Re-inventing type 1 diabetes: T-cell-based biomarkers and therapeutics Roberto Mallone, MD PhD DeAR Lab Avenir INSERM U986...
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...
Autoimmune T cells as diagnostic and  therapeutic targets in type 1 diabetes  How do T cells sense and destroy  β -cells? ...
Shortcutting antigen identification by accelerated co-cultured dendritic cells (acDC) <ul><li>No preliminary antigen and H...
T-cell-based diagnostics Mallone et al.,  Diabetes  56:613 (2007); Martinuzzi et al.,  Diabetes  57:1312 (2008); Martinuzz...
<ul><ul><li>->  Early surrogate endpoints of need for and outcome of vaccination: </li></ul></ul><ul><ul><li>tolerogenic o...
T-cell-based therapeutics + IL-10 acDC Generation of antigen-specific regulatory T cells DC-inducing cytokines Patent file...
The TRACR cohort: T1D Risk Assessment in Children with Relatives Children of T1D parents 1. Early diagnosis T-cell assays ...
Ingres, “Oedipus and the Sphinx ”, 1808 ?! !?
Upcoming SlideShare
Loading in …5
×

12 rencontres biomédicale LIR Roberto Mallone

1,308 views

Published on

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

Published in: Health & Medicine, Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,308
On SlideShare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • 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!
  • 12 rencontres biomédicale LIR Roberto Mallone

    1. 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. 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>-> 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 > Risk Early surrogate endpoints
    3. 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. 4. Shortcutting antigen identification by accelerated co-cultured dendritic cells (acDC) <ul><li>No preliminary antigen and HLA selection </li></ul><ul><li> -> full population coverage </li></ul><ul><li> -> 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 & 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. 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. 6. <ul><ul><li>-> 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. 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. 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. 9. Ingres, “Oedipus and the Sphinx ”, 1808 ?! !?

    ×