Advancing Opportunities To Prevent Type 1 Diabetes

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1 Advancing Opportunities To Prevent Type 1 Diabetes Dr. Allison Green Centre for Immunology and Infection Hull York Medical School York University

2 Type 1 Diabetes Insulin deficiency destabilizes regulation of glucose levels in the body leading to life-threatening medical conditions. 86,00 diabetics undergo amputations every year. Both genetic and environmental factors thought to contribute to Type 1 diabetes development. Predicted that 50 million people will have type 1 diabetes by Global increase of ~5% per year, fastest rise in pre-school children. There is no cure

3 Type 1 Diabetes occurs when our immune system turns against our b cells Healthy islet Damaged islet DAPI CD4 insulin attacked by DAPI CD4 insulin white blood cells

4 The immune system is tightly regulated to prevent damage to our own tissues Purging of autoreactive cells Traffic Light system for activation Healthy cell Dying cell STOP! GET READY! GO!

5 The immune system is a complex; multitudes of cells and molecules work to protect our bodies from damage by harmful pathogens Unique and compensatory signal pathways keep the immune system one step ahead of a pathogen s destructive arsenal

6 Potential targets for therapeutic intervention of type 1 diabetes Gillespie, K. M. CMAJ 2006;175:

7 Targets of immune intervention in type 1 diabetes. JA Bluestone et al. Nature 464, (2010) doi: /nature08933

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9 Non-Obese Diabetic (NOD) mouse Disease process birth 3-5 weeks (mouse) 5-12 weeks (mouse) weeks (mouse) insulitis diabetes priming regulation aggressor The autoimmune team in T1D Dendritic cell B cell Process Present Activate autoantibodies activation survival CD4 T cell Secretory help cytokines CD8+ T cell T regulatory cell (Treg) Suppressor cells Beta cell death Serial killer

10 Can we vaccinate against T1D? Pathogens Autoimmunity Antigenic components with adjuvants Enhanced effector immunity (Adaptive Immune System) Antigenic components no adjuvants Enhanced T regulatory cell immunity (Adaptive Immune System) Timing, dose route? Oral, intranasal. Prediabetic high risk or new onset? Antigen selected? GAD, insulin derivatives, Heat Shock Protein-derived peptide 277? Vector? Trojan horses e.g. plasmid IL-10, Lactococcus lactis? Combinational therapy? Anti-CD3 + insulin? Tolerogenic dendritic cells (tdcs)? With or without antigen pulse? Safety if paramount; enhance regulation NOT aggression M. Peakman (2012), F1000 Biology Reports, 4: 19 (doi: /B4019

11 Do defects in T regulatory (Treg) cell development or function underlie T1D? Genetic link CD25 polymorphisms Numbers and functionality decreased in T1D patients Repertoire more restricted in T1D patients?

12 % new Tregs (normalised) % Tregs exported (normalised) Is vaccination to promote Treg cell biology a reality for controlling T1D? Thymus Periphery Cuss, S and Green, EA (2012). J Immunol., 189, Decreased production of new Treg cells Significantly impaired export of Tregs to periphery Control mouse NOD mouse Control mouse NOD mouse Kearsley, J and Green, EA. in prep

13 Our rationale: to develop a therapy where a brief pulse of an immunosuppressive agent specifically in islets will abort only the autoimmune assault. Transforming growth factor beta Major immunosuppressive cytokine Major inducer of T regulatory cells Linked to cancer (positively and negatively) Linked to fibrosis b cells producing TGF-b (red) in absence of the antibiotic doxycycline

14 % not diabetic A brief pulse of TGF-b in the aggressor phase significantly impedes type 1 diabetes progression birth Disease process 4-5 weeks (mouse) 8-12 weeks (mouse) insulitis diabetes priming TGF-b aggressor TGF-b Age in weeks Wållberg and Green, (2011), JI, 186,

15 birth Disease process 4-5 weeks (mouse) 8-12 weeks (mouse) insulitis diabetes priming TGF-b aggressor TGF-b Initial CD8+ T cell attack on beta cells generates memory responses (CD8+) Continued effector and memory aggression to beta cells T1D Also impedes success of islet transplantation

16 TGFb rapidly abrogates ongoing CTL and CD8+ T cell memory generation Wållberg and Green, (2011), JI, 186,

17 Edmonton Protocol for Islet Transplantation Offered to patients whom glucose control is poor 1% of all transplantees will die on the operating table. Over time islets become non-functional

18 Generation of Functional Human Pancreatic β Cells In Vitro F. W. Pagliuca et al., (2014), Cell, 159, Billions of beta cells can be made in a single flask

19 Maja Wållberg Diabetes UK RD Lawrence Fellow

20 Induced expression of TGF-β for the first 21 days after transplantation significantly delays graft rejection. Red= insulin Green = cells Thomas D C et al. Diabetes 2013;62:

21 The autoimmune team in T1D Dendritic cell B cell Process Present Activate autoantibodies activation cytokines CD4 T cell Secretory help CD8+ T cell Serial killer Beta cell death

22 Co-transplantation of TGFb-preconditioned DCs with islets prevents graft rejection TGFb + Thomas D C et al. Diabetes 2013;62: Giannoukas et al., (2011). Phase I study of autologous tolerogenic dendritic cells in type 1 diabetes. Diabetes Care, 34,

23 Unanswered Questions Natural Disease Course Transplantation Gillian Griffiths Cambridge University Joelotron.com Why timing? Gene Profile? Influence of islet environment; TNF enriched versus non enriched? TGFb in vivo versus in vitro effects? Allogenic transplantation? Human DCs? Mechanism(s)?

24 A cure for T1D- the way forward Better biomarkers Changing immune cell phenotypes MRI Stratifying data Re-analyse clinical trial data More robust pre-clinical models Randomised studies (NC3R Arrive Guidelines) Humanised mice A cure should not be a driving force in success of a therapy Delaying, or partial resolving disease buys time from development of complications

25 Is there hope? Yes! Patients TEAMWORK Clinicians Scientists

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