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.

Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model

“…Furthermore, it is established that early inflammatory events accelerate detrimental host responses and fibrotic reactions, thus modulation of local inflammatory processes during early engraftment should lead to decreased adaptive responses. When compared to soluble anti‐inflammatory approaches, such as TNF‐α inhibitors, IL‐1 receptor antagonists, and anti‐tissue factor, the use of polymeric grafting is appealing, as this strategy imparts similar trends in positive islet engraftment but avoids the side effects associated with the systemic delivery of anti‐inflammatory agents …”

“…6 This innate response leads to substantial cell damage and loss during engraftment, with resulting stress signals and cellular debris potentiating adaptive immune response. The addition of systemic anti-inflammatory agents, such as TNF-α inhibitors (eg, etanercept and infliximab), IL-1 receptor antagonists (eg, anakinra), and others, improves islet engraftment and survival [11][12][13][14][15][16][17][18][19] ; however, increasing the drug regimen in CIT patients is not desirable.…”

Alpha-1-antitrypsin in cell and organ transplantation

“…Many islets gathered for transplantation perish from ischemia and other biologic insults that may begin in the donor, increase during recovery of the pancreas, progress through purification and culture of the islets, then continue posttransplantation until a new blood supply develops 35, 36, 37, 38. Poor survival of donor islets has imperiled clinical deployment of islet transplantation because multiple donors are required to render a single recipient diabetes‐free.…”

“…Poor survival of donor islets has imperiled clinical deployment of islet transplantation because multiple donors are required to render a single recipient diabetes‐free. An “immediate blood‐mediated inflammatory reaction” upon reperfusion of islets is mediated at least in part by increased release of the pro‐coagulant “tissue factor” and activation of extracellular protease cascades, which can be inhibited by AAT 35, 37. The massive, clinically unacceptable loss of islets due first to cell death, then to inflammation and thrombosis in the peritransplant period sensitize the host and are exacerbated by the inability to achieve tolerance.…”

Anti‐inflammaging effects of human alpha‐1 antitrypsin

“…First, application of hAAT has been shown to alleviate symptoms in many disease models whereby immunity and inflammation were implicated, such as type 1 diabetes (Lu et al ., 2006; Zhang et al ., 2007; Ma et al ., 2010), islet cell transplantation (Lewis et al ., 2008), rheumatoid arthritis (Grimstein et al ., 2010, 2011), stroke (Moldthan et al ., 2014), and bone loss (Cao et al ., 2011). A recent study indicated AAT treatment inhibited instant blood‐mediated inflammatory reaction (IBMIR) and islet apoptosis after islet cell transplantation (Wang et al ., 2017). In addition, human AAT suppresses TNF and MMP‐12 production and enhances IL‐10 secretion in macrophages by increasing cAMP levels and activating cAMP‐dependent protein kinase A (Churg et al ., 2007; Janciauskiene et al ., 2007; Subramaniyam et al ., 2008).…”