Can Type 1 Diabetes
Be Prevented?
Della Matheson, RN, CDE
Research Coordinator, Type 1 Diabetes TrialNet
University of Miami, Diabetes Research Institute
Type 1 Diabetes Prevention in NOD
Mice
AAV murine IL-10
AAV rat preproinsulin gene (vLP-1)
Adenovirus expressing mIL-4
Aerosol insulin
Allogenic thymic macrophages
Alpha Galactosylceramide
Alpha-interferon (rIFN-alpha)
Alpha/beta T cell receptor thymocytes
Aminoguanidine
Androgens
Anesthesia
Antioxidant MDL 29,311
Antisense GAD mRNA
Azathioprine
Anti-B7-1
Bacille Calmette Gue’rin (BCG)
Baclofen
Bee venom
Biolistic-mediated IL-4
Blocking peptide of MHC class II
Bone marrow transplantation
Castration
Anti-CD3
Anti-CD4
CD4+CD25+regulatory T cells
Anti-CD8
Anti-CD28 MAb
Cholera toxin B subunit-insulin protein
Class I derived self-I-A beta(g7) (54-76) peptide
Cold exposure
Anti-complement receptor
Complete Freund’s adjuvant
Anti-CTLA-4
Cyclic nucleotide phosphodiesterases (PDEs)
Cyclosporin
Cyclosporin A
DC deficient in NF-kappaB
DC from pancreatic lymph node
DC with IL-4
Deflazacort
Deoxysperogualin
Dexamethasone/progesterone/growth hormone/estradiol
Diazoxide
1,25 dihydroxy Vitamin D3, KH1060
1,25 dihydroxycholecalciferol
1,25 dihydroxyl Vitamin D3
Elevated temperature
Emotionality
Encephalomyocarditis virus (ECMV)
Essential fatty acid deficient diets
FK506
FTY720 (myriocin)
GAD 65 peptides in utero
Anti-GAD monoclonal antibody
Galactosylceramide
Glucose (neonatal)
Glutamic acid decarboxylase
(intraperitoneal, intrathymic, intravenous, oral)
Glutamic acid decarboxylase 65 Th2 cell clone
Glutamic acid decarboxylase peptides
(intraperitoneal, intrathymic, intravenous, oral)
Gonadectomy
Guanidinoethyldisulphide
Heat shock protein 65
Heat shock protein peptide (p277)
Hematopoietic stem cells encoding proinsulin
Housing alone
Human IGF-1
I-A beta g7(54-76) peptide
Anti-I-A monoclonal antibodies
Anti-ICAM-1
IgG2a antibodies
Immobilization
Inomide
Anti-integrin alpha 4
Insulin (intraperitoneal, oral, subcutaneous, nasal)
Insulin B chain (plasmid)
Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal)
Insulin-like growth factor I (IGF-I)
Anti-intercellular adhesion molecule-1 (ICAM-1)
Interferon-alpha (oral)
Interferon-gamma
Anti-interferon-gamma
Interferon-gamma receptor/IgG1 fusion protein
Interleukin-1
Interleukin-4
Interleukin-4-Ig fusion protein
Interleukin-4-plasmid
Interleukin-10
Interleukin-10-plasmid DNA
Interleukin-10-viral
Interleukin 11-human
Interleukin-12
Intrathymic administration of mycobacterial heat shock protein 65
Intrathymic administration of mycobacterial heat shock peptide p277
Islet cells-intrathymic
L-Selectin (MEL-14)
Lactate dehydogenase virus (LDH)
Large multilamellar liposome
Lazaroid
Anti-leukocyte function associated antigen (LFA-1)
Anti-LFA-1
Linomide (quinoline-3-carboxamide)
Lipopolysaccharide-activated B cells
Lisofylline
Lymphocyte choriomeningitis virus (LCMV)
Anti-lymphocyte serum
Lymphoctyte vaccination
Lymphocytic choriomeningitis virus
Anti-L-selectin
Lymphotoxin
LZ8
MC1288 (20-epi-1,25-dihydroxyvitamin D3)
MDL 29311
Metabolically inactive insulin analog
Anti-MHC class I
Anti-MHC class II
MHC class II derived cyclic peptide
Mixed allogeneic chimerism
Mixed bone marrow chimeras
Monosodium glutamate
Murine hepatitis virus (MHV)
Mycobacterium avium
Mycobacterium leprae
Natural antibodies
Natural polyreactive autoantibodies
Neuropeptide calcitonin gene-related peptide
Nicotinamide
Nicotine
Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation
NKT cells
NY4.2 cells
OK432
Overcrowding
Pancreatectomy
Pentoxifylline
Pertussigen
Poly [I:C]
Pregestimil diet
Prenatal stress
Preproinsulin DNA
Probucol
Prolactin
Rampamycin
Recombinant vaccinia virus expressing GAD
Reg protein
Reg protein
Rolipram
Saline (repeated injection)
Schistosoma mansoni
Semi-purified diet (e.g., AIN-76)
Short term chronic stress
Silica
Sirolimus/tacrolimus
Sodium fusidate
Soluble interferon-gamma receptor
Somatostatin
Non-specific pathogen free conditions
Streptococcal enterotoxins
Streptozotocin
Sulfatide (3’sulfogalactosylceramide)
Superantigens
Superoxide dismutase-desferrioxamine
Anti-T cell receptor
TGF-beta 1 somatic gene therapy
Th1 clone specific for hsp60 peptide
Anti-thy-1
Thymectomy (neonatal)
Tolbutamide
Tolerogenic dendritic cells induced by vitamin D receptor ligands
Top of the rack
Treatment combined with a 10% w/v sucrose-supplemented drinking water
Tumor necrosis factor-alpha
TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))
Vitamin E
Anti-VLA-4
Discovery of Insulin
Auto-Antibodies
Canadian-European
Cyclosporin Study
Remissions
Azathioprine &
Steroids
Skyler, Diabetes 1988; 37:1574-1582 Silverstein et al NEJM 1988;319:599-604
Natural History of Type 1 Diabetes
PUTATIVE
ENVIRONMENTAL
TRIGGER
CELLULAR (T CELL) AUTOIMMUNITY
HUMORAL AUTOANTIBODIES
BETA CELL MASS
(ICA, IAA, Anti-GAD65, IA2Ab, ZnT8 )
LOSS OF FIRST
PHASE
INSULIN RESPONSE
GENETIC
PREDISPOSITION
(IVGTT)
GLUCOSE INTOLERANCE
INSULITIS
BETA CELL
INJURY
(OGTT)
“PRE”DIABETES
CLINICAL
ONSET
DIABETES
TIME
ADA Position Statement: 1990
•Sufficient data exist to warrant intervention studies for prevention of T1D
•Intervention for prevention should be attempted only in the context of
defined clinical trials
•Intervention studies are best accomplished by randomized controlled studies
•A registry of intervention studies should be maintained, and all planned
studies should be reported to a coordinating body
•Screening of high risk populations is encouraged
•Risk assessment, counseling, and follow-up must be offered.
•Studies must be evaluated on the basis of potential risks vs. benefits;
children should not be excluded, on the basis of age alone, from a therapeutic
study that may benefit them by preventing diabetes
How Risk is Determined
• Step 1: Screening antibody testing
• Step 2: Monitoring
OGTT
HbA1c
HLA (DQA0102, DQB0602)
Risk Score (age, BMI, C-peptide)
Survival Distribution Function
DPT-1 – Time to Diabetes
By Number of Antibodies
1.0
0.9
0.8
0.7
0.6
0.5
P- Value< 0.001
(Log Rank Test)
Number at Risk
0.4
0.3
24151
1718
405
378
147
0.2
0.1
0.0
0
22297
1401
297
255
95
17049
1045
229
192
61
1
2
3
9052
557
118
78
30
7439
457
91
49
22
6198
371
66
31
16
4
5
6
3524
199
35
14
8
0
1
2
3
4
7
8
Years Followed
n = 26799
STRATA:
11807
743
163
130
40
0
1
2
3
4
Combined DPT-1 Parenteral & Oral Insulin Trials
1.0
Survival Distribution Function
0.9
Indeterminate:
BG > 200 mg/dl at 30, 60, or 90 min
0.8
0.7
0.6
0.5
0.4
Normal Glucose Tolerance
P- Value< 0.001
(Log Rank Test)
0.3
Indeterminate only
0.2 Number at Risk
57
0.1 64
26
536
0.0
42
51
20
499
23
35
16
410
16
19
9
308
9
6
7
220
3
2
3
110
1
1
1
1
43
2
0
1
2
3
4
5
6
Combined
1
IGT only
7
8
Comb IFG+(IGTor Indet)
IGT Only
Indet Only
NGT
9
10
Years Followed
STRATA:
Comb IFG + (IGT or Indet)
Indet Only
IGT Only
NGT
DPT-1 Objective
• To determine of antigen based
therapy (specifically insulin) could
prevent or delay onset of T1D
• Parenteral Insulin
In Subjects with High Risk: > 50% 5 year risk
• Oral Insulin
In Subjects with Moderate Risk: 25-50% risk
The DPT·1 Funnel
 103,391
Relatives Screened
 97,635 Eligible Samples
 97,273 Samples Analyzed

3483 Samples ICA+
(3.58%)

711 Subjects
Randomized
DPT-1 Parenteral Study – Time to Diabetes
By Treatment
1.0
Survival Distribution Function
0.9
0.8
0.7
0.6
Treated
0.5
0.4
Control
0.3
0.2
0.1
0.0
P- Value= 0.796
(Log Rank Test)
Number at Risk
169
170
0
144
131
96
101
69
69
39
40
13
14
1
2
3
4
5
1
6
Years Followed
STRATA:
Intervention
Observation
Intervention
Observation
7
DPT-1 Oral Insulin Trial
Time to Diabetes By Treatment
Survival Distribution Function
1.0
0.9
0.8
Treated
0.7
Control
0.6
0.5
0.4
P- Value= 0.188
(Log Rank Test)
0.3
0.2
Number at Risk
0.1
186
186
174
170
146
137
110
102
85
71
40
37
23
12
1
2
3
4
5
6
Oral Insulin
Oral Placebo
0.0
0
Years Followed
STRATA:
Oral Insulin
Oral Placebo
7
DPT-1 Oral Study - Time to Diabetes - By Treatment
Subset: IAA Confirmed > 80 nU/ml
Survival Distribution Function
1.0
Projected 4.5 – 5 year delay
0.9
0.8
Treated
0.7
0.6
0.5
Control
0.4
P- Value= 0.015
(Log Rank Test)
0.3
0.2
Number at Risk
0.1
130
133
122
121
104
96
86
69
66
46
40
32
23
12
1
2
3
4
5
6
Oral Insulin
Oral Placebo
0.0
0
Years Followed
STRATA:
Diabetes Care 2005; 28:1068-76
Oral Insulin
Oral Placebo
7
1.0
Insulin Effect Most Evident in Subjects
with Baseline
IAA ≥ 300
IAA >= 300
0.6
Projected 10 year delay
Log-rank P=0.01
0.4
Peto Pr. P=0.01
0.2
Hazard Ratio: 0.41 (0.21, 0.80)
N=63 (Ins.) and 69 (Plac.)
0.0
Proportion Free of Diabetes
0.8
Oral Insulin
Placebo
0
1
2
3
Years
4
5
6
endit
European Nicotinamide
Diabetes
Intervention Trial
es
Percentage developing diabetes
Overall Treatment Effect:
Intention To Treat Analysis
50
40
30
Nicotinamide
20
Placebo
10
0
0
N = 549
Placebo 275
Nicotinamide 274
1
2
3
4
Years since randomisation
245
260
232
232
205
208
184
171
5
NIDDK NIAID NICHDNCRR
JDRF
ADA
TrialNet Sites in North America
14 Clinical Centers
+ 200 North American Affiliates
TrialNet International Sites
+ 25 International Affiliates
Turku, Finland
Malmo, Swedem
Bristol, UK
Melbourne, Australia
Milan, Italy
Munich, Germany
Other NIH Funded Consortiums
Immune Tolerance Network
TRIGR Study (Trial to Reduce IDDM in the
Genetically At Risk) breastfeeding/hydrolyzed
formula vs standard formula; 2,160 babies to be
followed x 10 years; results expected in 2017
TEDDY(Environmental Triggers and Determinants
of Type 1 Diabetes) 7,801 babies: 788 first degree
relatives with genetic risk (10% risk), 7013 nonrelatives with genetic risk (3%)
2836 families (11,626) sib pairs
493 families (1479):
trio’s
968 Controls
Natural History of Progression
to Type 1 Diabetes New Onset Studies:
Risk:
Risk: Low
Low
To Moderate
BETA CELL MASS
(no antibodies)
•Natural History
(Screening
113,000)
C
(antibodies present
Normal OGTT)
•Natural History
(Monitoring)
ORAL INSULIN
NIP Pilot
CTLA-4IG
Helminths
Genetic &
Mechanistic Studies
ANTICD3
Risk:
High
•MMF/DZB
•AntiCD20
•CTLA-4 Ig
•GAD-alum
•Anti-IL1β
•Metabolic Control
(DirectNet)
•Thymo (ITN)
•IL-2/Rapa (ITN)
•AntiCD3 (ITN)
•Alefacept (ITN) not yet
completed
(multiple
antibodies
&/or abnormal Diabetes
OGTT)
Diagnosed
Strategies for Interdicting
Type 1 Diabetes
Immunosuppressive Agents: Inhibit or
Prevent Activity of the Immune System:
Cyclosporin √
Azathiaprine √
MMF/DZB
Thymoglobulin (ATG)
IL2/Rapamycin
Anti-CD20 (Rituximab) √
CTLA-4Ig (Abatacept) √
Anti-CD3 (Teplizumab) √
Not yet reported:
Alefacept (anti-CD2)
APC
TH 0
cell
TH 2
ß cell
Protective Cytokines
IL-4, IL-4, IL10
Beta cell survival
How Immunosuppressive Agents Work
APC
TH 0
cell
ß cell
Death
IL-1, TNF-ą,
TN-ß, IFN-y
02, H202, NO
TH 1
TH 2
Cytotoxic
MØ
& T Cells
Destructive Cytokines
Other Strategies for Interdicting
Type 1 Diabetes
Antigen-Specific Therapies
•rhGAD65 with Alum (Diamyd)
•Oral Insulin √
Probiotic Therapy
Helminths (TSO)
Protective T cells
APC
TH
0
cell
ß cell
Death
IL-1, TNF-ą,
TN-ß, IFN-y
02, H202, NO
TH
Cytotoxic
MØ
& T Cells
1
TH2
Destructive
Cytokines
IFN-y, IL-2
Choosing the Right Therapy
• The Benefit vs. Risk Ratio must be
appropriate to the degree of risk for
development of type 1 diabetes
• Must have proven efficacy
• Must be able to include children
Anti-CD3 (Teplizumab)
•High Risk: > 75% Risk for development of type 1
diabetes over the next 5 years
•140-170 participants ; follow-up 4-6 years
•1:1 randomization; Teplizumab: Control
•14 Day Infusion (51mcg/m2 -826mcg/m2 day
13)
•Ages: 8-45
of 633 participants in studies using
AntiCD3, 378 were children
4-
Risk: AntiCD3
• Lymphopenia (low WBC): 15%
with 2% graded as severe
• Infections 49.5% with 48.6% mild
to moderate
• Cytokine Release Syndrome:
5.7% with 85% mild moderate chills, fever, headache, nausea,
vomiting, achiness
• Rash 42-62%
hOKT3g1(Ala-Ala) in new onset Type
1 diabetes
C-peptide
Hemoglobin A1c
160
140
Insulin use
10
0.9
Drug
Control
Drug
Control
0.8
9
Drug
Control
100
80
60
Insulin dose (U/kg)
Hemoglobin A1c (%)
AUC (pmol/ml/240min)
120
8
7
0.7
0.6
0.5
0.4
40
6
0.3
20
5
0
0
6
12
Month
18
24
0
5
10
15
Month
20
25
30
0.2
0
5
10
15
Month
20
25
30
Therapies for Moderate Risk: CTLA 4Ig
(Abatacept)
Moderate risk: >32% 5 year risk
• 2 antibodies (but not mIAA)
• Normal OGTT
• Ages 6-45
• 1:1 randomization, 206 participants
• 14 infusions over 1 year (2 in the first
month, then 1 monthly)
• Follow: primary outcome: abnormal GTT
secondary outcome: diabetes
CTLA-4Ig (Abatacept) Risks
Infusion and Hypersensitivity Reactions:
2% (47 of 2,514)
Infectious Adverse Events:
54% in Abatacept and 48% Control;
most upper respiratory infections with no
increase in neutropenia or EBV
Therapies for Moderate Risk: Oral
Insulin
Oral Insulin: >32% 5 year risk
• 2 antibodies, one of which is “insulin
autoantibody (mIAA)”
• Normal Oral Glucose Tolerance Test
• Ages 4-45
• Risk – no adverse events or side effects
observed in DPT-1
• 1 capsule per day (7.5mg)
• 1:1 randomization
Antigen Based Therapy/Oral
Tolerance: Mode of Action
Protective
Cytokines
Oral Antigen
Regulatory (Th2 / Th3)
Lymphocytes Producing
Protective Cytokines
Inhibition of -Cell
Autoimmunity and
Prevention of Diabetes
Insulin Producing
-cells
Autoimmune
Lymphocytes
Therapy for Low to Moderate Risk
Helminths: Trichuris suis ova
(Porcine whipworm ova)
•Proof of principle established
in inflammatory bowel
disease and MS
•Oral bi-weekly administration
•Well tolerated
•Use of therapeutic helminth
therapy based on the “Hygiene
Hypothesis”
Hygiene Hypothesis
1910 = 65% helminthic infections; current = < 2%
1901 Paul Ehrlich dictum: “autotoxicus”: body’s immune system would
never attack host tissue to cause disease
20th Century brought an end to this theory with the identification of > 80
autoimmune diseases.
Enhance expression
Of Protective
T Regulatory Cells
Coronado Biosciences
Patients and
Methods
This was a randomized, double blind, placebocontrolled trial conducted at the University of Iowa
and select private practices. Trichuris suis ova were
obtained from the US Department of Agriculture.
The trial included 54 patients with active colitis,
defined by an Ulcerative Colitis Disease Activity
Index of > or =4. Patients were recruited from
physician participants and were randomly assigned
to receive placebo or ova treatment. Patients
received 2500 Trichuris suis ova or placebo orally at
2-week intervals for 12 weeks.
Results
ASP 1002 significantly improved UCDAI versus
placebo (stool frequency, presence of blood in the
stool, mucosal appearance)
Conclusion
Ova therapy seems safe and effective in patients
with active colitis.
Summers, et.al., Gastroenterology 2005
Coronado Biosciences
40
Does not multiply in human host
Colonization is self-limited in humans
No systemic phase
No direct transmission
Ova stable
Coronado Biosciences
Side Effects limited to GI symptoms:
nausea, upper abdominal cramping,
Diarrhea, flatulence occurring during the first
few weeks of treatment and then subsiding
41
Cooke, et.al., Parasite Immunology 1999
Coronado Biosciences
42
Saunders, et.al, Infect. Immunol 2007
Coronado Biosciences
43
Can Type 1 Diabetes be Prevented?
BETA CELL MASS
GENETIC
PREDISPOSITION
Combination Therapies may need to be
employed
• primary prevention
• anti-inflammatory agents
• beta cell expansion therapies
INSULITIS
• antigen-specific therapies
BETA CELL
• immunosuppressive agents
INJURY
ORAL
INSULIN
CTLA-4IG
“PRE”DIABETES
ANTICD3
Helminths
CLINICAL
ONSET
DIABETES
TIME
New Onset Studies
Underway:
•UCSF, Phase 1 Study: Infusion of T regulatory
cells; 14 participants, ages 18-45
•Albert Einstein College of Medicine, Bronx NY,
Phase 4: Exenatide; 20 patients, ages 12-18
•University Sao Paulo General Hospital, Phase 1:
High Dose Immunosuppression and Autologous
Hematopoeitic Stem Cells; 30 participants, ages
16-35
Why is Prevention
Important?
Without prevention there is no Cure!!!!
Evidence of reactivated autoimmunity
after whole organ and islet cell
transplantation
Get Involved – participate in Research
www.clinicaltrials.gov
www.diabetestrialnet.org
www.immunetolerance.org
Debt of Gratitude