Strategies for improving islet transplantation outcome

Abstract

Allogeneic islet transplantation offers the possibility to treat selected patients with brittle Type 1 Diabetes Mellitus (T1DM). Limited availability of islets is a major obstacle to the more widespread use of islet transplantation as a therapy for the majority of patients with T1DM. This is exacerbated by extensive islet cell death during the early post transplantation period, which increases the number of islets required to achieve insulin independence. Additionally, disturbances to normal islet architecture and morphology, as well as suboptimal vascular engraftment during the post transplantation period, contribute to the long term decline in graft function. As well as substantial stresses to the islets during the post transplantation period, functional p-cell mass is lost during pre-transplant culture, further contributing to the inefficient use of valuable donor islets. Mesenchymal Stem Cells (MSCs) secrete a number of soluble trophic factors to affect neighbouring cells, making them excellent candidates for improving the survival of islet cells during culture and after transplantation. The overall aims of the studies described in this thesis were to investigate strategies to improve islet transplantation outcome. Using a syngeneic minimal islet mass model, it was demonstrated that MSC co-transplantation improved the rate and number of streptozotocin-induced diabetic mice attaining normoglycaemia by one month. The beneficial influence of MSCs was attributed to the maintenance of normal islet size and morphology, as well as increased rate and overall extent of islet revascularisation. Additional studies demonstrated that dispersing islets beneath the kidney capsule of diabetic mice produced superior transplantation outcome to that of islets which were implanted as a single pellet, confirming the importance of maintaining normal islet size and morphology at the implantation site.

Date of Award	May 2012
Original language	English
Awarding Institution	King's College London
Supervisor	Aileen King (Supervisor) & Peter Jones (Supervisor)