Worming and De-worming: Implications for Crohn’s … and De-worming: Implications for Crohn’s...
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Worming and De-worming: Implications for Crohn’s Disease and Ulcerative Colitis Environment vs. Genes Results of Two T. suis Studies Mechanisms of Action Joel Weinstock
Transcript of Worming and De-worming: Implications for Crohn’s … and De-worming: Implications for Crohn’s...
Worming and De-worming: Implicationsfor Crohn’s Disease and Ulcerative Colitis
Environment vs. GenesResults of Two T. suis Studies
Mechanisms of ActionJoel Weinstock
The Increasing Incidence of Immune Regulatory DisordersFrom Bach J-F., (2002) 347:911-920
Viral, bacterialand protozoan
infections
ExcessImmune reactivity
Crohn’s diseaseand other diseases
GENETIC PREDISPOSITION
POOR SANITATION, IMPURE FOOD AND CROWDED LIVING CONDITIONS
Helminthic infections
Regulatory T Cell Conditioning
(Prevents)InhibitsExcess
Reactivity
Normal Ulcerative Colitis
Etiologic Interplay
NatureNature NurtureNurture
IBDIBD
GenesGenes EnvironmentEnvironment
High
Medium
Low
Global Prevalence of IBD
High
Medium
Low
Global Prevalence of IBD,But What About Worm?
Helminths Modulate Immune Responses in People
• Th2 response to tetanus toxoid (Sabin, J. Infect. Dis. 173:269)
• Children have reduced atopy(Yazdanbakhsh, Science 296:490)
• PBMC IL10 and TGFβ production(Doetze, Int. Immuol. 12:623)
From Bench to Bedside
Using helminths to treat IBD
Trichuris suis(Porcine whipworm)
• Self-limited colonization
• No multiplication in host
• No direct transmission
• Eggs stable and easy to produce
Trichuris suis Therapy
inActive Ulcerative Colitis
Design – Ulcerative Colitis Study
~ Treatment every 2 weeks
~ Placebo vs. T. suistwo-tailed Fisher’s exact test
T. suis ova
12 weeks
Placebo
Phase 2
Placebo
T. suis ova
12 weeks
Phase I
Overall Response
~No side effects, complications
Time to Response
P<0.0001
Trichuris suis Therapy
inActive Crohn’s Disease
CD Open-Label Study
0 12 24Weeks
Administered 2500 T. suis ova every 3 weeks
( CDAI >100)(CDAI <150)
Remission/Response Rates
Overall Summary
~ In UC, T. suis superior to placebo
~ In CD, 72% remission79% response
~ No side effects or complications
ConclusionT. suis is safe and effective in IBD
Heligmosomoides Polygyrus
H. Polygyrus in the Duodenum
Effect of H. polygyrus on TNBS Colitis
H. poly
14 days
Histology
TNBS
Effect of H. polygyrus on TNBS Colitis
Piroxicam-induced, IL10 KO Colitis
Piroxicam(NSAID)
2 wks
Colitis
Effect of H. polygyrus on IL10 KO Colitis
Histology2 wk
Worm
Control
NSAID
NSAID
2 wk
H. polygyrus Colonization SuppressesIL10 KO Colitis
How do worms in the duodenumregulate the ileum and colon?
TregFoxP3
TGFβ
CD25
Mostly CD4
Regulatory T Cells
IL10TGFβ
Tr1
IL10TGFβ
Th3 Th2
IL4, IL5IL13, IL10
CD8
48 h
APC +αCD3 T Cell
Proliferation
LP T Cells
UninfectedSplenic T Cells
Worms orNO Worm
Do LP T Cells Inhibit Splenic T Cell Proliferation?
Inhibition of Splenic T Cell Proliferation
T CellsIL12
Th1 Cells @
IFNγ
Stat4
Effect of H. polygyrus on Normal Terminal Ileum
H. poly
14 days
LP Th1 Cytokine
Production
H. poly Suppresses IFNγ and IL12 Production
48 h
APC +αCD3 T Cell
IFNγ Production
LP T Cells
UninfectedSplenic T Cells
Worms
Do LP T Cells Inhibit Splenic T Cell IFNγ Production?
Inhibition of Splenic T Cell IFNγ Secretion-Another Regulatory T Cell-
Lipopolysaccharide (LPS)
TLR4Helminths
TGFβ
RegulatoryT cells(Th3?)
CD4
LPS
RegulatoryT Cells
TGFβIL10
EffectorT Cells
@
Prevent inflammationNo contact required
Major Points
Th2 cytokines (IL4, IL5, IL13)
PgE2
SummarySummary
1. Genetics vs. Environment (Helminths)
2. Helminths (worms) as IBD therapy3. Mechanisms of action
CollaboratorsUniversity of Iowa
David ElliottRobert SummersDav RamkumarKhurram Qadir
Robin ThompsonBetty Musgrave
Dan BergArt BlumAhmed MetwaliTommy Setiawan
Bushra SuliemanAndy ArsenescuNedim InceCyrus Tamboli
USDA, MarylandJoseph Urban
University of WisconsinZsuzsa FabryMatyas SandorJohn Fleming
Royal Institute, DenmarkDarwin MurrelAllan Roepsdtorff
-CCFA and Broad Foundation-NIH-Frank Hamilton
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Joel Kline
