Alpha-1-Antitrypsin and a Broad Spectrum Metalloprotease Inhibitor, RS113456, Have Similar Acute Anti-Inflammatory Effects

Churg, Andrew; Dai, Jing; Zay, Katalin; Karsan, Aly; Hendricks, Richard; Yee, Calvin; Martin, Robert L.; Mackenzie, Rebecca B.; Xie, Changshi; Zhang, Li; Shapiro, Stuart Z.; Wright, Joanne L.

doi:10.1038/labinvest.3780324

Cited by 139 publications

(116 citation statements)

References 28 publications

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“…Proinflammatory responses can indirectly, but powerfully, influence the commitment of Ag-activated T cells to various protective (Treg) or cytopathic phenotypes (Th1, Th2, Th17) and proinflammatory cytokines directly create ␤ cell damage and insulin resistance. To test this hypothesis, we treated new-onset overtly diabetic mice with a short course of human AAT, an acute-phase reactant with serine proteinase inhibitor (28, 29) and antiinflammatory and antiapoptotic effects (18)(19)(20)(21)(22)29). Because serum levels of AAT rise sharply in response to inflammation (30), we speculate that the function of AAT is to limit the duration and magnitude of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Adverse inflammation in muscle and fat causes faulty insulin signaling and insulin resistance (16) in type 2 diabetes mellitus (13) and, as recently shown, T1DM (7,17). Hence, we have tested the hypothesis that treatment with AAT, an acutephase reactant with known antiinflammatory and antiapoptotic effects (18)(19)(20)(21) including effects on islets (21,22), is effective in NOD mice with overt new-onset T1DM. In short, we are probing the hypothesis that inflammatory mechanisms trigger T1DM.…”

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confidence: 99%

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Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

Koulmanda¹,

Bhasin

Hoffman

et al. 2008

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

153

161

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Invasive insulitis is a destructive T cell-dependent autoimmune process directed against insulin-producing ␤ cells that is central to the pathogenesis of type 1 diabetes mellitus (T1DM) in humans and the clinically relevant nonobese diabetic (NOD) mouse model. Few therapies have succeeded in restoring long-term, drug-free euglycemia and immune tolerance to ␤ cells in overtly diabetic NOD mice, and none have demonstrably enabled enlargement of the functional ␤ cell mass. Recent studies have emphasized the impact of inflammatory cytokines on the commitment of antigen-activated T cells to various effector or regulatory T cell phenotypes and insulin resistance and defective insulin signaling. Hence, we tested the hypothesis that inflammatory mechanisms trigger insulitis, insulin resistance, faulty insulin signaling, and the loss of immune tolerance to islets. We demonstrate that treatment with ␣1-antitrypsin (AAT), an agent that dampens inflammation, does not directly inhibit T cell activation, ablates invasive insulitis, and restores euglycemia, immune tolerance to ␤ cells, normal insulin signaling, and insulin responsiveness in NOD mice with recent-onset T1DM through favorable changes in the inflammation milieu. Indeed, the functional mass of ␤ cells expands in AAT-treated diabetic NOD mice.autoimmunity ͉ type 1 diabetes ͉ inflammation A destructive T cell-dependent autoimmune process directed against insulin-producing ␤ cells causes type 1 diabetes mellitus (T1DM) in humans and the nonobese diabetic (NOD) mouse model (1, 2). Although many therapeutic interventions, including viral-mediated gene transfer of human ␣1-antitrypsin (AAT) (3), can prevent T1DM or resolve the T cell-rich, ␤ cell-invasive insulitis lesion in prediabetic hosts, surprisingly few therapies have succeeded in restoring long-term drug-free euglycemia and immune tolerance to ␤ cells in overtly diabetic NOD mice (4-8). Although each of these successful therapies directly targets T cells, each bears an element that may dampen proinflammatory responses or their consequences upon target tissues.Inflammatory cytokines direct the commitment of antigenactivated CD4 ϩ T cells to specific effector or Foxp3ϩ regulatory phenotypes (9-11). In addition, islets are sensitive to proinflammatory cytokines (12-15). Adverse inflammation in muscle and fat causes faulty insulin signaling and insulin resistance (16) in type 2 diabetes mellitus (13) and, as recently shown, T1DM (7,17). Hence, we have tested the hypothesis that treatment with AAT, an acutephase reactant with known antiinflammatory and antiapoptotic effects (18-21) including effects on islets (21,22), is effective in NOD mice with overt new-onset T1DM. In short, we are probing the hypothesis that inflammatory mechanisms trigger T1DM. Results AAT Does Not Inhibit T Cell Activation.Purified carboxyfluorescein diacetate succinmidyl ester (CFSE)-labeled C57BL/6 mouse T cells were stimulated with plate-bound anti-CD3 plus soluble anti-CD28 mAbs. AAT did not impair T cell proliferation or acquisition of an ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

Koulmanda¹,

Bhasin

Hoffman

et al. 2008

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

153

161

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“…Transcription factor NF-kB has been reported to control MMP-12 gene expression (Churg et al, 2001). Thus, we examined the localization of NF-kB in nuclear and cytyosolic fractions from A431 cells to determine whether or not NF-kB was involved in regulating MMP-12 gene expression.…”

Section: Egf Induced Nuclear Translocation Of Nf-kb Subunits P65 and mentioning

confidence: 99%

Fucosyltransferase IV Enhances Expression of MMP-12 Stimulated by EGF via the ERK1/2, p38 and NF-kB Pathways in A431Cells

Yang¹,

Liu²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…20 Churg et al recently have demonstrated that human alpha-1 antitrypsin (hAAT) can suppress silicainduced PMN influx into the lung and macrophage inflammatory protein-2 (MIP-2) and monocyte chemotactic protein-1 (MCP-1) gene expression. 21 Human AAT also partially suppressed nuclear transcription factor-kB (NF-kB) translocation and increased the levels of inhibitor of NF-kB (I-kB). 21 It has also been demonstrated that adenovirus-mediated AAT gene transfer can significantly decrease neointimal formation after mechanical dilation, and reverses the local inflammation that characterizes viral controls.…”

Section: Introductionmentioning

confidence: 99%

Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice

et al. 2004

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Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic b cells. Although the exact immunologic processes underlying this disease are unclear, increasing evidence suggests that immunosuppressive, immunoregulatory and anti-inflammatory agents can interrupt the progression of the disease. Alpha 1 antitrypsin (AAT) is a multifunctional serine proteinase inhibitor (serpin) that also displays a wide range of anti-inflammatory properties. To test the ability of AAT to modulate the development of type I diabetes, we performed a series of investigations involving recombinant adeno-associated virus vector (rAAV)-mediated gene delivery of human alpha-1 antitrypsin (hAAT) to nonobese diabetic (NOD) mice. Recombinant AAV-expressing hAAT (rAAV2-CB-AT) was administered intramuscularly to 4-week-old female NOD mice (1 Â 10 10 i.u./mouse). A single injection of this vector reduced the intensity of insulitis, the levels of insulin autoantibodies, and the frequency of overt type I diabetes (30% (3/10) at 32 weeks of age versus 70% (7/10) in controls). Transgene expression at the injection sites was confirmed by immunostaining. Interestingly, antibodies against hAAT were present in a majority of the vector-injected mice and circulating hAAT was undetectable when assessed 10 weeks postinjection. This study suggests a potential therapeutic role for AAT in preventing type I diabetes as well as the ability of AAV gene therapy-based approaches to ameliorate disease effectively.

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Alpha-1-Antitrypsin and a Broad Spectrum Metalloprotease Inhibitor, RS113456, Have Similar Acute Anti-Inflammatory Effects

Cited by 139 publications

References 28 publications

Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

Fucosyltransferase IV Enhances Expression of MMP-12 Stimulated by EGF via the ERK1/2, p38 and NF-kB Pathways in A431Cells

Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice

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