Transcript Prediction of Type 1 Diabetes Mellitus

Prediction of Type 1 Diabetes (T1DM)
& related Autoimmune Diseases (AD)
Marco Songini, MD
Diabetes Unit
Azienda Ospedaliera Brotzu
Cagliari (Italy)
Type 1 diabetes develops from the interaction between
susceptibility genes and enviromental determinants. The major
genetic susceptibility to type 1 diabetes is conferred by
markers from HLA locus, but other genes are involved. The
non genetic contribution to the disease (i.e. nutritional factors
and infective agents) is even less wll-defined. This may imply
aetiological heterogeneity in patients so that particular
combinations of genetic susceptibility factors require exposure
to specific non-genetic factors in order to initiate the disease
developing process in type 1 diabetes. It is well known that
immune markers (ICA, GADA, IA2, IAA) appear many years
before clinical onset of type 1 diabetes. These “windows” offers
the chance to pinpoint subjects at risk eventually suitable to
preventive therapies. At present, intervention trials are
recommended in the small subset of the population at high risk
identified by genetic and immune markers.
Complementary strategies in the prediction of T1DM
Strategy 1
Strategy 2
AIM:
AIM:
TEST INTERVENTION
STRATEGIES
High specificity/
low sensitivity
REDUCE INCIDENCE
OF IDDM
Low specificity/
high sensitivity
families
general population
immune markers
genetic + immune markers
high risk subgroup
moderate risk subgroup
Bingley, E. Bonifacio & E. Gale;Diabetes, vol. 42, feb. 1993
Preventive strategies for T1DM (1)
Selective immunosuppression, using depleting or
nondepleting monoclonal antibodies to lymphocyte
cell surface molecules such as CD3, CD4, CD8, T cell
receptor and major histocompatibility complex
(MHC) antigens, or blocking peptides to T cell
receptors
Immunostimulation by viruses, cytokines, calcitriol,
concanavalin A, bacille Calmette-Guèrin (BCG),
Freund’s adjuvant or tranfusion of deficient
lymphocyte subsets B-Cell rest by suppressive therapy
with insulin
E. Bosi & G.F. Bottazzo; Clin. Immunother. 3 (2) 1995
Preventive strategies for T1DM (2)
Protection from oxygen radical-mediated and nitric oxidemediated
damage
by
nicotinamide,
(desferrioxamine) and aminoguanidine
Environmental
intervention
deferoxamine
by manipulation
temperature, diet (gluten free) and hormonal milieu
of
Induction of tolerance to B-cells by bone marrow
transplantation, lymphocyte transfusion, intrathymic islet
transplantation,
neonatal
B-cell
stimulation
and
administration (intravenous, intrathymic, intraperitoneal or
oral) of putative B-cell autoantigens such as insulin or
glutamic acid decarboxylase
E. Bosi & G.F. Bottazzo; Clin. Immunother. 3 (2) 1995
Tests to predict T1 DM & AD
Autoantibodies: ICA, GADA, IA2-A, IAA, AD-Abs
HLA-phenotype: DR3/DR4 (DQ2/DQ8), AD phenos
HLA-genotype: Eterodimers 57Non Asp/53Arg
DQ beta/DQ Alfa, AD genos
? Cell mediated markers: Alteration of lymphocyte
subsets CD4/CD8, etc.
Immunological markers for T1DM
ICA
Islet Cell
Abs
IAA
Insulin
AutoAbs
Indirect
immunofluorescence
on human pancreatic
cryosections
Risk at 10 yrs
FH+
>10 JDFU 41%
>80 JDFU 80%
Risk at 5 yrs
FH+ 44%
In Children
R.I.A. first antibodies Risk at 10 yrs
ICA + IAA
to appear
81%
Immunological markers for T1DM
IA2-A
Protein Tyrosin
Phosphatase
AutoAbs
GADA
Glutamic Acid
Decarboxilase
AutoAbs
More
R.I.A. common
among
children
High
specificity
low
sensitivity
More
R.I.A. common
among
adults
High
sensitivity
low
specificity
Immunological markers for T1DM
Combined markers in FH+
Positivity for 3 or 4 antibodies yelds a risk of
88-100% to become diabetic in 10 years
The best association of autoantibodies is:
GADA + IA2-A
GADA + IA2-A + IAA in young children
Pastore MR et al Diabetes Care 1998, 9; 1445-50
We are able to assay GADA + IA2-A
on blood spots
E. Bosi, E. Bonifacio et al . Diabetes Care - March 1999
Background
The preclinical stage of type 1 diabetes and
related AD can last even many years
These “windows” offers the chance to pinpoint
subjects at risk eventually suitable to
preventive therapies
Genetic markers for T1DM
HLA typing
predisposing:
HLA DR3-DQ2, DR4-DQ8
protective:
HLA DR2-DQ6
Lernmark A Diabetes Metabolism Rev 1998, 14,3-29
Genetic markers for T1DM
HLA
Molecular biology of DQ chains of class second
DQ A301, DQ B302, DQ B501 Alleles:
99% of diabetic patients
50% of normal people
Lernmark A Diabetes Metabolism Rev 1998, 14,3-29
DQ B602 is fully protective for T1DM
Gianani R et al. J Autoimmunity 1996, 9; 423-425
Genetic markers for T1DM (1)
Locus
6p21
11p21
15q
11q13
6q25
18q
2q31
6q27
ls
IDDM1 2,6
IDDM2 1,29
IDDM3 IDDM4 1,07
IDDM5 1,16
IDDM6 1,1
IDDM7 1,13
% References
35 Davies (1994)
9,4 Davies (1994), Bennet (1995)
-
Field (1994)
2,5 Hashimoto (1994), Davies (1994)
5,5 Davies (1994)
3,5 Meriman (unpub.), Davies (1994)
and Gabbay (1995)
4,5 Owerbach
Davies (1994), Copeman (1994),
IDDM8 1,42 12,9 Luo (1995), Davies (1996)
Genetic markers for T1DM (2)
ls
Locus
3q21-q25
IDDM9
%
References
1,26 8,5 Reed and Todd (unpubl.)
Gough and Todd (unpubl.)
10p11.2-q11.2 IDDM10 1,45 13,7 Davies, Hashimoto (1994)
TOT.
14 95.5
GCK
7p
14q24.3-q31 IDDM11
2q33
IDDM12 (CTLA-4)
2q34
IDDM13
6q21
IDDM15
Rowe (1995)
Field (1996)
Nistico (1996)
Morahan (1996)
Delepine (1997)
Natural History of T1DM
Popul islet-related Abs+ Follow- Risk References
up
Identical Twins
10 yrs 100%Tun RY, BMJ 1994
1st degree relatives (FH+) 5 yrs
70% ICARUS Group Study
Polyendocrinopathy (FH-) 10 yrs
25% Bosi E, Diabetes 1991
Polyendocrinopathy (FH+) 10 yrs
70% Bosi E, Diabetes 1991
High risk newborns (FH+) 2 yrs
50% BABYDIAB (Germany)
High risk newborns (gene+) 2 yrs
50% DIPP Project (Finland)
Sardinian school children (gen)7 yrs 24% SSI Study (Sardinia)
Natural history of T1DM
Triggers ? Triggers ?
Auto Abs +
75%
tt
50%
FPIR
OGTT + Triggers ?
25%
GENES (susc)
0
Time
TYPE 1
DIABETES
Screening for pre-T1DM and related AD
•France
• Spain
Schoolchildren • Holland
• SSI
• Finland
Newborn
• Sweden
• Oxford
• Estonia
• USA
• Germany
• DAISY (USA)
• BABYDIAB (Germany, Australia)
• SNI (Sardinia)
• DIPP (Finland)
• DIABFIN (Italy)
Cost of predicting T1DM
Cost of insulin
•Conventional Therapy (CT) $1450
therapies
(per year)
•Intensive Therapy (ICT)
$ 2 x CT
•CSII
$ 3 x CT
•DPT-1
$1751
•DIPP (follow up=10 yrs)
(newborns)
$245
$733
Cost of Screening
(for each enrolled
case)
Hahl et al. Diabetologia (1998) 41:79-85
Cost of DM (?AD) •$ 92 billions
Birth
100%
Genetic+Abs
screening
13%
Counselling
Abs follow up
Birth
100%
Abs screening
100%
Abs follow up
Prevention of T1DM and other
related AD
T1DM&AD are theoretically
preventable
• Because there are environmental causes
• Because we are beginning to understand the
genetic and immune basis
• Because they develops very slowly
• Because we have good predictive tests
• Because we can stop them in animals
• Because we can run clinical trials
T1DM & AD are suitable diseases for
preclinical screening and intervention
• Serious consequences (in USA 50 deaths yearly from
DKA)
• Treatment following diagnosis expensive,
demanding, limited effect on complications
• Identifiable preclinical phase also for AD
• Identifiable subjects “not at risk” also for AD
• ...but as yet no preventive therapy of proved
efficacy (no penicillin for prediabetes!)
Assigning risk
• Primary prevention: must be based on family
history or high risk HLA - and will miss a lot of
cases!
• Secondary prevention: immune-markers
relatively stable after age 5; almost inevitable
progression with multiple antibodies; excellent
screening efficiency (islet imaging)
Setting up an intervention: in whom?
• Primary: Neonates with family history or high
risk HLA
• Secondary:
– Infants: HLA DR3/4 with antibodies
– Children/young adults with multiple Abs
(T1DM&AD)
– Older adults with LADA
Setting up an intervention: with what?
Should work:
– In animal models
– In newly diagnosed type 1
– In pilot trials (assessed how?)
Must have:
– An acceptable safety profile
– Ease of administration
Setting up an intervention: conclusions
• At present trials must be large, structured,
costly and long term
• Will depend on international collaboration
• We need a disciplined consensus process for
evaluating and prioritizing new therapies
• Role of pharmaceutical industry? clinicians
should have a say
T1DM prevention trials
Primary
Cow’s milk avoidance: TRIGR
Gluten free diet: PREVFIN
Secondary
Nicotinamide: DENIS, ENDIT, New Zealand
Insulin: DPT-1, EPLL SCIT; Schwabing, Brunetti 1999
Tertiary
Cyclosporin: GETREM, French and Canadian studies
Linomide : Franco-Swedish trial
Intervention trials: assumptions
Trial
N
ENDIT
DENIS
DPT (high)
DPT (inter)
530
130
340
490
Yr Diabetes
%
5
40:26
3
30:6
4
84:55
4
24:12
Mahon and Dupre,1997
RRR
%
35
80
35
50
Cyclosporin before onset of T1DM
• 6 relatives vs 9 historical controls
• All controls developed diabetes in 12
months
• 4/6 cyclosporin treated patients developed
diabetes within 4 years (5, 24, 24 and 47
months)
Carel et al., 1996
Intervention in early infancy?
•
•
•
•
•
Level of risk?
Safety of intervention? Long term data?
Acceptability/compliance?
Efficacy demonstrated in other AD?
Can the intervention be tested effectively in this
category of patient?
Emergence of at least one auto-Ab
by the age of 2 years (n=173)
FOLLOW-UP, MONTHS
3
6
9
12
18
24
CASEIN
0/83
HYDROLYSATE
0/75
1/72
3/71
1/67
1/62
CM-BASED
1/84
6/79
7/78
6/77
7/76
0/87
FORMULA
The Second TRIGR Pilot Study
TOTAL
3/84
(3.6%)
p=0.06
10/89
(11.2%)
No. of births/month
EURODIAB Sardinia (1989-98)
birth seasonality
20
18
16
14
12
10
8
6
4
2
0
P<0.001
Jan-March
Jan-March
N=1928, 0-29yr
Apr-June
Jul-Sept
Apr-June
Jul-Sept
Seasons of birth
Oct-Dec
Oct-Dec
Future Directions?
• Surrogate end-points
• Safety and acceptability need to be balanced
against efficacy
• Early “one-off” therapy would be ideal
• Explicit standards for performance of trials
• Fewer, better quality studies based on
international consensus
• Lessons from other human autoimmune
disease?