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12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
12 rencontres biomédicale LIR Roberto Mallone
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12 rencontres biomédicale LIR Roberto Mallone

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2ND INTERNATIONAL RESEARCH MEETING …

2ND INTERNATIONAL RESEARCH MEETING
4 JUNE 2010- HÔTEL DE MARIGNY PARIS

Published in: Health & Medicine, Technology
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  • This scenario would lead to a complete shift in paradigm in the management of T1D: you see here Edipus questioning the Sphyinx, he offers his finger, perhaps he is thinking to his capillary blood glucose and insulin injections… … but the Sphynx looks disappointed… maybe the solution to her riddle lies elsewhere… Thank you for your attention!
  • Transcript

    • 1. Re-inventing type 1 diabetes: T-cell-based biomarkers and therapeutics Roberto Mallone, MD PhD DeAR Lab Avenir INSERM U986 Cochin-Saint Vincent de Paul Hospital Paris, France
    • 2. Type 1 diabetes: an orphan disease <ul><ul><li>Clinical T1D is only </li></ul></ul><ul><ul><li>the tip of the iceberg </li></ul></ul>-&gt; Identify and correct immunological mechanisms, not metabolic consequences <ul><ul><li>T1D epidemic in Western countries </li></ul></ul>Today Tomorrow Diagnosis End-stage Clinical-based Early Immune-based Therapy Insulin Immunosuppression Immune Tolerance No immunosuppression Follow-up Risk vs. Benefit? Late clinical endpoints Benefit &gt; Risk Early surrogate endpoints
    • 3. Autoimmune T cells as diagnostic and therapeutic targets in type 1 diabetes How do T cells sense and destroy β -cells? X β cells T cell HLA antigen HLA molecules and antigens differ among patients HLA-A1 HLA-A2 HLA-A3 Antigen X Antigen Y Antigen Z T cell T cell T cell X X X
    • 4. Shortcutting antigen identification by accelerated co-cultured dendritic cells (acDC) <ul><li>No preliminary antigen and HLA selection </li></ul><ul><li> -&gt; full population coverage </li></ul><ul><li> -&gt; full antigen coverage </li></ul><ul><li>Rapid, simple </li></ul><ul><li>Minimal blood requirements </li></ul><ul><li>Fresh or frozen cells </li></ul>Martinuzzi et al., submitted Patent filed by Inserm-Transfert T-cell activation T cell T cell Antigen processing &amp; presentation acDC Blood Sample 0.25-1 ml Monocyte CD4 CD8 B NK NKT acDC precursor DC-inducing cytokines Crude antigen source ( β -cell proteins or apoptotic bodies) CD137 CD4 CD8 No antigen + antigen
    • 5. T-cell-based diagnostics Mallone et al., Diabetes 56:613 (2007); Martinuzzi et al., Diabetes 57:1312 (2008); Martinuzzi et al., in preparation <ul><ul><li>100% diagnostic sensitivity when combining T-cell and antibody markers </li></ul></ul>Better: T cells identify clinical type 1 diabetes Insulin-dependent type 1 diabetes patients <ul><ul><li>Already present in 1 st degree relatives </li></ul></ul>Proinsulin-specific IFN- γ T-cell responses Healthy subjects 1 st degree relatives T1D patients 0% 36.4% 60.0% Earlier: T cells identify latent β -cell autoimmunity
    • 6. <ul><ul><li>-&gt; Early surrogate endpoints of need for and outcome of vaccination: </li></ul></ul><ul><ul><li>tolerogenic or immunogenic </li></ul></ul>T-cell-based therapeutic monitoring Vaccinations are being effective Collaboration with L.C. Harrison, WEHI, Melbourne, Australia Insulin -specific IFN- γ T-cell responses 1) Blunting autoimmune responses <ul><ul><li>INIT-III trial: </li></ul></ul><ul><ul><li>At-risk subjects treated with nasal insulin </li></ul></ul>Smallpox -specific IFN- γ T-cell responses Collaboration with B. Combadière, Pitié-Salpêtrière, Paris <ul><ul><li>IMMUVAR trial: </li></ul></ul><ul><ul><li>Healthy subjects re-vaccinated for smallpox </li></ul></ul>2) Boosting protective responses
    • 7. T-cell-based therapeutics + IL-10 acDC Generation of antigen-specific regulatory T cells DC-inducing cytokines Patent filed by Inserm-Transfert C. Boitard, patent pending Testing on preclinical humanized mouse models Human A2-DQ8 HLA-transgenic mouse Human β -cell antigen transgenic mouse x A2/DQ8/ β -cell antigen transgenic mouse
    • 8. The TRACR cohort: T1D Risk Assessment in Children with Relatives Children of T1D parents 1. Early diagnosis T-cell assays ± antibodies ± HLA at risk subject 2. Prognostic stratification Longitudinal T-cell assays enrollment for immune therapy 4. Therapeutic follow-up Early surrogate T-cell endpoints therapy 3. Tailoring of immune therapy Which patients? Which T cells? T-cell-targeting therapeutics
    • 9. Ingres, “Oedipus and the Sphinx ”, 1808 ?! !?

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