title: 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.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Gou
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC.
authors.forename: David B
authors.initials: DB
authors.lastname: Adams
authors.affiliation: MedStar Georgetown University Hospital, Washington, DC.
authors.forename: Wanxing
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Morgan
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC wangho@musc.edu.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects* / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery*; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D005340:Fibrinogen; D013925:Thromboplastin; D048031:JNK Mitogen-Activated Protein Kinases; D010447:Peptide Hydrolases