Liver Ischemia Contributes to Early Islet Failure Following Intraportal Transplantation: Benefits of Liver Ischemic-Preconditioning

Abstract

Early graft failure following intraportal islet transplantation (IPIT) represents a major obstacle for successful islet transplantation. Here, we examined the role of islet emboli in the induction of early graft failure and utilized a strategy of ischemic-preconditioning (IP) to prevent early islet destruction in a model of syngeneic IPIT in STZ-induced diabetic mice. Numerous focal areas of liver necrosis associated with the islet emboli were observed within 24 h post-IPIT. Pro-inflammatory cytokines, IL-1b and IL-6, were significantly increased 3 h after IPIT, while TNF-a was elevated for up to 5 days post-IPIT. Caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells were observed in the transplanted islets trapped in areas of necrotic liver at 3 h and 1 day post-IPIT. Hyperglycemia was corrected immediately following IPIT of 200 islets, but recurrence of hyperglycemia was observed within 14 days associated with a poor response to glucose challenge. IP, a procedure of pre-exposure of the liver to transient ischemia and reperfusion, protected the liver from embolisminduced ischemic injury and prevented early islet graft failure. These data suggest that islet embolism in the portal vein is a major cause of functional loss following IPIT that can be prevented by liver IP.

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

“…As demonstrated in several studies (52)(53)(54), the supply of oxygen in both the early posttransplant period and long-term is largely limited at the intraportal transplantation site, but is nevertheless crucial for islet survival and function. Islets exposed to chronic hypoxia are especially susceptible to hypoxia-mediated inflammatory reactions, oxidative stress, and apoptosis.…”

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

“…However, 50-75% of islets fail to engraft at an early phase, representing a major impediment for successful IPIT (Yin et al, 2006). Alloantigen-specific immune-mediated destruction is one of the causes for early islet failure, but nonspecific inflammatory or innate immune response may be more important as shown in a syngeneic mouse model system where approximately 30% of the islets lose their function by day 1 of transplantation (Yin et al, 2006) and as high as 60% by day 3 (Biarnés et al, 2002). In a pig model 50% of islets were destroyed within 20 min after IPIT (Eich et al, 2007).…”

Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts

“…The long-term success of human islet transplants has been limited, however, with 75% of patients who achieved insulin independence requiring insulin within 2 years posttransplant (1). Although immune rejection of islet allografts certainly plays a role in graft failure, nonimmune-mediated beta cell loss is also likely to play an important role (2)(3)(4)(5)(6).…”