Monitoring Peripheral Tissue Immune Response to Peptide Immunomodulation in Type 1 Diabetes - Monitor 4
Duration of Study in the UK
3 years, 0 months, 3 days
Immunotherapy has the potential to make a paradigm change to the prevention and management of Type 1 diabetes (T1D) as preservation of even 5% of beta-cell function allows over 50% of people to reach target glycaemic levels. A key limiting factor is the reliance on variable metabolic markers as outcome measures in trials, which provide no insight about changes in the underlying disease process. There is an urgent need to develop biomarkers that can provide early guidance for therapeutic developments in smaller short-term studies, informing larger trials. To achieve this, we aim to develop methodology that provides insight into the autoimmune process itself. To date, monitoring of the immune process in humans has been exclusively in peripheral blood. This has proved problematic due to the low frequency of circulating autoreactive T-cells (cells responsible for the destruction of insulin producing beta-cells in people with T1D). We will use skin and draining lymph node sampling post beta-cell antigen challenge in humans to develop a novel approach to monitor autoreactive T-cells which are often the therapeutic target of immunomodulatory agents. We postulate that autoreactive T-cells will relocate from the pancreas to the skin and draining lymph node after the challenge where they will be easily accessible.
We will first modulate autoreactive T-cells with immunomodulating GAD peptide (small part of GAD protein known as GAD-P10) in people with T1D. GAD is a big molecule found in insulin producing cells, and is one of the proteins that are attacked by autoreactive T-cells in T1D. We will then use whole GAD molecule (GAD-alum) to stimulate immune response in the skin following immunomodulation by GAD peptides.
We aim to detect changes by analysing full transcriptome and TCRs using single cell RNA sequencing (10x genomics) technique.
This would have the potential to substantially accelerate the development of effective immunotherapy in T1D.
North West - Greater Manchester East Research Ethics Committee
Date of REC Opinion
20 Apr 2022
Further Information Favourable Opinion