DOES HELMINTHIASIS

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DOES HELMINTHIASIS PROTECT AGAINST IBD ?
BY HALA S. EL-WAKIL,MD
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CROHNS DISEASE (CD) is an idiopathic, chronic
intestinal inflammation marked by periods of
remission and relapse. CD can affect any part of
the gut from mouth to rectum producing aphthous
ulceration, transmural inflammation, granulomas,
strictures, and fistulae
The frequency of Crohns disease (CD) has
increased substantially over the last 50 years.
It is most prevalent in highly industrialised
temperate regions. CD and ulcerative colitis (UC)
are rare in less developed countries. The
prevalence of IBD varies according to occupation
and geography. Both UC and CD are less frequent
in people with blue collar jobs involving
exposure to dirt and physical exercise.


Weinstock J.V. et al., 53(1) Gut
2004
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The decreasing frequency of helminthic
colonization appears to correlate with the
increasing prevalence of CD.
The "IBD hygiene hypothesis" states that raising
children in extremely hygienic environments
negatively affects immune development which
predisposes them to immunological diseases such
as IBD
Parasitic worms (helminths) are common in
tropical climates and in populations subject to
crowding and poor sanitation. Children are most
subject to helminthic colonization. Many
helminths live within or migrate through the
human gut where they interact with the mucosal
immune system. The host mounts a mucosal response
that includes Th2 cytokine production limiting
helminthic colonization

Elliott DE et al, 14 FASEB 2000
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IBD most likely results from inappropriately
vigorous immune responses to normal intestinal
contents. CD appears to be an overly vigorous
Th1-type inflammation that produces IFNc and
TNF-a. The cytokine profile of UC is not as
polarized, but does show elevated IFNc production
in some studies.
Helminths and their eggs are the most potent
stimulators of mucosal Th2 responses which
opposes the Th1 response associated with
autoimmune disease and CD

Radford-Smith 54(1)
Gut 2005
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• T lymphocytes secrete cytokines that have
  autocrine and paracrine effects on T cell
  function
• A naïve Th cell, first presented with a specific
  antigen, will secrete (IL-2) and begin to
  proliferate.

With prolonged antigen exposure
Th1 (IFN c, LT, TNF-a)
Th2 (IL-4, IL-5, IL-10, IL-13)

• Mosmann et al., 136 J. Immunol. 1986

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Th1 cytokines

• Delayed-type hypersensitivity reactions
• Macrophage activation
• Cellular cytotoxicity
• Switch B cell immunoglobulin (Ig) production to
  subclasses that fix complement

-
Th2 cytokines

• Eosinophilia
• B cell proliferation
• Switch B immunoglobulin production to IgA, IgE,
  and IgG subclasses that do not fix complement .
• 
  Romagnami S. 12 Annu. Rev.
  Immunol. 1994

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Nippostrongylus brasiliensis, a murine intestinal
nematode, stimulates Th2 activity.
Nippostrongylus delays kidney graft rejection in
rats. Cross-regulatory suppression of Th1
activity probably is the mechanism

Ledingham et al., 61
Transplatation 1996
Interleukin 10 deficient mice spontaneously
develop a Th1-type colitis characterised by
infiltration of the lamina propria with
interferon-c producing CD4 T cells. Colonisation
with T muris retards development of colitis in
IL-10 deficient mice

Weinstock et
al., 53(1) Gut 2004
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The modulation of immune response in S. mansoni
infected mice ,with S.mansoni egg deposition, can
suppress the autoimmune type I insulin
dependant diabetes mellitus induced by multiple
low doses streptozotocin.

El-Wakil HS. et al., 30 (3) J. Egypt. Soc.
Parasitol. 2000
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Mice rectally challenged with trinitrobenzenesulfo
nic acid and ethanol develop colitis, which is
prevented by inhibiting Th1 cytokine circuitry.
Mice pre-exposed to S. mansoni had diminished Th1
and augmented Th2 responses, with increased
mucosal IL-10 and reduced interferon- (IFN-c)
mRNA, with the protection from developing colitis
in this model
Moreels, T G et
al. Gut 20045399-107
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Microscopic damage score validated on
histological sections of the colon in the four
groups of rats control rats rats infected with
Schistosoma mansoni alone rats given an
intracolonic injection of 2,4,6-trinitrobenzene
sulphonic acid (TNBS) alone and rats with
concurrent infection with S mansoni plus
intracolonic injection of TNBS.
Moreels, T G et al. Gut 20045399-107
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• Helminth infection may bring other anticolitis
  mechanisms
• Increases in mucus and water secretion into the
  gut lumen via effects on goblet cells and mast
  cell activation. This may influence the
  interaction between gut bacteria, their products,
  and a diseased epithelium, as well as impacting
  on intestinal motility.
• Influence the microbial ecology of the gut and
  the neuroendocrine response, with an increase in
  neurotransmitters such as vasoactive intestinal
  polypeptide.

• Helminths also induce regulatory T cells and
  immune regulatory substances such as transforming
  growth factor b, IL-10, and prostaglandin E2 that
  assist in maintaining host mucosal homeostasis
• 
  
  Radford-Smith 54(1) Gut 2005

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Summers and colleagues report the results of
their open study of live Trichuris suis ova
therapy in 29 patients with Crohns disease (CD).
Treatment for 24 weeks yielded a response rate of
nearly 80 and a remission rate of nearly 73,
which was much greater than the anticipated
placebo effect. The treatment caused no side
effects or complications even in patients
receiving multiple immunosuppressants


Summers et al., 54 Gut 2005
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• Trichuris species are helminths with favourable
  characteristics for therapeutic use.
• They migrate to the terminal ileum and colon but
  do not invade the host tissue.

• T suis is not a natural human parasite but it has
  been shown experimentally to colonise humans
  briefly without causing disease.
• The ova can be produced using pathogen free pigs,
  and processed to assure absence of biological
  contaminants.
• T suis ova results in short term self limited
  colonisation of humans

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IS THERAPEUTIC HELMINTH INFECTION SAFE?

• Complications related to therapeutic helminth
  infection have not arisen thus far.
• Helminth therapy may require
• Screening for carriage of other potential
  pathogens prior to initiation of treatment.
• The choice of organism and the type of
  infection.
• Further controlled randomised studies
• 
  
  Radford-Smith 54(1) Gut 2005

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• Of special interest will be identification of
  antigens or epitopes responsible for the
  generation of a tolerant environment
• Recent work indicates that one candidate is the
  Schistosome oligosaccharide lacto-N-neotetraose.
  This molecule creates a Th2 biased immune
  environment by increased production of IL-10 and
  TGF-ß, and by directing naïve CD4 T cells down
  the Th2 path.
• Molecules such as this may represent potentially
  novel therapeutic agents for chronic inflammatory
  disorders such as IBD, and thus bypass the need
  for helminth inoculation and infection.