Download + 3-4%/year

TYPE 1 DIABETES MELLITUS
• increasing incidence [+ 3-4%/year]
up to 50/105/year, earlier age at onset
• multifactorial, polygenic disease
• islet of Langerhans
• b cell
1 autoantibody
• islet cell autoantibodies
anti-GAD
anti-IA2
anti-insulin
• prediabetes
2 autoantibodies
3 autoantibodies
Kulmala
et al.&1998,
J Clin
Invest
Bottazzo
Doniach
1974,
Lancet
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
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
AUTOANTIBODY DETECTION: LIMITS
POSITIVITY THRESHOLD
% individuals
 predictive positive value
in atypical forms of type 1
 delay to diabetes onset
in prediabetes
 other assays ?
0
50
90 95 97
99
autoantibody titer (percentiles)
ANTIGEN RECOGNITION BY T CELLS
TCD3
TCD3
CYTOKINES
T cell receptor
MHC
class II
CD8+ T CELL RESPONSE [ELISPOT assay]
Patient A2/A3 B18/B38
34-42 tetramet
200,00
180,00
nb spots/106 cells
160,00
140,00
120,00
100,00
60,00
40,00
20,00
Toma et al. PNAS, 2005
Pha
Seules
Mat A2
A2 HIV
45-53
44-51
42-51
41-50
38-46
34-42
0,00
34-42 tetramet
80,00
CD8
Pinske et al. PNAS, 2005
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
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:
Ins1-/-
 absence of diabetes
Moriyama H et et al. Proc Natl Acad Sci USA 2003
Thebault-Baumont, Tardivel et al. 2003, 2005
AUTOANTIBODY IN OFFSPRING OF DIABETIC PARENTS
anti-insulin autoantibodies
Ziegler et al, Diabetes, 1999
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
IMMUNE REGULATION IN TYPE 1 DIABETES
T
CD4+
CD62L+
T
CD4+
CD25+
Th2
Th3
IL-4,5
IL-10
REGULATORY
REGULATORY
CELLS
CELLS
-
Th3
T
NK
T
CD8+
T
CD4+
Th1
TGFb
ISLET
INFa
TLRs
EFFECTOR
T CELL
EFFECTOR
T CELL
b
CELL
cytokines
10 1
10 0
CD25
10 2
DETECTION
EXPANSION
IN
small
size
HUMAN
10 0
10 1
CD4
10 2
NOD
FoxP3
GITR
 number ?
CTLA4
 function ?
protection
Krukeja et al. 2002, J Clin Invest
Tang Q et al. 2004, J Exp Med
Lindley
etal.al.Nat
2005,
Diabetes
Shimon
Sakaguchi
1995
Kretschmer
KSet
Immunol
2005
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
TREATMENT OF DIABETES WITH ANTI-CD3
months
months
months
n = 40 (placebo) n = 40 (anti-CD3)
Keymeulen B et al. 2005, N Engl J Med
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
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
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
C-PEPTIDE
DIFFERENCIATION OF b CELLS FROM ES CELLS
ESC-DERIVED CELLS
HUMAN ISLETS
D’Amour et al. 2006, Nart Biotech