Immunopathogenesis of Type 1 Diabetes:
Approaches 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
Magnitude of Diabetes Worldwide
•
•
•
•
•
•
•
USA
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 Diabetes
per 100,000 per year Children <=14
V
C
hi
n
en a
ez
ue
la
Is
ra
el
K
uw
D ait
en
m
ar
k
La
zi
o
C
an
da
U
SA
Sa
rd
in
Fi ia
nl
an
d
40
35
30
25
20
15
10
5
0
Karvonnen et al., Diabetes Care, 23:1516, 2000
Type 1 DM incidence is rising 3-5% /year
1.4 million patients in the U.S.
60
50
Incidence /100,000/ yr
children age 0-14
Finland
40
30
Colorado
20
Germany
10
0
1950
1960
1970
1980
1990
2000
Rewers
Finland Incidence Type 1
DM/100K 1965-1996
50
45
40
35
30
25
20
15
10
5
0
1-4 yrs
5-9 yrs
10-14 yrs
Yrs. 65-74
Diabetes Care: 22:1066-1070
75-84
85-96
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.
Progression to Diabetes vs Number of Autoantibodies
(GAD, ICA512, Insulin)
Percent not Diabetic
100
80
3 Abs
2 Abs
1 Ab
60
40
20
0
0
2.5
5
7.5
10
12.5
15
Years of Follow-up
3 Ab n = 41
2 Abs n = 44
1 Abs n = 93
17
27
23
8
15
14
Verge et al, Diabetes 45:926-933, 1996
1
4
10
2
6
1
4
BDC
The Major Histocompatibility Complex
Class III
Class II
Human
Chromosome 6
DP
DQ
Antigen Processing
Genes
Mouse
Chromosome 17
Class I
Class II
K
I-A
DR
B
Complement
Proteins
Cytokines
Class III
I-E
Class I
C
A
Class I-like genes
and pseduogenes
Class I
D
L
DQB1*0402
 -chain
Leu56
-chain
Asp57
BDC
HLA-Defined T1 DM Risk Groups
DAISY, Denver Population, n=21,713
IDDM risk by age 20
HLA-DR
DQB1
High 1:15
3/4
0201/0302
2.4
Moderate
1:60-1:200
4/x
4/4
3/3
0302/
0302/
0201/0201
12.7
3.0
1.4
Average 1:300
3/x
3/4
0201/
0201/not 0302
12.5
1.0
Lower than 1:300
4/x, 4/4
2/x
others
/not 0302
0602
6.6
Frequency %
60.4
Different haplotypes are associated with T1D
in Japanese and Caucasian populations
Japanese
Caucasian
DRB1-DQB1
haplotype
Type 1 diabetes
susceptibility
HF1)
Type 1 diabetes
susceptibility
HF
DRB1*0405-DQB1*0401
susceptible
susceptible
unknown
present
present
rare
unknown
unknown
susceptible
rare
rare
present
unknown
protective
rare
present
susceptible
protective
present
present
DRB1*0901-DQB1*0303
DRB1*0301-DQB1*0201
DRB1*0401-DQB1*0302
DRB1*1501-DQB1*0602
1)
HF: Haplotype frequency,
http://square.umin.ac.jp/JSHI/frame.html
IDDM2 Genotypes in U.S. Caucasians
IDDM
Controls
100
80
60
%
40
20
0
I/I
I/III
III/III
VNTR Class
Pugliese et al., J. Autoimm 7: 687- 694, 1994
VNTR alleles affect INS
transcription in thymus
Thymus INS Transcription
Predisposing
Class I VNTR
Class I
VNTR
Protective
Class III VNTR
Pancreas INS Transcription
Class III
VNTR
Pugliese et al. Nature Genetics
15:293-297, 1997
Predisposing
Class I VNTR
Protective
Class III VNTR
Chromosome
λs
O.R.
IDDM1 mhc
6p21
3.35
“App 30”
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
3p13-p14
1.15
1.52 .649
6q21
1.56
22.4
9q33-q34
1.13
10p14-q11
1.12
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
IDDM15
IDDM10
LOD
Pgenome
116.3 10(-4)
3.34 .016
2.2 .191
“3”
3.21 .021
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
0.4
0.6
0.8
1.0
Proportion of Twins Without Diagnosis of DM
0.2
6 and younger n= 38
7-10 n= 33
11-14 n= 42
15-24 n= 37
25 and older n= 37
0.0
Difference significant (log-rank and gen'ld wilcoxon p= 0.001 , 0.001 )
0
10
Redondo, Diabetologia
20
30
40
50
Years Since DM Diagnosis in Index Twin
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
Autoreactivity:
CD4 and CD8 T cell responses
Prediabetic T cell responses to CD4
epitopes from IA-2
Keleman, Gottlieb et al. 2004. Journal of Immunology.15;172(6):3955-62.
Cytotoxic T-cells from HLA-A*0201 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 52:2649
T cell reactivity to CD8 Epitopes
from T1D subjects
IFN-gamma producing spots/2x05 PBMCs
550
patients (n=19)
controls (n=6)
300
50
50
40
30
20
10
0
2
V/A
C
H
Ouyang, et al, submitted
MIX
P5
IAP
P9
IAP
5
P21
R
G
I
2
P15
R
G
I
A
PH
Natural History of Type 1 Diabetes
PUTATIVE
ENVIRONMENTAL
TRIGGER
CELLULAR (T CELL) AUTOIMMUNITY
BETA CELL MASS
HUMORAL AUTOANTIBODIES
(ICA, IAA, Anti-GAD65, IA2Ab, etc.)
LOSS OF FIRST PHASE
INSULIN RESPONSE
(IVGTT)
GLUCOSE INTOLERANCE
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
(OGTT)
“PRE”DIABETES
CLINICAL
ONSET
DIABETES
TIME
Stochastic Model
Antigen Specific Tx
Non Specific Tx
PREVENTION
Primary Prevention
autoantibodies or diabetes as the
endpoint
avoidance of environmental agents ?
induction of autoantigen tolerance ?
Rewers-BDC
Early childhood diet
and T1 DM ?
TRIGR 3-yr Follow-up Results
Seroconversion to 1+ Autoantibody
20%
15%
p=0.043
Cows Milk
Formula
Casein
Hydrolysate
10%
5%
24
12
6
n=173
0
0%
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 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 curve
- European Nicotinamide Diabetes Intervention Trial (ENDIT) Group
Lancet 2004; 363: 925–31
Late stage
Early stage
Ongoing or Completed
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
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
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
Effect of Insulin Injections on
Diabetes & Insulitis
100
90
80
70
60
50
40
30
20
10
0
3
2.5
Insulitis Score
% Diabetes
Female NOD Mice
2
1.5
1
0.5
0
Placebo
Insulin
Placebo
Insulin
Atkinson, Diabetes 1991
Prevention of Diabetes with B:9-23
Peptide “Immunization”
Percent Not Diabetic
100
B:9-23 peptide
80
Tetanus control
60
40
20
0
0
10
20
30
40
50
60
Age in Weeks
D.Daniel ,D.Wegmann . PNAS,1996
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
% Diabetes-Free
100
control peptide (n = 21)
6024 (n = 21)
80
60
p < 0.02
40
20
0
0
20
40
Age (weeks)
Alleva, et al, Diabetes 2002
60
NBI-6024-specific Th2 cells adoptively
transferred protection in NOD mice
Figure 4.
100
80
60
APL-specific Th2 cell line
transfer
40
20
0
10
18
26
32
40
46
Days Following Transfer
53
60
From Alleva, et al. Diabetes. 2002 51(7):2126-34.
Mouse BHT-3021 provides significant delay
of diabetes onset in hyperglycemic
mice at all dosing frequencies
DNA dosing stopped
Percent Diabetic
100
PBS
Anti-CD3
II Hi QW
proIns
BHT-3021
QW
II Hi Q2W
proIns
BHT-3021
Q2W
II Hi Q4W
proIns
BHT-3021
Q4W
75
50
25
0
0
5
10
15
20
weeks post hyperglycaemia
25
Treatment of hyperglycemic mice with mouse BHT3021 restores normoglycemia
PBS
proIns II-DNA Hi Expression
600
500
500
400
400
mg/dl
mg/dl
600
300
300
200
200
100
100
0
0
entry BG
final BG
entry BG
final BG
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
P- Value= 0.796
(Log Rank Test)
0.2
Number at Risk
0.1
169
170
0.0
0
144
131
96
101
69
69
39
40
13
14
1
2
3
4
5
1
6
Years Followed
New Engl J Med 2002; 346:1679
STRATA:
Intervention
Observation
Intervention
Observation
7
Rationale for Oral Insulin
TH1
TH2
TH3
Cell
s
Cells
Cells
IFN-g, IL-2
Destructive
Cytokines
IL-4, IL-5, IL-10 TGF-
Protective
Cytokines
Oral Antigen Protocol
• Initial results appeared to suggest no effect of oral
insulin
• Secondary analysis suggests that for original
cohort (IAA>80) 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)
New Onset
Prediabetes
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
Secondary Prevention
 Goal - induction of diabetes remission
and preservation of C-peptide
 non-antigen-specific interventions
 antigen specific interventions
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 2000;342:381-9.
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 2000;342:381-9.
-Cell Function and Complications in the
Diabetes Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26:832–836, 2003
-Cell Function and Hypoglycemia in the
Diabetes Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26:832–836, 2003
Cellular Mechanics of Autoimmune Type 1 Diabetes
Regenerative Therapies
Target
Cellular
Therapy
NK

CD4CD25




Tc1

MMF
DZB
Anti-CD3
ATG
Effector Cells

B
MO
Rituximab
Tr1
Th1
Th2
Th3
NKT
Regulatory Cells
Insulin
GAD
IGRP
HSP60
Lack of Effect of BCG Vaccination in
New Onset T1D subjects
Fasting C-Peptide
Age
Stimulated C-Peptide
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.8
0.6
< 12
0.4
0.2
0
0
>=12
5
10
15
20
25
0
5
10
15
20
25
30
0
5
10
15
20
25
30
30
1.4
1.2
1
0.8
0.6
0.4
0.2
0
3
2.5
2
1.5
1
0.5
0
0
5
10
15
20
25
30
Adapted from Allen, et al, Diabetes Care 1999, 22:1703-07
Ongoing and Proposed Non-antigen Specific
Immunotherapy 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
Participating Centers
Existing Centers
• The Barbara Davis
Center
• Indiana University
• Stanford University
• University of Florida
• University of
Minnesota
• Virginia Mason
(Washington)
New Centers
• Joslin Diabetes
Center
• Columbia University
• UCSF
• Children’s Hospital of
Los Angeles
• Kansas City, Kansas
• Toronto, Canada
• Milan, Italy and
Munich, Germany
MMF/DZB TN-02 study
(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
Analogues on Islet Allograft Survival
Gregori, et al, JI, 2001
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)
APC
MMF: Mode of action
• Blocking of activated T and B cell
proliferation and antibody formation
T cell
• Does not block IL-1, IL-2 production
IL-2
Greenbaum, C
Benaroya Research Institute
Seattle, WA
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).
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
DZB inhibits disease activity in multiple
sclerosis patients failing to respond to interferon
Bielekova et al, PNAS, 2004
DZB: Mode of action
Inhibit IL-2 mediated activation of lymphocytes
IL-2
IL-2
DZB
α ß γ
α ß γ
Activated T cell
Activated T cell
Greenbaum, C;Benaroya Research Institute; Seattle, WA
Daclizumab in Pediatric Transplantation: CD25 and
7G7 Expression on T Cells
%
T cells
26
24
22
20
18
16
14
12
10
8
6
4
2
0
CD25
7G7
1
Baseline
Day 0
14
28
42
56
Ettenger RB. Transplant Proc. 1998;30:1956-1958.
84
182
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.
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; 346:1692-8.
hOKT3g1(Ala-Ala)
Binds to CD3
Ala-Ala
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.
Changes from Study Entry to 12 Months in the Total
C-Peptide Response to Mixed-Meal Tolerance Testing
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)
Monoclonal-Antibody Group
Herold K. et al., N Engl J Med 2002; 346:1692-8.
A single course of hOKT3g1(Ala-Ala) at dx of
diabetes improves insulin secretion for over 2
years
160
140
**
Drug
Control
**
**
AUC (pmol/ml/240min)
120
100
80
(p<0.0001
**p<0.02)
60
40
20
0
0
6
12
Month
18
24
Regenerative Therapies:
Exenatide(Byetta): Glucagon-like
Peptide (GLP-1) analogues
i. 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:
Exenatide(Byetta): Glucagon-like
Peptide (GLP-1) analogues
i. 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 Therapies
• CD4+CD25+ T regulatory cells – nonspecific 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
Insulin
GAD65
HSP60
Glucagon
IGRP
IAPP
Immunotherapy Cytokines
Cyclosporine
ALS
MMF
Anti-CD3
Anti-CD4
Anti-IL2R
Anti-Class II
Anti-IFNg
IFNa
Anti-TNFa
Anti-IL-12
IL-4, IL-10
TGFb
IL-18
Growth
Factors/Cellular
Gastrin/EGF
GLP-1
CD4CD25+
Th2 cells
Tr1 cells
Therapy of diabetes may eventually require combination therapy!
TrialNet Sites
TrialNet International Sites
• Australia
• United Kingdom
• Finland
• Italy & Germany
Sponsors
NIDDK
ADA
NIAID
NICHD
JDRF
NCRR
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.
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