1. TYPE 1 DIABETES MELLITUS
increasing incidence [+ 3-4%/year]
up to 50/105/year, earlier age at onset
multifactorial, polygenic disease
islet of Langerhans
increasing incidence [+ 3-4%/year]
up to 50/105/year, earlier age at onset
multifactorial, polygenic disease
prediabetes
Kulmala et al. 1998, J Clin Invest
3 autoantibodies
2 autoantibodies
1 autoantibody
b cell
islet cell autoantibodies
Bottazzo & Doniach 1974, Lancet
anti-GAD
anti-IA2
anti-insulin

2. MAIN ADVANCES 2003-2006 1- prediction
autoantibodies
genetic puzzle
2- proinsulin: the primary autoantigen
3- the importance of immune regulation
4- immunotherapy: the end of immunosuppression
5- the goal: b cell restoration
+ induction of immune tolerance
1- prediction
autoantibodies
genetic puzzle

3. STRATIFICATION OF RISK
anti-IA2 & anti-insulin
IgG2/IgG3/IgG4
anti-IA2b
&
IA2 multiepitopes
anti-IA2 & anti-insulin
autoantibody titers
Achenbach et al, Diabetes, 2006

4. AUTOANTIBODY DETECTION: LIMITS
POSITIVITY THRESHOLD
% individuals
autoantibody titer (percentiles)
 predictive positive value
in atypical forms of type 1
 delay to diabetes onset
in prediabetes
 other assays ?

5. ANTIGEN RECOGNITION BY T CELLS
CD3 T
CD3
CYTOKINES
T cell receptor
MHC
class II

6. CD8+ T CELL RESPONSE [ELISPOT assay]
Patient A2/A3 B18/B38
CD8+ T CELL RESPONSE [ELISPOT assay]
nb spots/106 cells
CD8
34-42 tetramet
Pinske et al. PNAS, 2005
Toma et al. PNAS, 2005

7. MAIN ADVANCES 2003-2006 1- prediction
autoantibodies
genetic puzzle
2- proinsulin: the primary autoantigen
3- the importance of immune regulation
4- immunotherapy: the end of immunosuppression
5- the goal: b cell restoration
+ induction of immune tolerance

8. ROLE OF PROINSULIN IN TYPE 1 DIABETES
PROINS 2-/-NOD MICE
acceleration of diabetes
 anti-insulin Abs
~ anti-GAD Abs
~ sialitis
PROINS 1-/-NOD MICE:
absence of diabetes
Ins1-/-
Moriyama H et et al. Proc Natl Acad Sci USA 2003
Thebault-Baumont, Tardivel et al. 2003, 2005

9. AUTOANTIBODY IN OFFSPRING OF DIABETIC PARENTS
anti-insulin autoantibodies
Ziegler et al, Diabetes, 1999

10. MAIN ADVANCES 2003-2006 1- prediction
autoantibodies
genetic puzzle
2- proinsulin: the primary autoantigen
3- the importance of immune regulation
4- immunotherapy: the end of immunosuppression
5- the goal: b cell restoration
+ induction of immune tolerance

11. - ISLET IMMUNE REGULATION IN TYPE 1 DIABETES T CD8+ b CELL T CD4+ Th1
REGULATORY
CELLS
EFFECTOR
T CELL T
CD4+
CD25+
REGULATORY
CELLS
EFFECTOR
T CELL T
CD4+
CD62L+ T
CD8+
Th2
IL-4,5
Th3
IL-10 - b
CELL
Th3
TGFb T
CD4+
Th1 T NK
cytokines
ISLET
INFa
TLRs

12. EXPANSION NOD protection DETECTION IN HUMAN number ? function ?
Tang Q et al. 2004, J Exp Med
Kretschmer K et al. Nat Immunol 2005
DETECTION IN
HUMAN
number ?
function ?
Lindley S et al. 2005, Diabetes
Krukeja et al. 2002, J Clin Invest
10 2
small size
CD25
10 1
FoxP3
GITR
CTLA4
10 0
10 0
10 1
10 2
CD4
Shimon Sakaguchi 1995 1

13. MAIN ADVANCES 2003-2006 1- prediction
autoantibodies
genetic puzzle
2- proinsulin: the primary autoantigen
3- the importance of immune regulation
4- immunotherapy: the end of immunosuppression
5- the goal: b cell restoration
+ induction of immune tolerance

14. TREATMENT OF DIABETES WITH ANTI-CD3 n = 40 (placebo) n = 40 (anti-CD3)
months
months
months
n = 40 (placebo) n = 40 (anti-CD3)
Keymeulen B et al. 2005, N Engl J Med

15. MAIN ADVANCES 2003-2006 1- prediction
autoantibodies
genetic puzzle
2- proinsulin: the primary autoantigen
3- the importance of immune regulation
4- immunotherapy: the end of immunosuppression
5- the goal: b cell restoration
+ induction of immune tolerance

16. GENERATION OF NEW BETA CELLS
transdifferenciation from
ductal cells
acinar cells
hepatic precursor cells
[through a dedifferenciation stage]
differenciation from
embryonic adult stem cells
embryonic stem cells

17. DIFFERENCIATION OF b CELLS FROM ES CELLS
definitive endoderm
primitive gut tube
posterior foregut
pancreatic endoderm
insulin cells
D’Amour et al.
Nat Biotechnol, 2006

18. DIFFERENCIATION OF b CELLS FROM ES CELLS
C-PEPTIDE
ESC-DERIVED CELLS
HUMAN ISLETS
D’Amour et al. 2006, Nart Biotech