The Fate of Allogeneic Pancreatic Islets following Intraportal Transplantation: Challenges and Solutions

Abstract

Pancreatic islet transplantation as a therapeutic option for type 1 diabetes mellitus is gaining widespread attention because this approach can restore physiological insulin secretion, minimize the risk of hypoglycemic unawareness, and reduce the risk of death due to severe hypoglycemia. However, there are many obstacles contributing to the early mass loss of the islets and progressive islet loss in the late stages of clinical islet transplantation, including hypoxia injury, instant blood-mediated inflammatory reactions, inflammatory cytokines, immune rejection, metabolic exhaustion, and immunosuppression-related toxicity that is detrimental to the islet allograft. Here, we discuss the fate of intrahepatic islets infused through the portal vein and propose potential interventions to promote islet allograft survival and improve long-term graft function.

Figure 1

Time frame of detrimental factors leading to early injury and late loss of function after islet transplantation is shown. Massive tissue loss due to IBMIR early during transplantation reduces successful engraftment. Islets endure a severely hypoxic environment in the first several days and rely only on passive oxygen diffusion for survival.

Figure 2

Coagulation, complement, and immune cells interact to orchestrate IBMIR, the primary cause of early massive loss of transplanted islets. Figure modified from Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1030.

Figure 3

(a) The three-signal pattern of T lymphocytes activated in islet allotransplantation. Action targets and brief mechanisms are displayed. (b) Current immunosuppressive protocol commonly used in clinical islet transplantation associated with improved long-term islet allograft survival.