Interleukin-1 Receptor Antagonist Enhances Islet Engraftment Without Impacting Serum Levels of Nitrite or Osteopontin

Hsu, Brend Ray‐Sea; Fu, Shin-Huei; Hsu, Su-Ting; Chen, S.-T.

doi:10.1016/j.transproceed.2008.10.099

Cited by 8 publications

(7 citation statements)

References 18 publications

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“…However, quite notably, IL1Ra levels exhibited a 3.1-fold rise in the hAAT group. The induction of IL-1Ra, the naturally occurring endogenous inhibitor of IL-1, by hAAT was reported by others in other experimental setups (17,76), and the role of IL-1Ra in IL-1 blockade and islet protection has had a recent surge in reports (12,(77)(78)(79). These changes may have influenced the outcome of macrophage stimulation.…”

Section: Discussionmentioning

confidence: 73%

α-1-Antitrypsin Gene Delivery Reduces Inflammation, Increases T-Regulatory Cell Population Size and Prevents Islet Allograft Rejection

Shahaf

Moser

Ozeri

et al. 2011

Mol Med

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Antiinflammatory clinical-grade, plasma-derived human α-1 antitrypsin (hAAT) protects islets from allorejection as well as from autoimmune destruction. hAAT also interferes with disease progression in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis (CIA) mouse models. hAAT increases IL-1 receptor antagonist expression in human mononuclear cells and T-regulatory (Treg) cell population size in animal models. Clinical-grade hAAT contains plasma impurities, multiple hAAT isoforms and various states of inactive hAAT. We thus wished to establish islet-protective activities and effect on Treg cells of plasmidderived circulating hAAT in whole animals. Islet function was assessed in mice that received allogeneic islet transplants after mice were given hydrodynamic tail-vein injection with pEF-hAAT, a previously described Epstein-Barr virus (EBV) plasmid construct containing the EBV nuclear antigen 1 (EBNA1) and the family of repeat EBNA1 binding site components (designated "EF") alongside the hAAT gene. Sera collected from hAAT-expressing mice were added to lipopolysaccharide (LPS)-stimulated macrophages to assess macrophage responsiveness. Also, maturation of peritoneal cells from hAAT-expressing mice was evaluated. hAAT-expressing mice accepted islet allografts (n = 11), whereas phosphate-buffered saline-injected animals (n = 11), as well as mice treated with truncated-hAAT-plasmid (n = 6) and untreated animals (n = 20) rapidly rejected islet allografts. In hAAT-expressing animals, local Treg cells were abundant at graft sites, and the IL-1 receptor antagonist was elevated in grafts and circulation. Sera from hAAT-expressing mice, but not control mice, inhibited macrophage responses. Finally, peritoneal cells from hAAT-expressing mice exhibited a semimature phenotype. We conclude that plasmid-derived circulating hAAT protects islet allografts from acute rejection, and human plasma impurities are unrelated to islet protection. Future studies may use this in vivo approach to examine the structure-function characteristics of the protective activities of AAT by manipulation of the hAAT plasmid.

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Section: Discussionmentioning

confidence: 73%

α-1-Antitrypsin Gene Delivery Reduces Inflammation, Increases T-Regulatory Cell Population Size and Prevents Islet Allograft Rejection

Shahaf

Moser

Ozeri

et al. 2011

Mol Med

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“…Transduction of human islets with the naturally occurring antagonist of IL-1 receptor (IL-1RA) by adenovirus protected them from formation of IL-1–induced nitric oxide (NO), functional inhibition, and apoptosis (17,18). Delivery of IL-1RA to rat islets resulted in increased β-cell replication in vitro and in vivo after transplantation into rats made diabetic with streptozotocin (19,20). In T1D patients, short-term administration of human IL-1RA (Anakinra) that antagonizes binding of IL-1β and IL-1α (21,22) resulted in decreased levels of circulating IL-8, downregulation of CD11b on monocytes, and upregulation of IL-8 receptor CXCR1, suggesting that IL-1RA may influence trafficking of monocytes (23).…”

mentioning

confidence: 99%

Synergistic Reversal of Type 1 Diabetes in NOD Mice With Anti-CD3 and Interleukin-1 Blockade

et al. 2011

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Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F(ab′)2 fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti–IL-1β mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL-4, and interferon (IFN)-γ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-V7+ T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-γ, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation.

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“…We were able to demonstrate that intragraft host-IL-1β expression was significantly reduced in the presence of hAAT, a change that favors islet survival [22], [38], [39], [40], [41], and that host-CD14 transcripts were reduced, reflecting, most likely, reduced host monocytic infiltration. Similarly, we found that graft-derived MCP-1 expression declined, a change shown to be beneficial in human islet transplantation [42].…”

Section: Discussionmentioning

confidence: 81%

Pancreatic Islet Xenograft Survival in Mice Is Extended by a Combination of Alpha-1-Antitrypsin and Single-Dose Anti-CD4/CD8 Therapy

et al. 2013

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Clinical pancreatic islet transplantation is under evaluation for the treatment of autoimmune diabetes, yet several limitations preclude widespread use. For example, there is a critical shortage of human pancreas donors. Xenotransplantation may solve this problem, yet it evokes a rigorous immune response which can lead to graft rejection. Alpha-1-antitrypsin (AAT), a clinically available and safe circulating anti-inflammatory and tissue protective glycoprotein, facilitates islet alloimmune-tolerance and protects from inflammation in several models. Here, we examine whether human AAT (hAAT), alone or in combination with clinically relevant approaches, achieves long-term islet xenograft survival. Rat-to-mouse islet transplantation was examined in the following groups: untreated (n = 6), hAAT (n = 6, 60–240 mg/kg every 3 days from day −10), low-dose co-stimulation blockade (anti-CD154/LFA-1) and single-dose anti-CD4/CD8 (n = 5–7), either as mono- or combination therapies. Islet grafting was accompanied by blood glucose follow-up. In addition, skin xenografting was performed in order to depict responses that occur in draining lymph nodes. According to our results hAAT monotherapy and hAAT/anti-CD154/LFA-1 combined therapy, did not delay rejection day (11–24 days untreated vs. 10–22 day treated). However, host and donor intragraft inflammatory gene expression was diminished by hAAT therapy in both setups. Single dose T-cell depletion using anti-CD4/CD8 depleting antibodies, which provided 14–15 days of reduced circulating T-cells, significantly delayed rejection day (28–52 days) but did not achieve graft acceptance. In contrast, in combination with hAAT, the group displayed significantly extended rejection days and a high rate of graft acceptance (59, 61, >90, >90, >90). In examination of graft explants, marginal mononuclear-cell infiltration containing regulatory T-cells predominated surviving xenografts. We suggest that temporal T-cell depletion, as in the clinically practiced anti-thymocyte-globulin therapy, combined with hAAT, may promote islet xenograft acceptance. Further studies are required to elucidate the mechanism behind the observed synergy, as well as the applicability of the approach for pig-to-human islet xenotransplantation.

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Interleukin-1 Receptor Antagonist Enhances Islet Engraftment Without Impacting Serum Levels of Nitrite or Osteopontin

Cited by 8 publications

References 18 publications

α-1-Antitrypsin Gene Delivery Reduces Inflammation, Increases T-Regulatory Cell Population Size and Prevents Islet Allograft Rejection

α-1-Antitrypsin Gene Delivery Reduces Inflammation, Increases T-Regulatory Cell Population Size and Prevents Islet Allograft Rejection

Synergistic Reversal of Type 1 Diabetes in NOD Mice With Anti-CD3 and Interleukin-1 Blockade

Pancreatic Islet Xenograft Survival in Mice Is Extended by a Combination of Alpha-1-Antitrypsin and Single-Dose Anti-CD4/CD8 Therapy

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