JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (DIL)
The DIL is led by John Todd (Director) and Linda Wicker (Co-Director). The lab is researching the causes of the autoimmune disease type 1 diabetes (T1D) in order to treat and prevent the disease by modulating the causative pathways. We achieve this by linking genetic determinants of disease with phenotypes and pathways in cells and in patients, using a wide range of molecular, metabolic, immunological, computational and statistical approaches.
Genetics: identification of T1D genes and their pathways is essential for understanding the biology underpinning disease susceptibility. We are integrating the latest and emerging genomics data - genetic variation, RNA and protein gene expression, methylation, transcription factor binding sites and chromatin phenotypes – to better define the T1D causal genes.
Phenotypes and mechanisms: identify aberrant cellular interactions and pathways caused by susceptibility genes that mediate a loss of immune tolerance to insulin-producing beta cells culminating in their destruction. These will provide potential targets for therapeutic intervention, as demonstrated by our work in the IL-2 pathway. This knowledge will contribute to understanding cell interactions altered by disease genes, an essential step for prioritizing potential immune-modulating agents to be investigated in experimental studies in T1D patients.
Experimental medicine: our hypothesis is that determination of the optimal dosing regimen of a potential therapeutic in terms of its molecular and cellular responses in vivo will greatly improve the likelihood of a beneficial outcome in future clinical trials. We are testing the utility of this approach in the ongoing investigation of the effects of ultra-low doses of IL-2 in patients with T1D, and will consider and evaluate other potential therapeutics. Secondly, we are part of an randomised control trial for primary prevention T1D in children in the population by feeding newborn children oral insulin every day for three years to promote immune tolerance to insulin, the primary autoantigen in T1D. Thirdly, we are planning investigation of the enhancing the healthy state, including improving tolerance to insulin through cross reactivity with a commensal antigen that we have discovered, of the intestinal microbiome using combinations of bacterial probiotics and prebiotics, in the context of deep microbiome genome sequencing and interactions with the HLA class II genotypes that increase and decrease risk of autoimmune responses to insulin and to T1D.
Potential project areas: Diabetes, autoimmunity, genomics, single cell omics, genetics, statistics, bioinformatics, immunology, experimental medicine, clinical trials.
Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells
Inaba A. et al, (2023), Nature Communications, 14
Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes
Zhang J-Y. et al, (2022), Nature Communications, 13
INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes.
Dunger DB. et al, (2022), Trials, 23
Low-dose IL-2 reduces IL-21+ T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients
Zhang J-Y. et al, (2022)
Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73.
Jarvis LB. et al, (2021), Commun Biol, 4