α1-Antitrypsin is an effector of immunological stasis

Arora, Prince K.; Miller, Harold C.; Aronson, Lawrence D.

doi:10.1038/274589a0

Cited by 87 publications

(29 citation statements)

References 8 publications

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“…AAT did not impair T cell proliferation or acquisition of an activated phenotype (CD25 high CD44 high CD62L low ) [supporting information (SI) Fig. S1] in accord with the reported failure of AAT to bind to T cells (23) or inhibit T cell proliferation (24,25).…”

Section: Resultssupporting

confidence: 62%

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.

154

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: Resultssupporting

confidence: 62%

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.

154

161

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“…Administered to animals, AAT reduced the susceptibility of islets to inflammation and prolonged islet allograft survival (13). Importantly, as reported elsewhere (14) and verified in the present study, AAT treatment allows for IL-2 activity while suppressing inflammation.…”

supporting

confidence: 59%

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

Lewis

Mizrahi²,

Toledano³

et al. 2008

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

175

220

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Human pancreatic islet transplantation offers diabetic patients tight glucose control but has low graft survival rates. The immunosuppressive drugs that are administered to graft recipients lack the antiinflammatory benefits of corticosteroids because of their diabetogenic effects. The serum protease inhibitor ␣1-antitrypsin (AAT) possesses antiinflammatory properties and reduces cytokine-mediated islet damage. In the present study, diabetic mice were grafted with allogeneic islets and treated with AAT monotherapy (n ‫؍‬ 24). After 14 days of treatment, mice remained normoglycemic and islet allografts were functional for up to 120 treatment-free days. After graft removal and retransplantation, mice accepted same-strain islets but rejected third-strain islets, thus confirming that specific immune tolerance had been induced.

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“…As early as 1978, it was reported that AAT does not engage with T lymphocytes, but rather brings along diminished T-cell responsiveness in the context of particular experimental setups in an indirect manner (13). As confirmed in several recent reports, AAT indeed does not interfere with the biological activity of IL-2 (7,8,(10)(11)(12), allowing T cells to release interferon (IFN)-γ and proliferate in an undeterred manner in the presence of IL-2.…”

Section: Cellular Targets Of Aatmentioning

confidence: 56%

“…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. In contrast, responses of purified T lymphocytes are consistently unaffected by AAT (7,8,(10)(11)(12)(13), allowing for a variety of responses to IL-2, as well as to concanav alin A and anti-CD3/CD28 stimulation, to persist. This cell-specific discretion, together with the ability to protect tissues from injury, sets AAT in a unique niche among modulators of the immune system, a separate entity to other antiinflammatory agents and classic immunosuppressants.…”

Section: Introductionmentioning

confidence: 97%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

147

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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α1-Antitrypsin is an effector of immunological stasis

Cited by 87 publications

References 8 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

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

Expanding the Clinical Indications for α1-Antitrypsin Therapy

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