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Tolerance to neonatal porcine islet xenografts induced by a combination of monoclonal antibodies Open Access

Descriptions

Other title
Subject/Keyword
Monoclonal antibody
Neonatal porcine islets
Xenotransplantation
Islet transplantation
Tolerance
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Arefanian, Hossein
Supervisor and department
Dr. Gina R. Rayat (Surgery)
Examining committee member and department
Dr. Gregory S. Korbutt (Surgery)
Dr. Catherine J. Field (Food & Nutritional Science)
Dr. Ray V. Rajotte (Surgery)
Dr. Bernhard J. Hering (Surgery, University of Minnesota)
Department
Department of Surgery
Specialization

Date accepted
2009-08-14T16:22:52Z
Graduation date
2009-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Islet transplantation is a more physiological way to treat type 1 diabetes. However, shortage of donor tissue and chronic administration of immune suppressive drugs has limited the widespread application of this therapy for all patients with type 1 diabetes, particularly children suffering from this disease. Xenogeneic islet transplantation particularly neonatal porcine islets (NPI) holds promise for clinical transplantation because of the potentially unlimited supply of islets. New evidence suggests that monoclonal antibodies (mAbs) specific for immune cell surface molecules could be employed in the prevention of islet graft rejection as well as induction of immunological tolerance to the transplanted grafts without the need for continuous administration of harmful immune suppressive drugs. It was shown by our group that short-term administrations of a combination of anti-LFA-1 and anti-CD154 mAbs which targets both adhesion and costimulatory pathways of T cell activation, is highly effective in preventing NPI xenograft rejection. In this thesis, we determined whether short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs could induce tolerance to NPI xenografts. Our data show that this combination of mAbs can induce dominant, species and tissue specific tolerance to NPI xenografts which is mediated by regulatory T cells in non-autoimmune prone B6 mice. We also found that T cell subsets such as CD4+ and CD8+ T cells as well as antigen presenting cells (APC) play an important role in the induction and maintenance of tolerance to NPI xenografts. In addition we found that PD-1/PDL interaction is important for induction and maintenance of tolerance to NPI xenografts. Finally, we found that this combined mAb therapy was effective in preventing NPI xenografts rejection in autoimmune prone NOD mice when it was combined with anti-CD4 mAb. It is may hope that the research presented in this thesis will provide insight into the nature of the immune responses to xenogeneic islet transplantation in humans and aid in the development of effective, tolerance inducing therapies, so that patients with T1DM will once again know a life free from their disease.
Language
English
DOI
doi:10.7939/R3RD8V
Rights
License granted by Hossein Arefanian (ha1@ualberta.ca) on 2009-08-13T21:10:52Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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