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

Abstract

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.

• Authors: Jingjing Wang, Zhen Sun, Wenyu Gou, David B Adams, Wanxing Cui, Katherine A Morgan, Charlie Strange, Hongjun Wang
• Journal: Diabetes (Diabetes) Vol. 66 Issue 4 Pg. 970-980 (04 2017) ISSN: 1939-327X [Electronic] United States
• PMID: 28069642 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• Blood Glucose
• Cytokines
• NF-kappa B
• Serine Proteinase Inhibitors
• Tumor Necrosis Factor-alpha
• alpha 1-Antitrypsin
• antithrombin III-protease complex
• Antithrombin III
• Fibrinogen
• Thromboplastin
• JNK Mitogen-Activated Protein Kinases
• Peptide Hydrolases

Topics

• Animals
• Antithrombin III (drug effects, metabolism)
• Apoptosis (drug effects, immunology)
• Blood Glucose (metabolism)
• Cell Death (drug effects)
• Cytokines (drug effects, immunology)
• Diabetes Mellitus, Experimental (metabolism, surgery)
• Fibrinogen (drug effects, metabolism)
• Graft Survival (drug effects, immunology)
• Humans
• Inflammation (immunology)
• Insulin-Secreting Cells (drug effects)
• Islets of Langerhans (drug effects, immunology, metabolism)
• Islets of Langerhans Transplantation
• JNK Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Mice
• NF-kappa B (drug effects, immunology)
• Peptide Hydrolases (drug effects, metabolism)
• Phosphorylation (drug effects)
• Serine Proteinase Inhibitors (pharmacology)
• Thromboplastin (drug effects, metabolism)
• Transplantation, Heterologous
• Transplantation, Homologous
• Tumor Necrosis Factor-alpha (drug effects, immunology)
• alpha 1-Antitrypsin (pharmacology)