Can Type 1 Diabetes Be Prevented? Della Matheson, RN, CDE Research Coordinator, Type 1 Diabetes...
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Transcript of Can Type 1 Diabetes Be Prevented? Della Matheson, RN, CDE Research Coordinator, Type 1 Diabetes...
Can Type 1 Diabetes Be Prevented?
Della Matheson, RN, CDEResearch Coordinator, Type 1 Diabetes TrialNetUniversity of Miami, Diabetes Research Institute
Type 1 Diabetes Prevention in NOD Mice
AAV murine IL-10AAV rat preproinsulin gene (vLP-1)Adenovirus expressing mIL-4Aerosol insulinAllogenic thymic macrophagesAlpha GalactosylceramideAlpha-interferon (rIFN-alpha)Alpha/beta T cell receptor thymocytes AminoguanidineAndrogensAnesthesiaAntioxidant MDL 29,311Antisense GAD mRNAAzathioprineAnti-B7-1Bacille Calmette Gue’rin (BCG)BaclofenBee venomBiolistic-mediated IL-4Blocking peptide of MHC class IIBone marrow transplantationCastrationAnti-CD3Anti-CD4CD4+CD25+regulatory T cellsAnti-CD8Anti-CD28 MAbCholera toxin B subunit-insulin proteinClass I derived self-I-A beta(g7) (54-76) peptideCold exposureAnti-complement receptorComplete Freund’s adjuvantAnti-CTLA-4Cyclic nucleotide phosphodiesterases (PDEs)CyclosporinCyclosporin ADC deficient in NF-kappaBDC from pancreatic lymph nodeDC with IL-4DeflazacortDeoxysperogualinDexamethasone/progesterone/growth hormone/estradiolDiazoxide1,25 dihydroxy Vitamin D3, KH10601,25 dihydroxycholecalciferol1,25 dihydroxyl Vitamin D3Elevated temperatureEmotionalityEncephalomyocarditis virus (ECMV)Essential fatty acid deficient dietsFK506FTY720 (myriocin)GAD 65 peptides in uteroAnti-GAD monoclonal antibodyGalactosylceramideGlucose (neonatal)Glutamic acid decarboxylase(intraperitoneal, intrathymic, intravenous, oral)Glutamic acid decarboxylase 65 Th2 cell cloneGlutamic acid decarboxylase peptides(intraperitoneal, intrathymic, intravenous, oral)
GonadectomyGuanidinoethyldisulphideHeat shock protein 65Heat shock protein peptide (p277)Hematopoietic stem cells encoding proinsulinHousing aloneHuman IGF-1I-A beta g7(54-76) peptideAnti-I-A monoclonal antibodiesAnti-ICAM-1IgG2a antibodiesImmobilizationInomideAnti-integrin alpha 4Insulin (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-gammaAnti-interferon-gammaInterferon-gamma receptor/IgG1 fusion proteinInterleukin-1Interleukin-4Interleukin-4-Ig fusion proteinInterleukin-4-plasmidInterleukin-10Interleukin-10-plasmid DNAInterleukin-10-viralInterleukin 11-human Interleukin-12Intrathymic administration of mycobacterial heat shock protein 65 Intrathymic administration of mycobacterial heat shock peptide p277Islet cells-intrathymicL-Selectin (MEL-14)Lactate dehydogenase virus (LDH)Large multilamellar liposomeLazaroidAnti-leukocyte function associated antigen (LFA-1)Anti-LFA-1Linomide (quinoline-3-carboxamide)Lipopolysaccharide-activated B cellsLisofyllineLymphocyte choriomeningitis virus (LCMV)Anti-lymphocyte serumLymphoctyte vaccinationLymphocytic choriomeningitis virusAnti-L-selectinLymphotoxinLZ8MC1288 (20-epi-1,25-dihydroxyvitamin D3)MDL 29311Metabolically inactive insulin analogAnti-MHC class IAnti-MHC class IIMHC class II derived cyclic peptideMixed allogeneic chimerismMixed bone marrow chimerasMonosodium glutamateMurine hepatitis virus (MHV)
Mycobacterium aviumMycobacterium lepraeNatural antibodiesNatural polyreactive autoantibodiesNeuropeptide calcitonin gene-related peptideNicotinamideNicotineNinjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulationNKT cellsNY4.2 cellsOK432OvercrowdingPancreatectomyPentoxifyllinePertussigenPoly [I:C]Pregestimil dietPrenatal stressPreproinsulin DNAProbucolProlactinRampamycinRecombinant vaccinia virus expressing GADReg proteinReg proteinRolipramSaline (repeated injection)Schistosoma mansoniSemi-purified diet (e.g., AIN-76)Short term chronic stressSilicaSirolimus/tacrolimusSodium fusidateSoluble interferon-gamma receptorSomatostatinNon-specific pathogen free conditionsStreptococcal enterotoxinsStreptozotocinSulfatide (3’sulfogalactosylceramide)SuperantigensSuperoxide dismutase-desferrioxamineAnti-T cell receptorTGF-beta 1 somatic gene therapyTh1 clone specific for hsp60 peptideAnti-thy-1Thymectomy (neonatal)TolbutamideTolerogenic dendritic cells induced by vitamin D receptor ligandsTop of the rackTreatment combined with a 10% w/v sucrose-supplemented drinking water Tumor necrosis factor-alphaTX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))Vitamin EAnti-VLA-4
Azathioprine & Steroids
Silverstein et al NEJM 1988;319:599-604
Canadian-European Cyclosporin Study Remissions
Skyler, Diabetes 1988; 37:1574-1582
Discovery of Insulin Auto-Antibodies
Natural History of Type 1 Diabetes
CELLULAR (T CELL) AUTOIMMUNITY
LOSS OF FIRST PHASE
INSULIN RESPONSE (IVGTT)
GLUCOSE INTOLERANCE(OGTT)
HUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD65, IA2Ab, ZnT8 )
PUTATIVEENVIRONMENTAL
TRIGGER
CLINICALONSET
TIME
BE
TA C
EL
L M
AS
S
DIABETES
“PRE”-DIABETES
GENETICPREDISPOSITION
INSULITISBETA CELL INJURY
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)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
241511718405378147
22297140129725595
17049104522919261
1180774316313040
90525571187830
7439457914922
6198371663116
Number at Risk
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
P- Value< 0.001(Log Rank Test)
352419935148
0 1 2 3 4 5 6 7
Years Followed
STRATA: 0 1 2
8
01234
3 4
DPT-1 – Time to Diabetes By Number of Antibodies
n = 26799
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6 7 8 9 10
Combined DPT-1 Parenteral & Oral Insulin Trials
576426536
Number at Risk
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
P- Value< 0.001(Log Rank Test)
Years Followed
IGT only
Normal Glucose Tolerance
Combined
Indeterminate only
STRATA: Comb IFG + (IGT or Indet) IGT OnlyIndet Only NGT
425120499
233516410
16199308
967220
Comb IFG+(IGTor Indet)IGT OnlyIndet OnlyNGT
323110
11
43
11
2
1
Indeterminate:BG > 200 mg/dl at 30, 60, or 90 min
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 Funnel103,391 Relatives
Screened 97,635 Eligible Samples 97,273 Samples
Analyzed 3483 Samples ICA+
(3.58%) 711 Subjects
Randomized
DPT-1 Parenteral Study – Time to DiabetesBy Treatment
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
169170
144131
96101
6969
3940
1314 1
Number at Risk
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
P- Value= 0.796(Log Rank Test)
InterventionObservation
0 1 2 3 4 5 6 7
Years Followed
STRATA: Intervention Observation
Control
Treated
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
186186
174170
146137
110102
8571
4037
2312
Number at RiskSu
rviv
al D
istr
ibu
tio
n F
un
ctio
n
P- Value= 0.188(Log Rank Test)
Oral InsulinOral Placebo
0 1 2 3 4 5 6 7
Years Followed
STRATA: Oral Insulin Oral Placebo
DPT-1 Oral Insulin Trial Time to Diabetes By Treatment
Control
Treated
DPT-1 Oral Study - Time to Diabetes - By TreatmentSubset: IAA Confirmed > 80 nU/ml
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
0 1 2 3 4 5 6 7
Years Followed
130133
122121
10496
8669
6646
4032
2312
Number at Risk
P- Value= 0.015(Log Rank Test)
Oral InsulinOral Placebo
STRATA: Oral Insulin Oral Placebo
Control
Treated
Diabetes Care 2005; 28:1068-76
Projected 4.5 – 5 year delay
Insulin Effect Most Evident in Subjects with Baseline IAA ≥ 300
N=63 (Ins.) and 69 (Plac.)
IAA >= 300
Years
Pro
po
rtio
n F
ree
of
Dia
be
tes
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0 Oral Insulin
Placebo
Log-rank P=0.01
Peto Pr. P=0.01
Hazard Ratio: 0.41 (0.21, 0.80)
Projected 10 year delay
endit
European Nicotinamide Diabetes
Intervention Trial
es
Perc
en
tag
e d
evelo
pin
g d
iab
ete
s
Nicotinamide
Placebo
0
10
20
30
40
50
0 1 2 3 4 5
Years since randomisation
PlaceboNicotinamide
275274
245260
232232
205208
184171
Overall Treatment Effect:Intention To Treat Analysis
N = 549
NIDDK NIAID NICHDNCRR
ADA
JDRF
TrialNet Sites in North America14 Clinical Centers
+ 200 North American Affiliates
Melbourne, AustraliaMilan, Italy
Turku, Finland
Bristol, UK
TrialNet International Sites
Malmo, Swedem
Munich, Germany
+ 25 International Affiliates
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 non- relatives with genetic risk (3%)
2836 families (11,626) sib pairs493 families (1479): trio’s
968 Controls
Natural History of Progression to Type 1 Diabetes
BETA
CELL
MA
SS
C
Risk: Low(no antibodies)
• Natural History
(Screening 113,000)
Genetic & Mechanistic Studies
Risk: LowTo Moderate(antibodies presentNormal OGTT)
• Natural History
(Monitoring)
Risk:High(multiple antibodies&/or abnormalOGTT)
DiabetesDiagnosed
New Onset Studies:• 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
ANTI-CD3
ORAL INSULINNIP Pilot
CTLA-4IG
Helminths
Strategies for Interdicting Type 1 Diabetes
Immunosuppressive Agents: Inhibit or Prevent Activity of the Immune System:
Cyclosporin √ Anti-CD20 (Rituximab) √Azathiaprine √ CTLA-4Ig (Abatacept) √MMF/DZB Anti-CD3 (Teplizumab) √Thymoglobulin (ATG)IL2/Rapamycin Not yet reported:
Alefacept (anti-CD2)
ß cell
APCTH 0cell
TH 2
Protective CytokinesIL-4, IL-4, IL10Beta cell survival
ß cell
APCTH 0cell
TH 1
CytotoxicMØ
& T CellsDeath IL-1, TNF-ą,
TN-ß, IFN-y
02, H202, NO
TH 2
How Immunosuppressive Agents Work
Destructive Cytokines
Other Strategies for Interdicting Type 1 Diabetes
Antigen-Specific Therapies • rhGAD65 with Alum (Diamyd)• Oral Insulin √
Probiotic TherapyHelminths (TSO)
ß cell
APCTH 0cell
TH 1
Destructive CytokinesIFN-y, IL-2
CytotoxicMØ
& T CellsDeath IL-1, TNF-ą,
TN-ß, IFN-y
02, H202, NO
TH2
Protective T cells
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 4-13)
• Ages: 8-45 of 633 participants in studies using AntiCD3, 378 were children
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
Month
0 6 12 18 24
AU
C (
pmol
/ml/2
40m
in)
0
20
40
60
80
100
120
140
160
DrugControl
Month
0 5 10 15 20 25 30
Insu
lin d
ose
(U/k
g)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
DrugControl
Month
0 5 10 15 20 25 30
Hem
oglo
bin
A1c
(%)
5
6
7
8
9
10
Drug Control
Insulin useHemoglobin A1cC-peptide
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
Insulin Producing-cells
Oral Antigen
Inhibition of -CellAutoimmunity and
Prevention of Diabetes
Autoimmune Lymphocytes
Regulatory (Th2 / Th3) Lymphocytes Producing
Protective Cytokines
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 disease20th Century brought an end to this theory with the identification of > 80autoimmune diseases.
Coronado Biosciences
Enhance expression Of Protective T Regulatory Cells
Coronado Biosciences 40
Patients and Methods
This was a randomized, double blind, placebo-controlled 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.
Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial
Summers, et.al., Gastroenterology 2005
Coronado Biosciences
Does not multiply in human host
Colonization is self-limited in humans
No systemic phase
No direct transmission
Ova stable
Benefits of Trichuris suis ova (TSO)
41
Side Effects limited to GI symptoms: nausea, upper abdominal cramping,Diarrhea, flatulence occurring during the first few weeks of treatment and then subsiding
Coronado Biosciences 42
Effect of Helminths on the Prevention of Insulin Dependent Diabetes Mellitus in Non-obese Mice
Cooke, et.al., Parasite Immunology 1999
Coronado Biosciences 43
Inhibition of Diabetes by Helminth Infection
Saunders, et.al, Infect. Immunol 2007
Can Type 1 Diabetes be Prevented?
CLINICALONSET
TIME
BE
TA C
EL
L M
AS
S
DIABETES
“PRE”-DIABETES
GENETICPREDISPOSITION
INSULITISBETA CELL INJURY
Helminths
ORAL INSULIN
CTLA-4IGANTI-CD3
Combination Therapies may need to be employed• primary prevention• anti-inflammatory agents• beta cell expansion therapies• antigen-specific therapies• immunosuppressive agents
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 AutologousHematopoeitic 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.govwww.diabetestrialnet.orgwww.immunetolerance.org