Intradermal α1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease

Ma, Hongxia; Lu, Yuanqing; Li, H.; Campbell-Thompson, Martha; Parker, Matthew; Wasserfall, Clive; Haller, Michael J.; Brantly, ML; Schatz, Desmond; Atkinson, Mark A.; Song, Sihong

doi:10.1007/s00125-010-1829-2

Cited by 42 publications

(33 citation statements)

References 22 publications

(42 reference statements)

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“…Islets are adversely effected by inflammatory cytokines (7). The potential attractiveness of AAT treatment to provide islet cytoprotection is enhanced by observations that short-term AAT treatment restores euglycemia and islet self-tolerance in overtly T1D NOD mice (16) as well as prevents diabetes in NOD mice (17,18). AAT is an antiprotease and it seems reasonable that this activity is central to its antiinflammatory and cytoprotective effects.…”

Section: Discussionmentioning

confidence: 99%

Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival

Koulmanda

Bhasin²,

Fan

et al. 2012

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

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The promise of islet cell transplantation cannot be fully realized in the absence of improvements in engraftment of resilient islets. The marginal mass of islets surviving the serial peritransplant insults may lead to exhaustion and thereby contribute to an unacceptably high rate of intermediate and long-term graft loss. Hence, we have studied the effects of treatment with alpha 1-antitrypsin (AAT) in a syngeneic nonautoimmune islet graft model. A marginal number of syngeneic mouse islets were transplanted into nonautoimmune diabetic hosts and islet function was analyzed in control and AAT treated hosts. In untreated controls, marginal mass islet transplants did not restore euglycemia. Outcomes were dramatically improved by short-term AAT treatment. Transcriptional profiling identified 1,184 differentially expressed transcripts in AAT-treated hosts at 3 d posttransplantation. Systems-biology-based analysis revealed AAT down-regulated regulatory hubs formed by inflammation-related molecules (e.g., TNF-α, NF-κB). The conclusions yielded by the systems-biology analysis were rigorously confirmed by QRT-PCR and immunohistology. These data suggest that short-term AAT treatment of human islet transplant recipients may be worthy of a clinical trial.type 1 diabetes | insulin | nonobese diabetic mice | immune response I n theory, islet transplantation offers great hope for eluding the complications of type 1 diabetes (T1D) or whole-organ pancreas transplantation. However, the clinical application of islet transplantation has been slowed by the inability to use islets from a single donor to restore euglycemia, even short term, in most islet allograft recipients and by the unacceptably high 5 y failure rate even for islet transplants that function at 1 y posttransplantation (1). As a result of nonimmunologic processes, many islets perish during harvest, purification, and shortly following transplantation (2, 3). Moreover, the marked nonimmunologic loss of islets may render the recipient prone to β-cell exhaustion long term (4). A multicenter review of autologous islet transplant outcomes reveals 31% of the autografts lose function within 7 d and 50% of the grafts that function at 7 d lose function within a year (5). Until these potentially linked problems, early nonimmunologic islet cell death, and failure to obtain enduring graft function are resolved, whole-organ transplantation, an intrusive and complication-prone procedure, will remain the transplant of choice because a single whole organ provides islet cell mass, sufficient to control hyperglycemia short and long term.Alpha 1-antitrypsin (AAT), an acute phase reactant serine protease inhibitor with antiinflammatory, antileukocyte migratory, antithrombotic, and antiapoptotic effects (6-9), exerts cytoprotective effects upon islets in vitro (8, 10). As expression of AAT sharply rises in response to inflammation, AAT may function to limit the duration and magnitude of inflammation (11). Furthermore, short-term AAT treatment restores euglycemia and self-tolerance to islets...

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Section: Discussionmentioning

confidence: 99%

Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival

Koulmanda

Bhasin²,

Fan

et al. 2012

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

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“…Moreover, in the autoimmune animal model for type 1 diabetes, the nonobese diabetic (NOD) mouse, AAT levels were half the levels found in the majority of other wildtype mouse strains (96). Indeed, preclinical data show a consistent benefit with AAT in the protection of islets and modification of immune systems across multiple models of diabetes (7,8,10,84,(96)(97)(98). Furthermore, after NOD mice revert to normoglycemia by a 14-d course of AAT, grafted autoreactive β cells are accepted in the animals in the absence of subsequent requirement for exogenous AAT (7).…”

Section: Type 1 Diabetesmentioning

confidence: 99%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

146

115

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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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“…However, it is challenging to control the progress of inflammaging. In several animal models of inflammation related diseases, hAAT has been shown to have remarkable effect on delaying or blocking the onset of diseases or alleviating the symptoms (Ma et al ., 2010; Cao et al ., 2011; Grimstein et al ., 2011; Moldthan et al ., 2014; Akbar et al ., 2016; Elshikha et al ., 2016). In fact, some of them are age‐associated diseases, such as arthritis and osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence indicates that hAAT is a multifunctional protein and may play an important role in modulating the immune system. First, application of hAAT has been shown to alleviate symptoms in many disease models whereby immunity and inflammation were implicated, such as type 1 diabetes (Lu et al ., 2006; Zhang et al ., 2007; Ma et al ., 2010), islet cell transplantation (Lewis et al ., 2008), rheumatoid arthritis (Grimstein et al ., 2010, 2011), stroke (Moldthan et al ., 2014), and bone loss (Cao et al ., 2011). A recent study indicated AAT treatment inhibited instant blood‐mediated inflammatory reaction (IBMIR) and islet apoptosis after islet cell transplantation (Wang et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

Anti‐inflammaging effects of human alpha‐1 antitrypsin

et al. 2017

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SummaryInflammaging plays an important role in most age‐related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha‐1 antitrypsin (hAAT) has immune‐regulatory, anti‐inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti‐inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT‐expressing lines was significantly longer than that of genetically matched controls. To understand the mechanism underlying the anti‐aging effect of hAAT, we monitored the expression of aging‐associated genes and found that aging‐induced expressions of Relish (NF‐ĸB orthologue) and Diptericin were significantly lower in hAAT lines than in control lines. RNA‐seq analysis revealed that innate immunity genes regulated by NF‐kB were significantly and specifically inhibited in hAAT transgenic Drosophila lines. To confirm this anti‐inflammaging effect in human cells, we treated X‐ray‐induced senescence cells with hAAT and showed that hAAT treatment significantly decreased the expression and maturation of IL‐6 and IL‐8, two major factors of senescence‐associated secretory phenotype. Consistent with results from Drosophila, RNA‐seq analysis also showed that hAAT treatment significantly inhibited inflammation related genes and pathways. Together, our results demonstrated that hAAT significantly inhibited inflammaging in both Drosophila and human cell models. As hAAT is a FDA‐approved drug with a confirmed safety profile, this novel therapeutic potential may make hAAT a promising candidate to combat aging and aging‐related diseases.

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Intradermal α1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease

Cited by 42 publications

References 22 publications

Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival

Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Anti‐inflammaging effects of human alpha‐1 antitrypsin

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