DESIGN AND IMPLEMENTATION

1
Immunopathogenesis of Type 1 DiabetesApproaches
to Prevention and Cure
Peter A. Gottlieb, MD George S. Eisenbarth, MD,
PhD Jay Skyler, MD Barbara Davis
Center University of Colorado Health Sciences
Center Diabetes Research Institute University
of Miami Medical School
2
Magnitude of Diabetes Worldwide

• USA
• Approximately 6 are diagnosed (90Type2)
• 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

3
Incidence Type 1 Diabetesper 100,000 per year
Children lt14
Karvonnen et al., Diabetes Care, 231516, 2000
4
Type 1 DM incidence is rising 3-5 /year
1.4 million patients in the U.S.
Incidence /100,000/ yr children age 0-14
Rewers
5
Finland Incidence Type 1 DM/100K 1965-1996
Diabetes Care 221066-1070
6
Main 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.

7
Progression to Diabetes vs Number of
Autoantibodies (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 1 1 Abs n
93 23 14 10 6 4
Verge et al, Diabetes 45926-933, 1996
BDC
8
(No Transcript)
9
DQB10402
? -chain
Leu56?
?-chain
Asp57?
BDC
10
HLA-Defined T1 DM Risk GroupsDAISY, Denver
Population, n21,713
11
Different haplotypes are associated with T1D in
Japanese and Caucasian populations
Japanese Caucasian DRB1-DQB1 Type 1
diabetes HF1) Type 1 diabetes HF haplotype
susceptibility susceptibility
DRB10405-DQB10401 susceptible present
unknown rare DRB10901-DQB10303 susceptible
present unknown rare DRB10301-DQB10201 unkno
wn rare susceptible present DRB10401-DQB10302
unknown rare susceptible present DRB11501-DQB1
0602 protective present protective present

• HF Haplotype frequency, http//square.umin.ac.jp/
  JSHI/frame.html

12
IDDM2 Genotypes in U.S. Caucasians
Pugliese et al., J. Autoimm 7 687- 694, 1994
13
VNTR alleles affect INS transcription in thymus
Thymus INS Transcription

cDNA
cDNA
DNA
DNA
Predisposing Class I VNTR
Protective Class III VNTR
Class I VNTR
Pancreas INS Transcription

Class III VNTR
Pugliese et al. Nature Genetics 15293-297, 1997
Predisposing Class I VNTR
Protective Class III VNTR
14
No Evidence IDDM 4,6,9,11,16,17,18 (O.R. MHC,
DR3/4-DQ8)
Adapted from Concannon et al, Diabetes
542995-3001, 2005
BDC
15
Proportion of Twins Without Diagnosis of DM
6 and younger n 38
7-10 n 33
11-14 n 42
15-24 n 37
25 and older n 37
Difference significant (log-rank and gen'ld
wilcoxon p 0.001 , 0.001 )
Years Since DM Diagnosis in Index Twin
Redondo, Diabetologia
16
Type 1a Diabetes An Autoimmune Disorder

• Autoantibodies to islet proteins insulin, GAD
  65, IA-2 (ICA512)
• T cell responses to islet proteins
• HLA association
• Immunosuppressive drugs can ameliorate the
  disorder ex. Cyclosporine
• Recurrence of autoimmunity in pancreas
  transplants between monozygotic twins

17
Autoreactivity CD4 and CD8 T cell responses
18
Prediabetic T cell responses to CD4 epitopes from
IA-2b
Keleman, Gottlieb et al. 2004. Journal of
Immunology.15172(6)3955-62.
19
Difficulty of Detecting T cell Responses to
Insulin in T1DM
o siblings - T1D
Tree, et al. Diabetes 2004, 271692-1699
20
Blocking DQ Reduces T cell Responses to GAD65 in
T1DM
o siblings - T1D
Tree, et al. Diabetes 2004, 271692-1699
21
Blocking of DQ leads to increased T cell
Responses to Insulin in T1DM
o siblings - T1D
Tree, et al. Diabetes 2004, 271692-1699
22
Cytotoxic T-cells from HLA-A0201 patients with
T1D recognize preproIAPP 5-13
ELISPOT analysis of peripheral blood mononuclear
responses to preproIAPP5-13 in patients with the
correct HLA to recognize the peptide.
Diabetes 2003 522649
23
T cell reactivity to CD8 Epitopes from T1D
subjects

Ouyang, et al, submitted
24
Natural History of Type 1 Diabetes
CELLULAR (T CELL) AUTOIMMUNITY
LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT)
GLUCOSE INTOLERANCE (OGTT)
25
Stochastic Model
Antigen Specific Tx
Non Specific Tx
Immunosuppresive Tx
26
PREVENTION
27
Primary Prevention

• autoantibodies or diabetes as the endpoint
• avoidance of environmental agents ?
• induction of autoantigen tolerance ?

Rewers-BDC
28
Viral Infection as a trigger for T1 DM ?
29
Enterovirus Infection Finnish DIPP Study
Hyoty et al Diabetes 491314, 2000
30
Enteroviruses - recent studies
31
No association between immunizations and islet
autoimmunityGraves et al., DAISY, Diabetes Care
1999

• No difference in vaccinated before 9 months of
  age
• No difference in the median age at the first dose
  of DTP, Hib, Polio, HepB
• No difference in the receiving HepB at birth
• No difference in the median number of doses of
  Polio, DTP

Similar findings Hummel et al. BABY-DIAB,
Diabetes Care 1996
Rewers
32
Early childhood dietand T1 DM ?
33
Infant diet and beta-cell autoimmunity
Norris et al. DAISY 2000
Hazard Ratio
Prospective cohort study 27 cases and 1,022
controls
Adjusted for HLA-DR,DQ and relationship to type 1
diabetic person
34
TRIGR 3-yr Follow-up Results Seroconversion to
1 Autoantibody
p0.043
n173
35

• 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.

36
Dietary Intake Western Diets

• The Ratio of n-6 to n-3 Fatty Acids in our diet
• 1800s 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)

37
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

38
ENDIT Kaplan-Meier failure curve
- European Nicotinamide Diabetes Intervention
Trial (ENDIT) Group Lancet 2004 363 92531
39
Ongoing or Completed Prevention Trials

• TRIGR - Casein Hydrolysate - ongoing
• (Cows 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

Early stage
Late stage
40
Antigen Specific Therapy

• Magic bullet Approach
• Targets autoreactive cells
• Generates protective cells
• Spares rest of immune system
• Minimal Toxicity
• Timing may be critical to efficacy

41
Insulin

• 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

42
Effect of Insulin Injections on Diabetes
Insulitis
Female NOD Mice
Atkinson, Diabetes 1991
43
Serum anti-insulin autoantibody levels in Insulin
Knockout NOD mice
Figure 1.
Figure 1 a) Insulin 1-/-, insulin 2-/-,
transgene NOD mice fail to develop IAA. b)
Insulin 1/-, insulin 2-/-, transgene or
transgene-) produce IAA.
Nature 2005, 435(7039) 220-223.
44
Lack of Native Insulin Expression Reduces DM in
Ins knockout ProIns (A16) NOD mice
Figure 4 a) NOD mice lacking both native insulin
genes. b) and c) Speed congenic female NOD mice
surrounding the insulin genes (insulin 1 region
(b) insulin 2 region (c)). d) Founder Tg strain
F with mutated preproinsulin gene on NOD
background (insulin 1/, insulin 2/,
transgene). e) Adoptive transfer of diabetes is
delayed.
Nature 2005, 435(7039) 220-223.
45
Prevention of Diabetes with B9-23 Peptide
Immunization
100
B9-23 peptide
80
Tetanus control
60
Percent Not Diabetic
40
20
0
0
10
20
30
40
50
60
Age in Weeks
D.Daniel ,D.Wegmann . PNAS,1996
46
Efficacy of NBI-6024 in animal models with new
onset Type I diabetes.
Figure 3. NBI-6024 Treatment of NOD mice Near
Onset of Disease
Alleva, et al, Diabetes 2002
47
NBI-6024-specific Th2 cells adoptively
transferred protection in NOD mice
Figure 4.
From Alleva, et al. Diabetes. 2002 51(7)2126-34.
48
Effect of NBI-6024 on T cell responses to native
B9-23 and APL over time in NBI-6024-0003 Trial
Alleva, et al. 2006. Scand J Immunol. 63(1)59-69
49
Mouse BHT-3021 provides significant delayof
diabetes onset in hyperglycemic mice at all
dosing frequencies
BHT-3021 QW BHT-3021 Q2W BHT-3021 Q4W
50
Treatment of hyperglycemic mice with mouse
BHT-3021 restores normoglycemia
51
Altered Peptide Ligand
Greenbaum, CBenaroya Research Institute
Seattle, WA
52
DPT-1 Parenteral Study Time to Diabetes By
Treatment
1.0
0.9
0.8
0.7
0.6
Treated
Survival Distribution Function
0.5
0.4
Control
0.3
P- Value 0.796 (Log Rank Test)
0.2
Number at Risk
0.1
169 170
144 131
96 101
69 69
39 40
13 14
Intervention Observation
1
0.0
0
1
2
3
4
5
6
7
Years Followed
Observation
STRATA
Intervention
New Engl J Med 2002 3461679
53
Rationale for Oral Insulin
54
Oral Antigen Protocol

• Initial results appeared to suggest no effect of
  oral insulin
• Secondary analysis suggests that for original
  cohort (IAAgt80) there is delay in onset compared
  to placebo treated patients.
• In fact, the higher the titer of IAA, the greater
  the protective effect that was observed.
• A new trial to confirm these observations is
  being planned by TrialNet (Start Date Nov, 2006)

55
Recent and Ongoing Antigen-specific Immunotherapy
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

Prediabetes
New Onset
56
Secondary Prevention

• Goal - induction of diabetes remission and
  preservation of C-peptide
• non-antigen-specific interventions
• antigen specific interventions

57
EDIC Long Term Benefit of Intensive Treatment

• The Diabetes Control and Complications
  Trial/Epidemiology of Diabetes Interventions
• and Complications Research Group. N Engl J Med
  2000342381-9.

58
EDIC Long Term Benefit of Intensive Treatment

• The Diabetes Control and Complications
  Trial/Epidemiology of Diabetes Interventions
• and Complications Research Group. N Engl J Med
  2000342381-9.

59
b-Cell Function and Complications in theDiabetes
Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26832836,
2003
60
b-Cell Function and Hypoglycemia in theDiabetes
Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26832836,
2003
61
Cellular Mechanics of Autoimmune Type 1 Diabetes
Regenerative Therapies
Cellular Therapy
MMF DZB Anti-CD3 ATG
Target
b
b
NK
b
Tc1
b
CD4CD25
Effector Cells
b
b
b
B
MO
Tr1
Rituximab
Th1
Th2
Regulatory Cells
Th3
Insulin GAD IGRP HSP60
NKT
62
Past Trials in New Onset Type 1 DM

• Cyclosporine A - no lasting effect
• Imuran - no lasting effect
• Corticosteroids - no lasting effect
• Plasmapheresis - no lasting effect
• BCG (Denver) - no effect
• Nicotinamide (DENIS) - no effect (At risk)
• Gluten-free diet (Italy) - no effect
• Q fever vaccine s.c. - no effect
• Nicotinamide and Vitamin E - no effect

63
Are CD4CD25High T cells Abnormal in Human T1DM?
64
Frequency of CD4CD25 T cells in long-standing
T1D and controls
7.5
3
5.0
2
CD4CD25high
CD4CD25
2.5
1
0
0
NC
T1D
NC
T1D
n19
n17
n19
n17
a
b
(From Vendrame, Putnam et al, Journal of
Autoimmunity, 2005)
65
Suppression by CD4CD25High T cells in T1D and
controls
(From Vendrame, Putnam et al, Journal of
Autoimmunity, 2005)
66
Cultured CD4CD25 T cells Retain Their
Suppressive Properties
(From Vendrame, Putnam et al, Journal of
Autoimmunity, 2005)
67
Metabolic Effects of AZA and Prednisone at 1 year
in New Onset T1DM
- Silverstein, et al. NEJM 1988, 319599-604
68
Lack of Effect of BCG Vaccination in New Onset
T1D subjects
Fasting C-Peptide
Stimulated C-Peptide
Age
lt 12
gt12
Adapted from Allen, et al, Diabetes Care 1999,
221703-07
69
Ongoing and Proposed Non-antigen Specific
Immunotherapy Trials in New Onset Type 1 DM

• 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 BjorkA Karlsson, Sweden
• Lisofylline i.v. - S Kirk, Virginia
• Vitamin Enicotinamide - P Pozzilli, Italy

• 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

70
MMF/DZB TN-02 Participating Centers
Existing Centers
New Centers

• The Barbara Davis Center
• Indiana University
• Stanford University
• University of Florida
• University of Minnesota
• Virginia Mason (Washington)

• Joslin Diabetes Center
• Columbia University
• UCSF
• Childrens Hospital of Los Angeles
• Kansas City, Kansas
• Toronto, Canada
• Milan, Italy and Munich, Germany

71
MMF/DZB TN-02 study(Mycophenolate Mofetil and
Daclizumab)

• MMF protects BB rats from developing DM MMF/DZB
  protect PolyICTreg 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).

72
Effect of MMF and Vitamin D Analogues on Islet
Allograft Survival
Gregori, et al, JI, 2001
73
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)

74
MMF Mode of action

• Blocking of activated T and B cell proliferation
  and antibody formation
• Does not block IL-1, IL-2 production

IL-2
Greenbaum, C Benaroya Research Institute Seattle,
WA
75
MMF Toxicities

• Leukopenia
• Gastrointestinal
• Increased rate of viral infections
• Lymphoproliferative disorder? No increase in
  multidrug regimens. No increase in single drug
  use (Psoriasis).
• Cancer? (Psoriasis data No).

76
MMF/DZB study Rationale for DZB(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

77
DZB inhibits disease activity in multiple
sclerosis patients failing to respond to
interferon
Bielekova et al, PNAS, 2004
78
Daclizumab (Zenapax)
Humanized IgG monoclonal antibody that binds to
the alpha subunit (CD25, p55alpha, Tac) of IL-2
receptor on the surface of activated lymphocytes
Greenbaum, C Benaroya Research Institute Seattle,
WA
79
DZB Mode of action
Inhibit IL-2 mediated activation of lymphocytes
IL-2
DZB
IL-2
?
a
?
a
ß
ß
Activated T cell
Activated T cell
Greenbaum, CBenaroya Research Institute
Seattle, WA
80
Daclizumab in Pediatric Transplantation CD25 and
7G7 Expression on T Cells
T cells
Baseline Day 0
Ettenger RB. Transplant Proc.
1998301956-1958.
81
MMF/DZB TN-02 Study

• 3 arm study MMF alone, MMF and 2 doses of DZB
  and placebo
• 36 subjects per arm, 120 total, through TrialNet
  centers (6 initially)
• Type 1 diabetes (autoantibodies) within 12 weeks
  of diagnosis
• Ages 8-45, without significant other disease
• Outcomes HbA1c, C-peptide, hypoglycemia, T cell
  assays
• Start Date Aug. 1, 2004. 92 patients enrolled,
  expect to finish enrollment this fall. No major
  problems to date. First subjects nearing 2 year
  window.

82
Potential Benefits of the Study

• Patient will be the most important part of a
  research team that is attempting to learn more
  about type 1 diabetes.
• Diabetes may be easier to manage.
• Less chance for long-term complications of
  diabetes.

83
Anti-CD3 Monoclonal Antibody in New-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 3461692-8.
84
hOKT3g1(Ala-Ala)
Binds to CD3
hOKT3g1(Ala-Ala) is a monoclonal antibody that
binds to the CD3 (T cell receptor) on human T
cells. The drug is a humanized antibody with a
mutation in the Fc chain to prevent binding to
the Fc receptor. Binding to the Fc receptor and
crosslinking of the CD3 molecule is thought to
activate T cells, cause release of cytokines,
and account for the toxicity of OKT3.
Ala-Ala
85
Changes from Study Entry to 12 Months in the
Total C-Peptide Response to Mixed-Meal Tolerance
Testing
Monoclonal-Antibody Group
Control Group
Total Area under the C-Peptide Response Curve
(nmol/l/4 hr)
Total Area under the C-Peptide Response Curve
(nmol/l/4 hr)
Herold K. et al., N Engl J Med 2002 3461692-8.
86
A single course of hOKT3g1(Ala-Ala) at dx of
diabetes improves insulin secretion for over 2
years



(plt0.0001 plt0.02)
87
Regenerative Therapies Exenatide(Byetta)
Glucagon-like Peptide (GLP-1) analogues

• A GLP-1 analogue
• Helps regulate insulin secretion and gastric
  emptying
• Initial studies ? FPIR and improved OGTT
• Animal studies ? beta cell mass
• Much experience in humans with T2D

88
Regenerative Therapies Exenatide(Byetta)
Glucagon-like Peptide (GLP-1) analogues

• A GLP-1 analogue
• Helps regulate insulin secretion and gastric
  emptying
• Initial studies ? FPIR and improved OGTT
• Animal studies ? beta cell mass
• Much experience in humans with T2D

89
Cellular Therapies

• CD4CD25 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?

90
How do we correct autoreactivity?Lessons from
Animal Models Modalities of Immunotherapy of T1DM

Therapy of diabetes may eventually require
combination therapy!
91
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92
TrialNet Sites
93
TrialNet International Sites

• Australia
• United Kingdom
• Finland
• Italy Germany

94
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95
TrialNet Interventions

• New-Onset Diabetes
• Anti-CD3 (via ITN collaboration)
• Mycophenolate Mofetil /- Anti-CD25
• Anti-CD20
• IL-2 plus Sirolimus Phase 1 Safety Study
• Relatives At Risk
• Natural History
• Oral Insulin
• Beta Cell Preservation (exenatide) pilot study
• Newborns
• Nutritional Omega-3-Fatty Acids

96
Other TrialNet Studies

• Comparison of Mixed Meal Tolerance Test and
  Glucagon Stimulation Test for Stimulation of
  C-Peptide
• Reproducibility and Validation of T-Cell Assays
  for Monitoring of Diabetes Intervention Trials
• Collaboration with Type 1 Diabetes Genetics
  Consortium (T1DGC)

97
What We Need

• Proven biomarkers for disease progression or
  improvement
• Better mechanistic assays
• Better rationale for moving potential
  interventions to RCTs
• The courage to study interventions with potential
  adverse side effects

98
Summary

• Antigen specific therapy trials in new onset and
  prediabetic subjects are being undertaken.
• Immunomodulatory trials are ongoing in new onset
  patients and the results with anti-CD3 are
  encouraging.
• Multicenter trials and networks will help us find
  effective therapies during the next decade.
• Combination therapy targeting multiple pathways
  may hold the greatest hope for prevention and
  cure.

99
1-800-HALT-DM1 (1-800 425-8361) www.diabetestri
alnet.org
100
Acknowledgements

• Gottlieb Lab
• Amy Putnam
• Becky Wagner
• Jennifer Rockell
• Marybeth Magilie
• BDC
• Katie Keleman
• John Hutton
• UCHSC
• Dan Waid
• David Wagner
• University of Siena
• Francesco Vendrame
• Francesco Dotta

• Neurocrine Biosciences Inc
• David Alleva
• Rich Maki
• Roland Jimenez
• Paul Conlon
• University of British Columbia
• Qin Ouyang
• Dina Panagiotopoulos
• Bruce Verchere
• Rusung Tan
• Virginia Mason Research Institute
• Nathan Standifer
• Jerry Nepom
• Funding from NIDDK and NIAID

101
Thank you.

• 1-800-HALT-DM1 (1-800425-8361)
• www.diabetestrialnet.org
• For copy of slides -
• www.barbaradaviscenter.org

102
Thank you!