Advancing islet transplantation: from engraftment to the immune response

Abstract

The promise and progress of islet transplantation for treating type 1 diabetes has been challenged by obstacles to patient accessibility and long-term graft function that may be overcome by integrating emerging technologies in biomaterials, drug delivery and immunomodulation. The hepatic microenvironment and traditional systemic immunosuppression stress the vulnerable islets and contribute to the limited success of transplantation. Locally delivering extracellular matrix proteins and trophic factors can enhance transplantation at extrahepatic sites by promoting islet engraftment, revascularisation and long-term function while avoiding unintended systemic effects. Cell- and cytokine-based therapies for immune cell recruitment and reprogramming can inhibit local and systemic immune system activation that normally attacks transplanted islets. Combined with antigen-specific immunotherapies, states of operational tolerance may be achievable, reducing or eliminating the long-term pharmaceutical burden. Integration of these technologies to enhance engraftment and combat rejection may help to advance the therapeutic efficacy and availability of islet transplantation.

Fig. 1

Timeline of transplanted islet engraftment. Islets require a period of weeks to become engrafted within host tissue. Immediately following implantation, islets are avascular and isolated from host tissue in an inflammatory environment. Islet cells are stressed at this early phase and may undergo anoikis, apoptosis and necrosis as a result of the foreign ECM and inadequate oxygenation and nutrient/waste exchange. ECM remodelling and angiogenesis in the transplant microenvironment and islet tissue are key parts of the islet engraftment process. The figure illustrates and describes the timeline of islet engraftment in host tissue from implantation to long-term maintenance, detailing the changes occurring in the transplant microenvironment and within islets, and challenges to function and survival. The understanding of this process enables the identification of opportunities for enhancing islet engraftment, survival and function throughout the process. These opportunities for enhancement and ways to achieve them are discussed in detail in the article text

Fig. 2

Recipient immune response to transplanted islets. The recipient immune system is activated through the initial surgical trauma and introduction of foreign material. In addition, damage to the islets causes the release of antigen (Ag) into the environment. The innate immune system responds through macrophage and neutrophil activation, causing inflammation in the microenvironment and infiltration of additional immune cells into the graft. Macrophages and neutrophils initiate a cascade through the release inflammatory cytokines and reactive oxygen species that activate the antigen-presenting cells (APCs) and damage the islet. Active APCs activate helper T cells (CD4) that continue to activate cytotoxic T cells (CD8), which destroy the islet. Regulatory T cells maintain APCs and helper T cells in inactive states, preventing the adaptive immune response from destroying the islet. The diagram to the right depicts the timeline and types of infiltrating cells in the graft site following transplantation. A number of interventions aimed at interrupting the immune cascade are listed to the right, and their point of action is indicated by the corresponding numbers on the diagram. These interventions are detailed in the article text