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Immunopathogenesis of Type 1 Diabetes:Immunopathogenesis of Type 1 Diabetes:
Approaches to Prevention and CureApproaches to Prevention and Cure
Peter A. Gottlieb, MD George S. Eisenbarth, MD, PhD
Jay Skyler, MD+
Barbara Davis CenterUniversity of Colorado Health Sciences Center
+Diabetes Research InstituteUniversity of Miami Medical School
Magnitude of Diabetes WorldwideMagnitude of Diabetes WorldwideUSA
• Approximately 6% are diagnosed (90%Type2)• All with Type 1 and 1/3 of Type 2 will require
insulin (Expected to Rise significantly)• Cost $100-$140 billion annually
Diabetes in Rest of the World• 2 - 25% in different Countries (average 10%)• Incidence rising every year everywhere,
especially for Type 2 Diabetes• Disease is still under-diagnosed and delayed in
diagnosis• Prevention of pre- type 1 and type 2 diabetes
Incidence Type 1 DiabetesIncidence Type 1 Diabetesper 100,000 per year Children <=14per 100,000 per year Children <=14
05
1015
2025
3035
40
Karvonnen et al., Diabetes Care, 23:1516, 2000
Type 1 DM incidence is rising 3-5% /yearType 1 DM incidence is rising 3-5% /year
0
10
20
30
40
50
60
1950 1960 1970 1980 1990 2000
Finland
Colorado
Germany
Incidence /100,000/ yr children age 0-14
1.4 million patients in the U.S.
Rewers
Finland Incidence Type 1 Finland Incidence Type 1 DM/100K 1965-1996DM/100K 1965-1996
05
1015
20
2530
3540
45
50
Yrs. 65-74 75-84 85-96
1-4 yrs
5-9 yrs
10-14 yrs
Diabetes Care: 22:1066-1070
Main PointsMain Points
• Type 1 diabetes is an autoimmune disease• It is a predictable disease with different
phases• Approaches to prevention and cure are
possible.• Combination therapy targeting multiple
pathways may hold the greatest hope for prevention and cure.
0
20
40
60
80
100
0 2.5 5 7.5 10 12.5 15
3 Abs
2 Abs
1 Ab
Progression to Diabetes vs Number of AutoantibodiesProgression to Diabetes vs Number of Autoantibodies(GAD, ICA512, Insulin)(GAD, ICA512, Insulin)Percent not Diabetic
Years of Follow-up
3 Ab n = 41 17 8 1 2 Abs n = 44 27 15 4 2 11 Abs n = 93 23 14 10 6 4
Verge et al, Diabetes 45:926-933, 1996 BDC
The Major Histocompatibility Complex
Human
Mouse
DP DQ DR B C A
K I-A I-E D L
Chromosome 6
Chromosome 17
Class II Class III Class I
Class II Class III Class IClass I
Complement Proteins
Cytokines Class I-like genesand pseduogenes
Antigen Processing Genes
DQB1*0402
Asp57
Leu56
-chain
-chain
BDC
IDDM risk by age 20 HLA-DR DQB1 Frequency %
High 1:15 3/4 0201/0302 2.4
Moderate 4/x 0302/ 12.71:60-1:200 4/4 0302/ 3.0
3/3 0201/0201 1.4
Average 1:300 3/x 0201/ 12.53/4 0201/not 0302 1.0
Lower than 1:300 4/x, 4/4 /not 0302 6.62/xothers
0602 60.4
HLA-Defined T1 DM Risk GroupsHLA-Defined T1 DM Risk GroupsDAISY, Denver Population, n=21,713DAISY, Denver Population, n=21,713
Japanese Caucasian
DRB1-DQB1 Type 1 diabetes HF1) Type 1 diabetes HF haplotype susceptibility susceptibility
DRB1*0405-DQB1*0401 susceptible present unknown rare
DRB1*0901-DQB1*0303 susceptible present unknown rare
DRB1*0301-DQB1*0201 unknown rare susceptible present
DRB1*0401-DQB1*0302 unknown rare susceptible present
DRB1*1501-DQB1*0602 protective present protective present
Different haplotypes are associated with T1D Different haplotypes are associated with T1D in Japanese and Caucasian populationsin Japanese and Caucasian populations
1) HF: Haplotype frequency, http://square.umin.ac.jp/JSHI/frame.html
IDDM2IDDM2 Genotypes in U.S. Caucasians Genotypes in U.S. Caucasians
I/III III/III0
20
40
60
80
100
I/I
IDDM Controls
VNTR Class
%
Pugliese et al., J. Autoimm 7: 687- 694, 1994
PredisposingClass I VNTR
ProtectiveClass III VNTR
Thymus INS Transcription VNTR alleles affect VNTR alleles affect INSINS
transcription in thymustranscription in thymus
PredisposingClass I VNTR
ProtectiveClass III VNTR
Pancreas INS Transcription
Class I VNTR
cDN
A
DN
A
cDN
A
DN
A
Class III VNTR
Pugliese et al. Nature Genetics
15:293-297, 1997
Chromosome λs O.R. LOD Pgenome
IDDM1 mhc 6p21 3.35 “App 30” 116.3 10(-4)
IDDM2 ins 11p15 1.16 2.2 1.87 .37
PTPN22 1p13 1.05 1.7 NS
IDDM12,7 (“CTLA-4”)
2q31-33 1.19
CTLA 1.01
“3”
CTLA 1.1
3.34 .016
3p13-p14 1.15 1.52 .649
IDDM15 6q21 1.56 22.4
9q33-q34 1.13 2.2 .191
IDDM10 10p14-q11 1.12 “3” 3.21 .021
11p15 1.16 1.87 .371
12q14-q12 1.10 1.66 .528
16p12-q11.1 1.17 1.88 .363
16q22-q2 1.19 2.64 .075
19p13.3-p13.2 1.15 1.92 .338
No Evidence: IDDM 4,6,9,11,16,17,18 (O.R. MHC, DR3/4-DQ8) Adapted from Concannon et al, Diabetes: 54:2995-3001, 2005 BDC
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
6 and younger n= 387-10 n= 3311-14 n= 4215-24 n= 3725 and older n= 37
Difference significant (log-rank and gen'ld wilcoxon p= 0.001 , 0.001 )
ProportionProportion of Twins Without Diagnosis of DM of Twins Without Diagnosis of DM
Years Since DM Diagnosis in Index TwinRedondo, Diabetologia
Type 1a Diabetes: An Autoimmune Type 1a Diabetes: An Autoimmune DisorderDisorder
• Autoantibodies to islet proteins: insulin, Autoantibodies to islet proteins: insulin, GAD 65, IA-2 (ICA512)GAD 65, IA-2 (ICA512)
• T cell responses to islet proteinsT cell responses to islet proteins• HLA associationHLA association• Immunosuppressive drugs can ameliorate Immunosuppressive drugs can ameliorate
the disorder – ex. Cyclosporinethe disorder – ex. Cyclosporine• Recurrence of autoimmunity in pancreas Recurrence of autoimmunity in pancreas
transplants between monozygotic twinstransplants between monozygotic twins
Autoreactivity: Autoreactivity: CD4 and CD8 T cell responsesCD4 and CD8 T cell responses
Prediabetic T cell responses to CD4 Prediabetic T cell responses to CD4 epitopes from IA-2epitopes from IA-2
Keleman, Gottlieb et al. 2004. Journal of Immunology.15;172(6):3955-62.
Cytotoxic T-cells from HLA-A*0201 patients Cytotoxic T-cells from HLA-A*0201 patients with T1D recognize preproIAPP 5-13with T1D recognize preproIAPP 5-13
Diabetes 2003 52:2649Diabetes 2003 52:2649
ELISPOT analysis of peripheral blood mononuclear responses to ELISPOT analysis of peripheral blood mononuclear responses to preproIAPP5-13 in patients with the correct HLA to recognize the preproIAPP5-13 in patients with the correct HLA to recognize the peptide.peptide.
T cell reactivity to CD8 Epitopes T cell reactivity to CD8 Epitopes from T1D subjectsfrom T1D subjects
0
10
20
30
40
5050
300
550 patients (n=19)
controls (n=6)
IFN
-ga
mm
a p
rod
uc
ing
sp
ots
/2x
05
PB
MC
s
Ouyang, et al, submitted
Natural History of Type 1 DiabetesNatural History of Type 1 Diabetes
CELLULAR (T CELL) AUTOIMMUNITYCELLULAR (T CELL) AUTOIMMUNITY
LOSS OF FIRST PHASE LOSS OF FIRST PHASE INSULIN RESPONSEINSULIN RESPONSE
(IVGTT)(IVGTT)
GLUCOSE INTOLERANCEGLUCOSE INTOLERANCE(OGTT)(OGTT)
HUMORAL AUTOANTIBODIESHUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD(ICA, IAA, Anti-GAD6565, IA, IA22Ab, etc.) Ab, etc.)
PUTATIVEPUTATIVEENVIRONMENTALENVIRONMENTAL
TRIGGERTRIGGER
CLINICALCLINICALONSETONSET
TIMETIME
BE
TA
CE
LL
MA
SS
BE
TA
CE
LL
MA
SS
DIABETES
“PRE”-DIABETES
GENETICPREDISPOSITION
INSULITISBETA CELL INJURY
Stochastic ModelStochastic Model
An
tigen S
pecific T
xA
ntigen
Sp
ecific Tx
Imm
un
osup
presive
Imm
un
osup
presiv e
Tx
Tx
Non
Sp
ecific Tx
Non
Sp
ecific Tx
PREVENTIONPREVENTION
Primary PreventionPrimary Prevention
autoantibodies or diabetes as the endpoint
avoidance of environmental agents ?
induction of autoantigen tolerance ?
Rewers-BDC
Early childhood dietEarly childhood dietand T1 DM ?and T1 DM ?
TRIGR 3-yr Follow-up Results TRIGR 3-yr Follow-up Results Seroconversion to 1+ AutoantibodySeroconversion to 1+ Autoantibody
0%
5%
10%
15%
20%
Cows MilkFormula
CaseinHydrolysate
p=0.043p=0.043
n=173n=173
Nutritional Intervention to Prevent Type 1 Diabetes (NIP – Diabetes)
Plan: Use of an omega 3 fatty acid (Docosahexanoic acid or DHA) to prevent the initial autoimmune process.
DHA supplementation will begin in:
• the last trimester of pregnancy
• the first 6 months after birth
It will be continued in medium or high risk infants for 3 years.
Dietary Intake – Western DietsDietary Intake – Western Diets
The Ratio of n-6 to n-3 Fatty Acids in our diet:
1800’s = 1 or 2 (n-6) to 1 (n-3)
Present = 20 or 30 (n-6) to 1 (n-3)
High n-3: anti-inflammatory anti-thrombotic hypolipidemic vasodilatory
(High n-6 has the opposite effect)(Am J. Clin Nutr. 70, 560-569, 1999)
III) Mechanisms of Action of Omega 3 Fatty Acids
Decrease AA in cell membranes alters PGE 1 and 2 production (inflammatory prostaglandins)
Decrease pro-inflammatory cytokines TNF, IL-1 and IL6 ( efficacy of IL4 and IL10)
Decrease ICAM-1 on monocyte surfaces in humans fed 3g fish oil/dx 21 days ( chronic inflammation)
DHA and /or vit D may have important immune modulating effects in babies at risk for developing
T1DM
ENDIT: Kaplan-Meier failure curveENDIT: Kaplan-Meier failure curve
- European Nicotinamide Diabetes Intervention Trial (ENDIT) Group Lancet 2004; 363: 925–31
Ongoing or CompletedOngoing or Completed Prevention Trials Prevention Trials
• TRIGR - Casein Hydrolysate - ongoing (Cow’s Milk Elimination)
• NIP - Nutritional Intervention to Prevent T1DM
– Starting June, 2006• DIPP - Nasal Insulin - ongoing• INIT - IntraNasal Insulin Trial
• ENDIT - Nicotinamide - Ineffective• DPT-1 - Oral Insulin – May be effective in
subgroup- Parenteral - Ineffective
• Anti-CD3 and Exanitide- proposed
Lat
e L
ate
stag
est
age
Ear
ly s
tage
Ear
ly s
tage
Antigen Specific TherapyAntigen Specific Therapy
• Magic bullet Approach
• Targets autoreactive cells
• Generates protective cells
• Spares rest of immune system
• Minimal Toxicity
• Timing may be critical to efficacy
InsulinInsulin• Beta Cell Specific
• Predominant T-cell reactivity islets NOD
• Insulin expressed lymphoid tissue by dendritic and macrophage-like cells
• Thymic messenger RNA for insulin related to “protective” insulin allele
• Proinsulin expression in thymus prevents NOD diabetes
Effect of Insulin Injections on Effect of Insulin Injections on Diabetes & InsulitisDiabetes & Insulitis
0
10
2030
40
50
60
7080
90
100
Placebo Insulin
% D
iab
etes
Female NOD MiceFemale NOD Mice
Atkinson, Diabetes 1991Atkinson, Diabetes 1991
0
0.5
1
1.5
2
2.5
3
Placebo Insulin
Insu
liti
s S
core
Prevention of Diabetes with B:9-23 Prevention of Diabetes with B:9-23 Peptide “Immunization” Peptide “Immunization”
0 10 20 30 40 50 60
0
20
40
60
80
100
Age in Weeks
Pe
rce
nt
No
t D
iab
eti
c
Tetanus control
B:9-23 peptide
D.Daniel ,D.Wegmann . PNAS,1996D.Daniel ,D.Wegmann . PNAS,1996
Efficacy of NBI-6024 in animal models Efficacy of NBI-6024 in animal models with ‘new onset’ Type I diabetes.with ‘new onset’ Type I diabetes.
0 20 40 60 Age (weeks)
0
20
40
60
80
100 %
Dia
be
tes-F
ree
control peptide (n = 21)
6024 (n = 21)
p < 0.02
Figure 3. NBI-6024 Treatment of NOD mice Near Onset of Disease
Alleva, et al, Diabetes 2002Alleva, et al, Diabetes 2002
NBI-6024-specific Th2 cells adoptively transferred protection in NOD mice
APL-specific Th2 cell line transfer
10 18 26 32 40 46 53 600
20
40
60
80
100
Days Following Transfer
Figure 4. Figure 4.
From Alleva, et al. Diabetes. 2002 51(7):2126-34.
0 5 10 15 20 250
25
50
75
100PBSAnti-CD3proIns II Hi QWproIns II Hi Q2WproIns II Hi Q4W
DNA dosing stopped
weeks post hyperglycaemia
Per
cent
Dia
beti
c
BHT-3021 QW
BHT-3021 Q2W
BHT-3021 Q4W
Mouse BHT-3021 provides significant delayof diabetes onset in hyperglycemic mice at all dosing frequencies
Treatment of hyperglycemic mice with mouse BHT-3021 restores normoglycemia
PBS
entry BG final BG0
100
200
300
400
500
600
mg
/dl
proIns II-DNA Hi Expression
entry BG final BG0
100
200
300
400
500
600
mg
/dl
DPT-1 Parenteral Study – Time to DiabetesDPT-1 Parenteral Study – Time to DiabetesBy TreatmentBy Treatment
1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
0.00.0
169169170170
144144131131
9696101101
69696969
39394040
13131414 11
Number at RiskNumber at Risk
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
nS
urv
ival
Dis
trib
uti
on
Fu
nct
ion
P- Value= 0.796P- Value= 0.796(Log Rank Test)(Log Rank Test)
InterventionInterventionObservationObservation
00 11 22 33 44 55 66 77
Years FollowedYears Followed
STRATA:STRATA: InterventionIntervention ObservationObservation
ControlControl
TreatedTreated
New Engl J Med 2002; 346:1679
Rationale for Oral InsulinRationale for Oral Insulin
TH1Cell
s
IFN-, IL-2
DestructiveCytokines
TH2Cells
IL-4, IL-5, IL-10 TGF-
TH3Cells
ProtectiveCytokines
Oral Antigen ProtocolOral Antigen Protocol
• Initial results appeared to suggest no effect of oral insulinInitial results appeared to suggest no effect of oral insulin• Secondary analysis suggests that for original cohort Secondary analysis suggests that for original cohort
(IAA>80) there is delay in onset compared to placebo (IAA>80) there is delay in onset compared to placebo treated patients.treated patients.
• In fact, the higher the titer of IAA, the greater the In fact, the higher the titer of IAA, the greater the protective effect that was observed.protective effect that was observed.
• A new trial to confirm these observations is being A new trial to confirm these observations is being planned by TrialNet (Start Date – Nov, 2006)planned by TrialNet (Start Date – Nov, 2006)
Recent and Ongoing Antigen-specific Recent and Ongoing Antigen-specific Immunotherapy Trials in T1DMImmunotherapy Trials in T1DM
• Joslin Parenteral Insulin: “Delay”• Schwabing Parenteral Insulin: “Delay”• DPT-1 Parenteral: No Effect• DIPP (intranasal): ?• Melbourne (intranasal): ?• DPT-1 Oral Insulin: Possible for subgroup• Italy/France Oral Insulin: No Effect• Maclaren Oral Insulin: ?• NBI 6024-0003 (Neurocrine) – Phase II Spring, 2007• B chain – Orban, Joslin - Phase I ?• hGAD s.c. in alum (Diamyd) 20ug dose only• Peptor Heat Shock Protein ?• Proinsulin DNA vaccine (Bayhill) Fall, 2006
Pre
diab
ete
Pre
diab
ete
ssN
ew O
nset
New
Ons
et
Secondary PreventionSecondary Prevention
Goal - induction of diabetes remission and preservation of C-peptide
non-antigen-specific interventions
antigen specific interventions
EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment
-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.
EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment
-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.
-Cell Function and Complications in the-Cell Function and Complications in theDiabetes Control and Complications TrialDiabetes Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26:832–836, 2003
-Cell Function and Hypoglycemia in the-Cell Function and Hypoglycemia in theDiabetes Control and Complications TrialDiabetes Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26:832–836, 2003
NKNK
BB
Th1Th1
MOMO
Tc1Tc1
TargetTarget
Effector CellsEffector CellsCD4CD25CD4CD25
Th2Th2
NKTNKT
Th3Th3
Tr1Tr1
Regulatory CellsRegulatory Cells
Cellular Mechanics of Autoimmune Type 1 DiabetesCellular Mechanics of Autoimmune Type 1 Diabetes
MMFMMFDZBDZBAnti-CD3Anti-CD3ATGATG
InsulinInsulinGADGADIGRPIGRPHSP60HSP60
Cellular Therapy
Regenerative Therapies
RituximabRituximab
Lack of Effect of BCG Vaccination in Lack of Effect of BCG Vaccination in New Onset T1D subjectsNew Onset T1D subjects
0
0.2
0.4
0.6
0.8
0 5 10 15 20 25 30
00.20.40.60.8
11.21.4
0 5 10 15 20 25 30
00.20.40.60.8
11.21.4
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
3
0 5 10 15 20 25 30
< 12
>=12
AgeFasting C-Peptide Stimulated C-Peptide
Adapted from Allen, et al, Diabetes Care 1999, 22:1703-07
Ongoing and Proposed Non-antigen Specific Ongoing and Proposed Non-antigen Specific Immunotherapy Trials in New Onset Type 1 DMImmunotherapy Trials in New Onset Type 1 DM
• MMF and DZB - Peter Gottlieb, TrialNet
• Multidose anti-CD3 hOKT3 - Kevan Herold, NY; Lucienne Chatenoud, France
• HSP 65 p277 s.c. - (Peptor) – Jerry Palmer, Seattle
• Multi-dose DZB - Henry Rodriguez, Indiana
• Exanitide and DZB – David Harlan, NIH
• Oral hIFN-alpha - Staley Brod, Texas
• Anti-CD20 – Mark Peskovitz, Indiana, TrialNet
• ATG (Sandostat) – Steve Gitelman, UCSF, ITN, TrialNet
• Rapamycin and IL-2, Alex Rabinovitch, Canada
• Fish oil - A-G Ziegler, Germany
• Diazoxide - E Bjork+A Karlsson,
Sweden
• Lisofylline i.v. - S Kirk, Virginia
• Vitamin E+nicotinamide - P Pozzilli,
Italy
MMF/DZB TN-02 MMF/DZB TN-02 Participating CentersParticipating Centers
• The Barbara Davis Center
• Indiana University• Stanford University• University of Florida• University of
Minnesota• Virginia Mason
(Washington)
• Joslin Diabetes Center• Columbia University• UCSF• Children’s Hospital of
Los Angeles• Kansas City, Kansas• Toronto, Canada• Milan, Italy and
Munich, Germany
New CentersExisting Centers
MMF/DZB TN-02 studyMMF/DZB TN-02 study(Mycophenolate Mofetil and Daclizumab)(Mycophenolate Mofetil and Daclizumab)
• MMF protects BB rats from developing DM; MMF/DZB protect PolyIC:Treg depleted DR BB rats from DM
• MMF is effective in islet allograft transplantation in mice, but not in NOD mice as a single agent
• MMF effective in a number of human autoimmune conditions including psoraisis, uveitis, autoimmune hepatitis and lupus nephritis.
• MMF has been an effective addition to multi-drug transplantation protocols in place of Azathioprine or as replacement for Calcineurin inhibitors where nephrotoxicity or islet toxicity is a concern (Polastri, et al, Acta Diabet, 2002).
Effect of MMF and Vitamin D Effect of MMF and Vitamin D Analogues on Islet Allograft SurvivalAnalogues on Islet Allograft Survival
Gregori, et al, JI, 2001Gregori, et al, JI, 2001
Mycophenolate Mofetil (MMF)Mycophenolate Mofetil (MMF)
• Inhibits inosine monophosphate dehydrogenase (IMPDH)
• Inhibits de novo pathway of guanosine nucleotide synthesis
– T and B cells need de novo pathway (other cell types use salvage pathway)
APCAPC
T cellT cell
MHC
TCR
IL-2
• Blocking of activated T and B cell proliferation and antibody formation
• Does not block IL-1, IL-2 production
MMF: Mode of action
Greenbaum, CBenaroya Research InstituteSeattle, WA
MMF ToxicitiesMMF Toxicities
• LeukopeniaLeukopenia
• Gastrointestinal Gastrointestinal
• Increased rate of viral infectionsIncreased rate of viral infections
• Lymphoproliferative disorder? No Lymphoproliferative disorder? No increase in multidrug regimens. No increase in multidrug regimens. No increase in single drug use increase in single drug use (Psoriasis). (Psoriasis).
• Cancer? (Psoriasis data – No).Cancer? (Psoriasis data – No).
MMF/DZB study Rationale for DZBMMF/DZB study Rationale for DZB(Mycophenolate Mofetil and Daclizumab)(Mycophenolate Mofetil and Daclizumab)
• Anti-IL2R Ab protects BB rat, but not NOD islet grafts• IL2-Receptor + Cells increased at diagnosis of DM• IL-2R+, CD4hi population harbor autoreactive T cells
(mouse and man)• DZB is effective as part of Edmonton protocol and in
other transplantation regimens• DZB has been shown to be effective in autoimmune
diseases such as uveitis and MS• Relative known toxicities of drugs are low
DZB inhibits disease activity in multiple sclerosis patients failing to respond to interferon
BielekovaBielekova et al, PNAS, 2004 et al, PNAS, 2004
Activated T cell
α γ
IL-2
ß
Activated T cell
α γ
IL-2
ß
DZB
DZB: Mode of action
Inhibit IL-2 mediated activation of lymphocytes
Greenbaum, C;Benaroya Research Institute; Seattle, WA
Daclizumab in Pediatric Transplantation: CD25 and Daclizumab in Pediatric Transplantation: CD25 and 7G7 Expression on T Cells7G7 Expression on T Cells
02468
101214161820222426
1 14 28 42 56 84 182
CD25
7G7
%T cells
Baseline Day 0 Ettenger RB. Transplant Proc. 1998;30:1956-1958.
MMF/DZB TN-02 StudyMMF/DZB TN-02 Study• 3 arm study: MMF alone, MMF and 2 doses of DZB and 3 arm study: MMF alone, MMF and 2 doses of DZB and
placeboplacebo• 36 subjects per arm, 120 total, through TrialNet centers (6 36 subjects per arm, 120 total, through TrialNet centers (6
initially)initially)• Type 1 diabetes (autoantibodies) within 12 weeks of Type 1 diabetes (autoantibodies) within 12 weeks of
diagnosisdiagnosis• Ages 8-45, without significant other diseaseAges 8-45, without significant other disease• Outcomes: HbA1c, C-peptide, hypoglycemia, T cell assaysOutcomes: HbA1c, C-peptide, hypoglycemia, T cell assays• Start Date: Aug. 1, 2004. 92 patients enrolled, expect to Start Date: Aug. 1, 2004. 92 patients enrolled, expect to
finish enrollment this fall. No major problems to date. First finish enrollment this fall. No major problems to date. First subjects nearing 2 year window.subjects nearing 2 year window.
Anti-CD3 Monoclonal Antibody in Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes MellitusNew-Onset Type 1 Diabetes Mellitus
Kevan C. Herold, MD; William Hagopian, MD, PhD;
Julie A. Auger, BA; Ena Poumian-Ruiz, BS;
Lesley Taylor, BA, David Donaldson, MD;
Stephen E. Gitelman, MD, David M. Harlan, MD;
Danlin Xu, PhD; Robert A. Zivin, PhD;
& Jeffrey A. Bluestone, PhD
Herold K. et al., N Engl J Med 2002; 346:1692-8.
hOKT3hOKT31(Ala-Ala)1(Ala-Ala)
Ala-A
la
Binds to CD3hOKT3hOKT31(Ala-Ala) is a monoclonal1(Ala-Ala) is a monoclonalantibody that binds to the CD3antibody that binds to the CD3(T cell receptor) on human T cells. (T cell receptor) on human T cells. The drug is a “humanized” antibodyThe drug is a “humanized” antibodywith a mutation in the Fc chain towith a mutation in the Fc chain toprevent binding to the Fc receptor.prevent binding to the Fc receptor.Binding to the Fc receptor and Binding to the Fc receptor and crosslinking of the CD3 moleculecrosslinking of the CD3 moleculeis thought to activate T cells, is thought to activate T cells, cause release of cytokines, and cause release of cytokines, and account for the toxicity of OKT3.account for the toxicity of OKT3.
Changes from Study Entry to 12 Months in the Total C-Peptide Response to Mixed-Meal Tolerance Testing
Herold K. et al., N Engl J Med 2002; 346:1692-8.
To
tal
Are
a u
nd
er t
he
C-P
epti
de
Res
po
nse
Cu
rve
(nm
ol/
l/4
hr)
Monoclonal-Antibody Group
To
tal
Are
a u
nd
er t
he
C-P
epti
de
Res
po
nse
Cu
rve
(nm
ol/
l/4
hr)
Control Group
A single course of h(Ala-Ala) at dx of diabetes improves insulin secretion for over 2
years
Month
0 6 12 18 24
AU
C (
pm
ol/m
l/2
40
min
)
0
20
40
60
80
100
120
140
160
DrugControl ** ** **
(p<0.0001(p<0.0001**p<0.02)**p<0.02)
Regenerative Therapies: Regenerative Therapies: Exenatide(Byetta): Glucagon-like Exenatide(Byetta): Glucagon-like
Peptide (GLP-1) analoguesPeptide (GLP-1) analoguesi. A GLP-1 analogue
ii. Helps regulate insulin secretion and gastric emptying
iii. Initial studies = FPIR and improved OGTT
iv. Animal studies = beta cell mass
v. Much experience in humans with T2D
Regenerative Therapies: Regenerative Therapies: Exenatide(Byetta): Glucagon-like Exenatide(Byetta): Glucagon-like
Peptide (GLP-1) analoguesPeptide (GLP-1) analoguesi. A GLP-1 analogue
ii. Helps regulate insulin secretion and gastric emptying
iii. Initial studies = FPIR and improved OGTT
iv. Animal studies = beta cell mass
v. Much experience in humans with T2D
Cellular TherapiesCellular Therapies
• CD4+CD25+ T regulatory cells – non-specific or antigen-specific
• Naïve Dendritic Cells pulsed with autoantigens to induce T Regs
• Stem Cells that can restore regulatory balance – what type?
How do we correct autoreactivity?Lessons from Animal Models: Modalities
of Immunotherapy of T1DM
Antigens Immunotherapy Cytokines Growth Factors/Cellular
Insulin Cyclosporine Anti-IFNg Gastrin/EGF GAD65 ALS IFNa GLP-1 HSP60 MMF Anti-TNFa CD4CD25+
Glucagon Anti-CD3 Anti-IL-12 Th2 cells IGRP Anti-CD4 IL-4, IL-10 Tr1 cells IAPP Anti-IL2R TGFb
Anti-Class II IL-18
Therapy of diabetes may eventually require combination therapy!Therapy of diabetes may eventually require combination therapy!
TrialNet Sites
TrialNet International SitesTrialNet International Sites
• AustraliaAustralia
• United KingdomUnited Kingdom
• FinlandFinland
• Italy & GermanyItaly & Germany
SummarySummary• Antigen specific therapy trials in new onset and Antigen specific therapy trials in new onset and
prediabetic subjects are being undertaken.prediabetic subjects are being undertaken.
• Immunomodulatory trials are ongoing in new Immunomodulatory trials are ongoing in new onset patients and the results with anti-CD3 are onset patients and the results with anti-CD3 are encouraging.encouraging.
• Multicenter trials and networks will help us find Multicenter trials and networks will help us find effective therapies during the next decade.effective therapies during the next decade.
• Combination therapy targeting multiple pathways may hold the greatest hope for prevention and cure.
1-800-HALT-DM1 (1-800 – 425-8361)www.diabetestrialnet.org
