Testing the pathogenicity of human islet-infiltrating CD4+ T cells in a humanized mouse model

Research Opportunity
Project Status
Medicine and Radiology
St Vincent's Hospital
Supervisor Email Number Webpage
A/Prof Stuart Mannering Personal web page

Project Details

Advances in the immunology of autoimmune, or type 1, diabetes have relied heavily upon the NOD mouse model of autoimmune diabetes.  While the mouse is a useful model it doesn't allow us to directly understand the human autoimmune response that causes type 1 diabetes works.

Recently we have isolated and characterized CD4+ T cells from the pancreatic islets of an organ donor who suffered from type 1 diabetes. Many of these cells recognized epitopes derived from human proinsulin presented by the human HLA class II molecule HLA-DQ8 (Pathiraja et al. Diabetes 2015). While these features fit very well with the predicted properties of pathogenic CD4+ T cells, it remains unknown if these islet-infiltrating T cells actually cause type 1 diabetes.

In collaboration with Dr Serreze at the Jackson Laboratories in the USA we have generated a mouse that expresses human HLA-DQ8 and human proinsulin.  We are currently working towards introducing human T cells, isolated from the residual pancreatic islets of organ donors who suffered from type 1 diabetes, into these mice. We are also developing NOD mouse lines that have human genes knocked in in place of the murine equivalents. We anticipate that such mice will become the bedrock of translation studies by facilitating the detailed analysis of human autoimmune T-cell responses in an animal model. Specifically, these models will be essential for the systematic development of antigen specific therapies for type 1 diabetes.

This is a long-term project that has been initiated by the previous PhD student who is due to finish in early 2017. Many of the techniques and reagents are well established, which will provide a solid foundation for the next student. There is an increasing emphasis on human biomedical research, however some questions can only be addressed in an animal model. This project will prepare a student for working at the interface between animal models and human immunology.

This project is conducted in St Vincent’s Institute of Medical Research, Human T-Cell Laboratory.

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Medicine and Radiology

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St Vincent's Hospital

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