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John Todd

Identification of molecular and cellular mechanisms of autoimmune disease

The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (DIL) is a group of multidisciplinary investigators within the CIMR spanning computational biology to basic immunology and focused on identifying, understanding and modulating therapeutically the aetiological pathways that cause the common autoimmune disease, type 1 diabetes (T1D).

In collaboration with my Co-Director, Linda Wicker, and the groups within the DIL, we aim to identify and characterise the function of genes that contribute to disease susceptibility in humans (see Linda’s research page for further achievements). For example, the T1D genes CTLA4, IL2R (CD25), BACH2, PTPN2, PTPN22, IFIH1, IL21 and IL2 (ImmunoBase.org) underpin the function of FOXP3+CD25+CD4+ regulatory T cells (Tregs) and their balanced activity to suppress potentially autoimmune T effector cells (Teffs). Enhancing Treg function and modulating Teffs are therapeutic targets in T1D and the subject of intense investigation, forming the basis of our Translational Medicine Group, which we have set up successfully in the past 12 months, led by Dr Frank Waldron-Lynch.

Previously, we reported that higher expression of CD25 on memory CD4+ T cells (determined by genotype), which provides homeostatic levels of IL-2 required for Treg activity, correlates with protection from T1D; hence ways of enhancing homeostatic IL-2 production could be therapeutic. We have been characterising Tregs and Teffs (and other cells, including naïve T cells) at the cellular and molecular levels with the aim of increasing Treg CD25 expression and activity. In the last 12 months, one major new approach has been the design and execution of our first mechanistic study: an in vivo analysis of the effects of administering ultra-low-dose IL-2 to T1D patients  (Adaptive study of IL-2 dose on regulatory T cells in Type 1 diabetes; DILT1D; Chief Investigator, Frank Waldron-Lynch; http://www.clinical-trials-type1-diabetes.com/); in April 2014, only 12 months since DILT1D started, we have recruited all 40 patients and will be analysing and extending the results of this trial. This approach complements and contrasts with our studies of gene-to-phenotype (http://www.cambridgebioresource.org.uk/) and case versus control immunophenotypic alterations in that we can study patients’ immune systems within an individual across time, with reduced assay variation observed in comparisons across individuals.

We study other genetically identified pathways, for example, the IL-6 pathway.  We have shown that an allele of an amino acid-changing DNA polymorphism in the IL-6 receptor gene protects from T1D and several other diseases by lowering signalling through this proinflammatory receptor. Furthermore, we have shown using bioinformatics (Olly Burren) — in particular, the ImmunoBase database we have created to facilitate cross-disease analyses (https://www.immunobase.org/page/Welcome/display) —  and statistical approaches (Chris Wallace) that the genetics of T1D overlap to the greatest extent with that of juvenile idiopathic arthritis (JIA). In a birth cohort of children at high risk of T1D we have discovered a type 1 interferon gene expression signature, which includes the T1D gene, IFIH1, that precedes autoantibody seroconversion. We have also discovered a biomarker for this IFN signature that can be analysed by flow cytometry analysis of SIGLEC-1 receptor expression on monocytes. We have reproduced and extended observations that vitamin D precursor can be metabolised to the active hormone in T cell activation cultures, which leads to an increase in the negative immune regulatory molecule CTLA-4 in Teffs. By correlating the most associated T1D risk SNPs across the known T1D loci, we have found that these SNPs often colocate with enhancer sequences and that this enrichment is most significant when foetal thymus tissue and primary T and B cells are analysed (http://www.broadinstitute.org/mammals/haploreg/haploreg.php).

Future directions

Ongoing analyses of DILT1D have enabled us to secure funding from the Sir Jules Thorn Charitable Trust for a mechanistic study aimed at optimising the frequency of IL-2 dosing. We anticipate this trial will start in the summer of 2014 and be completed at the end of 2015. We will also continue phenotypic and functional studies in our ongoing characterization of the human immune system, including prioritisation of genes, molecules and pathways that might be therapeutically tractable.

Key papers

Ferreira, R.C., Guo, H., Coulson, R.M.R., Smyth, D.J., Pekalski, M.L., Burren, O.S., Cutler, A.J., Doecke, J.D., Flint, S., McKinney, E.F., Lyons, P.A., Smith, K.G.C., Achenbach, P., Beyerlein, A., Dunger, D.B., Wicker, L.S., Todd, J.A., Bonifacio.E., Wallace, C. and Ziegler, A.-G. A type I interferon transcriptional signature precedes autoimmunity in children genetically at-risk of type 1 diabetes.  Diabetes (2014).

Ferreira, R.C., Freitag, D.F., Cutler, A.J., Howson, J.M.M., Smyth, D.B., Kapotage, S., Clarke, P., Boreham, C., Coulson, R.M., Pekalski, M.L., Wei-Min, C., Onengut-Gumuscu, S., Rich, S.S., Butterworth, A.S., Malarstig, A., Danesh, J. & Todd, J.A.  (2013)  Functional IL6R variant impairs classical IL-6 receptor signalling and influences risk of diverse inflammatory diseases.  PLoS Genet. 9, e1003444 (2013).

Downes, K., Marcovecchio, L., Clarke, P., Cooper, J.D., Ferreira, R.C., Howson, J.M.M., Jolley, J., Nutland, S., Stevens, H.E., alker, N.M., Wallace, C., Dunger, D.B. & Todd, J.A. Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients.  Diabetologia 57, 366–372 (2014).

Pekalski, M.L., Ferreira, R.C., Coulson, R.M., Cutler, A.J., Guo, H., Smyth, D.J., Downes, K., Dendrou, C.A., Castro Dopico, X., Esposito, L., Coleman, G., Stevens, H.E., Nutland, S., Walker, N.M., Guy, C., Dunger, D.B., Wallace, C., Tree, T.I., Todd, J.A. & Wicker, L.S. Postthymic Expansion in Human CD4 Naive T Cells Defined by Expression of Functional High-Affinity IL-2 Receptors.   J. Immunol.  190, 2554–2566 (2013).

Wallace, C., Rotival, M., Cooper, J.D., Rice, C.M., Yang, J.H.M., McNeill M., Smyth, D.J., Niblett, D., Cambien, F., The Cardiogenics Consortium, Tiret, L., Todd, J.A., Clayton, D.G. & Blankenberg, S. Statistical colocalisation of monocyte gene expression and genetic risk variants for type 1 diabetes. Hum. Mol. Genet. 21, 2815–2824 (2013).

Garg, G., Tyler, J.R., Yang, J.H.M., Cutler, A.J., Pekalski, M., Bell, L., Nutland, S., Peakman, M., Todd, J., Wicker, L. & Tree, T.I.M. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+ CD25+ regulatory T cell function.  J. Immunol. 188, 4644–4653 (2012).

Heinig, M., Petretto, E., Wallace, C., Bottolo, L., Rotival, M., Lu, H., Li, Y., Sarwar, R., Langley, S.R., Bauerfeind, A., Hummel, O., Lee, Y.A., Paskas, S., Rintisch, C., Saar, K., Cooper, J., Buchan, R., Gray, E.E., Cyster, J.G., Cardiogenics Consortium, Braud, P., Gracey, J., Krishnan, U., Moore, J.S., Nelson, C.P., Pollard, H., Attwood, T., Crisp-Hihn, A., Foad, N., Jolley, J., Lloyd-Jones, H., Muir, D., Murray, E., O'Leary, K., Rankin, A., Sambrook, J., Godfroy, T., Brocheton, J., Proust, C., Schmitz, G., Heimerl, S., Lugauer, I., Belz, S., Gulde, S., Linsel-Nitschke, P., Sager, H., Schroeder, L., Lundmark, P., Syannen, A.C., Neudert, J., Scholtz, M., Deloukas, P., Gray, E., Gwilliams, R., Niblett, D., Erdmann, J., Hengstenberg, C., Maouche, S., Ouwehand, W.H., Rice, C.M., Samani, N.J., Schunkert, H., Goodall, A.H., Schultz, H., Roider, H.G., Vingron, M., Blackenberg, S., Munzel, T., Zeller, T., Szymczak, S., Ziegler, A., Tiret, L., Smyth, D.J., Pravenec, M., Aitman, T.J., Cambien, F., Clayton, D., Todd, J.A., Hubner, N. & Cook, S.A. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010).

Dendrou, C.A., Plagnol, V., Fung, E.Y.M.G., Yang, J.H.M., Downes, K., Cooper, J.D., Nutland, S., Coleman, G., Himsworth, M., Hardy, M., Burren, O., Healy, B., Walker, N.M., Koch, K., Ouwehand, W.H., Bradley, J.R., Wareham, N.J., Todd, J.A. & Wicker, L.S. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genet. 41, 1011–1015 (2009).

Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

Smyth, D.J., Plagnol, V., Walker, N.M., Cooper, J.D., Downes, K., Yang, J.H.M., Howson, J.M.M., Stevens, H., McManus, R., Wijmenga, C., Heap, G.A., Dubois, P.C., Clayton, D.G., Hunt, K.A., Van Hell, D.A. & Todd, J.A. Shared and distinct genetic variants in type 1 diabetes and celiac disease.  New Engl. J. Med. 359, 2767–2777 (2008).

 

Professor John Todd FRS

University Chair

Department: Medical Genetics

Director: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory

contact: john.todd@cimr.cam.ac.uk

01223 762101

01223 762103 (PA Judy Brown)

 

 

Plain English

Type 1 diabetes is a serious threat to health worldwide. Individuals with this autoimmune disorder cannot regulate their blood sugar levels properly, because the cells in the body that produce the hormone insulin are inappropriately destroyed by immune cells. From many years of analysis, we have determined several regions of DNA (genes) that significantly increase the probability of an individual developing diabetes. Many of the susceptibility genes are expressed in a particular type of white blood cell, ‘regulatory T cells’, that help prevent the destruction of insulin-producing cells.  Based on these insights, we have rationalized that boosting the action of these cells using an ultra-low dose of a factor called interleukin-2 (IL-2) might provide protection against type 1 diabetes. We are now recruiting patients with type 1 diabetes and testing how their regulatory T cells respond to IL-2 treatment. After optimizing IL-2 dose, we plan to test the clinical efficacy of this treatment. These investigations will also lead to new, fundamental insights into how the human system works, in disease and in health.

Funding

Eli Lilly

JDRF

Wellcome Trust

NIHR Cambridge Biomedical Research Centre

The Sir Jules Thorn Charitable Trust

European Commission FP7

National Institutes of Health (USA)

Hoffman-La Roche