy has the potential to improve graft survival in human islet transplantation and other cellular therapies on the horizon.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

et al. 2017

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“…Its release from macrophage cells was most apparent in M1-like macrophages [83]. Added to cultures and tested in animal models, AAT is further suggested to drive macrophages towards an M2-like profile, as indicated by increased efferocytosis [84], increased IL-1Ra secretion [85] and reduced TNFα production [17]. Each immunological setting must, however, be appreciated in its larger context, especially in light of the highly differential conditions which exist in any experimental tumor response against cancer cells.…”

Section: Cancer and Circulating Aat: Is There An Apparent Association?mentioning

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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“…Many effects of AAT may involve inhibition of proteases produced by 1 cell that act on adjacent cells and/or inhibition of protease‐activated receptors. Together with intracellular effects, these membrane effects likely contribute to a net decrease in cytokines that favor sensitization, such as IL‐1, TNFα, IL‐6, and IL‐32, while promoting tolerance by preserving transforming growth factor‐β and increasing IL‐10 and IL‐1 receptor antagonist 4, 6, 7, 24, 25, 26, 27, 28. These effects likely contribute to the induction of regulatory T cells (Tregs) that promote allograft survival 6, 7, 9, 25, 26, 27, 28.…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

Alpha-1-antitrypsin in cell and organ transplantation

Berger

Liu

Uknis

et al. 2018

American Journal of Transplantation

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Limited availability of donor organs and risk of ischemia‐reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha‐1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma–derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT‐deficient individuals. Accumulating evidence suggests that AAT has additional anti‐inflammatory and tissue‐protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro‐ vs anti‐inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune‐modulatory effects of AAT and its well‐established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.

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α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation

Cited by 40 publications

References 54 publications

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

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

Alpha-1-antitrypsin in cell and organ transplantation

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