Physiology of Islet Engraftment

Abstract

Pancreatic islet transplantation is a tempting strategy to treat patients with type 1 diabetes mellitus, since if successful it could provide a cure for the disease. At present, there is, however, a poor long-term outcome of such transplantations compared to the results for whole pancreas transplantation. One explanation for this may be inadequate engraftment of the transplanted cells in the new microenvironment. The engraftment process includes immediate survival in the post transplantation phase. There is likely extensive cell death immediately following transplantation mainly due to inflammatory responses triggered by e.g. hypoxia. Also the long-term survival and function of the transplanted islets is encompassed by the term engraftment. This is influenced by the cellular turn-over rate, and the degree of revascularization and reinnervation of the islet tissue. To regain optimal function in surviving cells, new vascular and nervous systems similar to those in endogenous islets need to form. Both qualitative and quantitative changes compared to endogenous islets have, however, been described in the new vascular system that develops following transplantation, and these changes seem to have consequences for islet blood perfusion, metabolism and function. Comparatively little is known regarding the extent of functional re-growth of nerves that occurs, and its influence on graft function. This review also discusses the challenges of engraftment that seem specific for intraportally transplanted islets, e.g. the instant blood mediated immune reaction, the loss of glucagon response to hypoglycemia, and the lower β-cell proliferation rate in intraportally transplanted islets than in islets grafted to the kidney.

Angiopoietin-1 Production in Islets Improves Islet Engraftment and Protects Islets From Cytokine-Induced Apoptosis

“…It has been estimated that Ͻ30% of transplanted islets can gain stable engraftment despite the infusion of Ͼ10,000 IE/recipient (3,55). This deficiency in islet engraftment appears to ensue in syngeneic and immune-deficient hosts, which is indicative of non-immune-mediated insults to transplanted islets, such as prolonged hypoxia (7,8,12,56) or instant blood-mediated inflammatory reaction (57)(58)(59). Furthermore, these adverse effects are compounded by immunosuppressants, which are shown to compromise the viability, function, and revascularization of newly transplanted islets (60 -63).…”

“…However, only a fraction of implanted islets (Ͻ30% islet mass) can survive and become engrafted (1)(2)(3)(4)(5)(6). In addition to immune rejection, the rate and extent of islet revascularization has been viewed as a significant factor that may contribute to the loss of functional islet mass posttransplantation (7,8). Unlike whole-organ transplantation in which grafts are implanted as vascularized tissue and intragraft blood flow is readily resumed posttransplantation, islets are transplanted as single islets or islet clusters, which are considered avascular after collagenase digestion, a relatively harsh procedure that severs the arterial and venous connections of islets and presumably damages intraislet endothelium and extracellular matrix of islets.…”