Prediction and prevention of Type 1 diabetes

Type 1 diabetes is the result of the destruction of insulin-secreting pancreatic beta cells by a process in which autoimmune recognition of beta cell proteins is implicated. Our research group has interests in the identification and characterisation of beta cell targets of the autoimmune response in Type 1 diabetes, with the view of developing strategies to identify individuals at risk for disease, and to apply antigen specific immune intervention to prevent disease progression in high-risk subjects. 

Diabetes5

Photo: Sorting of autoantigen-specific B-cells for cloning and expression of recombinant autoantibodies from blood samples of diabetic patients.  Autoantigen-specific B-cells are rare, but are found at higher frequency in the antibody positive patient

Characterisation of antibody epitopes provides information on the specificity of autoimmune responses in diabetes that are critical for the development of therapies that specifically target diabetogenic autoimmune responses.

We have developed procedures for the purification of autoantigen (IA-2)-specific  B-cells using fluorescence activated cell sorting (FACS) and have cloned and expressed recombinant antibody fragments from single antigen positive B cells for studies on the specificity of the autoimmune response. 

A combination of site directed mutagenesis and Nuclear Magnetic Resonance (NMR) shift assays allow a detailed analysis of protein-protein interactions that allow a better understanding of the structures recognised in disease.


Diabetes7‌ 

 

Left photo: Schematic representation of the structure of the IA-2 autoantigen in Type 1 diabetes

 

Diabetes4

Funded by Diabetes UK and performed in collaboration with Professor Sasi Conte, Randall Division of Cell and Molecular Biophysics, Kings College London

 

Diabetes8

B-cells as a target of immunotherapy

Islets in Type 1 diabetes are lost in Type 1 diabetes as a consequence of a destructive inflammation.  CD20 expressing B-cells are part of the inflammation and depletion of antigen specific B-cells may block the inflammation and prevent disease progression

Trials of agents that deplete or interfere with the function of T-cells and B-cells of the immune system have shown considerable promise for Type 1 diabetes prevention and treatment, but the most effective of these treatments have major effects on general immune function that make them unsuitable for widespread use in diabetes therapy.

Consequently, there is much interest in the development of strategies that are able to very specifically target those immune responses that are responsible for destruction of insulin secreting pancreatic beta cells cells. CD20 positive B-cells infiltrate the insulin-secreting pancreatic islets during the process of beta cell destruction and play a major role in promoting the T-cell response in disease.

Our research has identified major regions of a major autoantigen that are targeted by B-cells in Type 1 diabetes and have designed novel therapeutic agents to specifically deplete these cells. With the support of a research grant from Diabetes UK, we are currently testing the efficacy of these reagents to deplete these cells for Type 1 diabetes prevention.

 

 

Diabetes4

Funded by a Diabetes UK Research Grants to Michael Christie 

School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln. LN6 7TS 

email: enquiries@lincoln.ac.uk
tel: + 44 (0)1522 886654