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Title: Immunoisolation approaches for islet transplantation
Author: Kerby, Alan
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2013
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The widespread use of islet transplantation as a treatment for type 1 diabetes is limited in part by the necessity for long term immunosuppression. The principle of immunoisolation is to create a physical barrier surrounding the islets to prevent immune destruction after implantation, therefore removing the requirement for immunosuppression. Alginate microcapsules are the most commonly used immunoisolation device which are typically implanted intraperitoneally. Intraperitoneal microencapsulated islet grafts are suboptimal, requiring at least double the number of islets to reverse hyperglycaemia compared to non-encapsulated islet grafts. The large size of microencapsulated islet grafts also restricts the selection of implantation site. We aimed to determine if the subcutaneous site is a suitable alternative site to the intraperitoneal site for microencapsulated islet grafts. It was discovered that equivalent microencapsulated islet grafts that were efficacious at the intraperitoneal site were ineffective at the subcutaneous site. Helper cells can be used to improve islet transplantation by secreting beneficial factors. L cells produce glucagon-like peptide-1 which is known to have several positive effects on islets. Co-encapsulation of islets with L cells increased islet insulin secretion but did not improve graft outcome. Mesenchymal stem cells (MSCs) can be co-transplanted to improve the graft outcome of non-encapsulated grafts. Islets co-encapsulated with MSCs had improved insulin secretion and also improved graft outcome. Immunoisolation of islets by conformal coating has the potential to maximise the diffusion of vital molecules and minimise the graft volume, enabling transplantation to preferred sites. Using allogeneic islets implanted at the kidney subcapsular site it was found that non-encapsulated grafts rejected whereas a novel conformal coating protected grafts from rejection in 5/7 of recipients. In summary, immunoisolated graft efficacy can be optimised by the selection of site, the use of helper cells, and with a novel conformal coating approach.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available