Targeting inflammation during islet transplantation
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Inflammation | .(JavaScript must be enabled to view this email address) |
Dr Robyn Sutherland (Co-supervisor) |
Immunology | .(JavaScript must be enabled to view this email address) |
Details of project
For some individuals with type 1 diabetes (T1D), being glucose unaware is a persistent life threatening condition. One definitive treatment is islet transplantation, which is effectively a cure for T1D. Currently, islet transplantation is limited by poor engraftment of islets from multiple donors, and the rejection of these islets after a number of years. Both of these processes are linked to the innate immune system and inflammation.
One substance that could be contributing to the failure of islet transplantation is islet amyloid polypeptide (IAPP), which is produced by beta cells when they make insulin and is found near transplanted islets [1]. We have discovered that IAPP oligomers activate the innate immune receptor Nlrp3, making the pro-inflammatory cytokine IL-1b [2]. It has also been recently shown that blocking IL-1b facilitates islet transplantation in mice [3].
In this project we propose to dissect the molecular basis for this, and in collaboration with industry, test neutralising antibodies targeting these inflammatory pathways. We will use mice with genetic deletions of innate immune receptors in models of islet transplant, and perform pre-clinical trials using new biologic reagents in humanised mouse models of disease.
The primary outcome of this project will be to improve islet transplantation as a potential cure for T1D. Because this disease afflicts almost half a million children between the ages of 0-14, the potential to provide these individuals with decades of improved quality of life is particularly appealing.
Project references
- Westermark GT, Westermark P, Berne C, Korsgren O. Widespread amyloid deposition in transplanted human pancreatic islets. N Engl J Med. 2008 359:77-9.
- Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol. 2010 11:897-904.
- Westwell-Roper C, Dai DL, Soukhatcheva G, Potter KJ, van Rooijen N, Ehses JA, Verchere CB. IL-1 blockade attenuates islet amyloid polypeptide-induced proinflammatory cytokine release and pancreatic islet graft dysfunction. J Immunol. 2011.
Research interests
Research in the Masters lab is focused on inflammation from the innate immune system. This can happen in many different contexts, for example during a bacterial or virus infection, when cells die during an organ or tissue transplant, or when genetic mutations activate innate immune pathways. The innate immune response is also fundamentally involved in the pathogenesis of many chronic inflammatory diseases like rheumatoid arthritis, Crohns disease and even type 2 diabetes.
Previously we have made discoveries relevant to all of these areas [1-4], and we maintain close links to industry and the clinic to make sure our discoveries can continue to have a direct effect on human health in the future. This is a particularly exciting time to be working on inflammation because so many new drugs are coming to the clinic, and we have the diverse research tools to determine where and why these can provide benefit.
Selected publications
- Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009 360:2426-37.
- Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009 27:621-68.
- Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010 11:897-904.
- Masters SL, Mielke LA, Cornish AL, et al. Regulation of interleukin-1beta by interferon-gamma is species specific, limited by suppressor of cytokine signalling 1 and influences interleukin-17 production. EMBO Rep. 2010 11:640-6.
Research theme
Chronic inflammatory diseases
Scientific discipline
- Biochemistry
- Cell Biology
- Immunology
- Innate Immunity
- Molecular Biology