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TSO
A NEW APPROACH TO THERAPY OF
ULCERATIVE COLITIS AND CROHN'S
DISEASE
BEFORE
AFTER
Endoscopic evaluation of a patient with ulcerative colitis before and after therapy with
Trichuris suis. Treatment with T. suis afforded healing of the inflammation as seen by
flexible sigmoidoscopy. Numbers in upper left corner indicate location (centimeters from
anal orifice) where photograph was made.
Inflammatory Bowel Disease
There are several diseases that fall within the grouping of inflammatory bowel disease
(IBD). The two main divisions are Crohn’s disease and ulcerative colitis. Ulcerative colitis is
further divided into ulcerative pancolitis (whole colon involved), left-sided ulcerative colitis
(inflammation restricted to rectum through descending colon), and ulcerative proctitis
(inflammation restricted to rectum). The term “indeterminate colitis” is used if a patient has an
illness that could be either ulcerative colitis or Crohn’s because it shares features of both. The
cause of IBD is not known. Some of the differences between Crohn’s disease and ulcerative
colitis are listed in Table 1.
Table 1: Characteristics of Crohn’s disease and ulcerative colitis
Crohn’s disease
Ulcerative colitis
Inflammation can involve any part of GI tract.
Normal areas can separate inflamed areas.
Inflammation is transmural.
Perianal inflammation is common.
Strictures and fistulae occur.
Inflammation recurs after resection.
Inflammation limited to colon and rectum.
Inflammation is contiguous from rectum.
Inflammation only involves mucosa.
Perianal inflammation is absent.
Strictures and fistulae are absent.
Inflammation does not recur after colectomy.
Crohn’s disease can involve any part of the GI tract but ulcerative colitis is limited to the
colon. Crohn’s disease can have normal areas of bowel separating inflamed areas. The
inflammation in Crohn’s disease is “transmural” involving the mucosa, muscle layers, and serosa
of the bowel. The inflammation is usually limited to the mucosa in ulcerative colitis. Because
Crohn’s disease inflammation is transmural, strictures (narrowing of the bowel lumen due to
scar) can form and cause obstruction. Also, this transmural inflammation can lead to fistulae
(abnormal channels between organs). Fistulae can cause bowel contents to leak from openings
to the skin (“enterocutaneous fistulae”), bladder (“enterovesicular fistulae”), vagina
(“enterovaginal fistulae”), or luminal contents can escape into the abdominal cavity and cause
abscess. An important difference between ulcerative colitis and Crohn’s disease is that Crohn’s
disease recurs after surgery. Therefore, Crohn’s disease is not curable by surgery. Removing the
colon can “cure” ulcerative colitis, but this is a very severe treatment option.
Pathogenesis of IBD
IBD results from an inappropriate inflammatory response to substances present in the
intestinal lumen. The chronic intestinal inflammation may be triggered by a transient infection.
However, the actual trigger is not identified in most patients. Current research efforts focus on
determining what causes the inappropriate inflammation to persist.
Basic and clinical research suggest that IBD results from a poorly regulated immune
system. Support for this concept includes mice with various immune defects that develop colitis.
In most of these mouse models, intestinal inflammation is associated with increased release of
mucosal inflammatory cytokines like IL12, TNFα and IFNγ. Studies in patients show a similar
increase in intestinal inflammatory cytokines (1-3).
Genetics of IBD
Genetic predisposition may play a role in IBD. For example, some patients with Crohn’s
disease have mutations in a gene called Card15 or Nod2. Card15 is an intracellular protein
expressed by monocytes and intestinal paneth cells (4) that recognizes bacterial muramyl
dipeptide (5). It is unknown how Card15 mutation influences intestinal inflammation. Most
(>80%) patients with Crohn’s disease do not have Card15 mutation and most people with
Card15 mutations do not develop IBD. Mutations of Card15 do not associate with ulcerative
colitis. It is likely that multiple gene interactions associated with environmental factors lead to
IBD.
Epidemiology of IBD
There are many patients with IBD. The percentage of the population with IBD in
northern Europe and the United Kingdom is rising and was recently estimated as 0.5% (6). IBD
is a disease that became prevalent in the twentieth century in developed countries. There has
been a dramatic rise in the incidence (onset of new cases) Crohn’s disease over the last century
(Table 2). The incidence of IBD still seems to be increasing in many parts of the world (7;8).
Improved diagnosis does not explain the dramatic increase in IBD and other autoimmune
diseases (7;9).
Table 2. New cases Crohn’s disease diagnosed yearly.
New cases each year per 100,000 people
Region
Cardiff, Wales
Minnesota, USA
Derby, England
N. Isles, Scotland
Central Sweden
Copenhagen, Denmark
Beer Sheva, Israel
1930's
1940's
1950's
1960's
1970's
1980's
0.25
0.7
0.8
1.5
2.5
0.9
1.7
1.5
3.2
4.5
2.0
4.0
3.3
0.7
0.6
4.9
6.8
3.7
6.0
5.1
2.5
1.2
8.3
7.0
6.7
8.2
6.7
4.6
2.1
IBD remains rare in less-developed tropical countries (Figure 1). Epidemiological
studies show that people from tropical countries have the same genetic predisposition to IBD as
do people living in industrialized regions. A possible explanation for the regional differences is
that living in developed countries exposes people to disease-causing agents absent in lesserdeveloped countries. However, no such causative agent unique to developed countries has been
identified. Conversely, perhaps living in lesser-developed countries exposes people to protective
factors that prevent IBD.
In the mid-1990’s a group of investigators at the University of Iowa hypothesized that
exposure to helminths (parasitic worms) protected from IBD (10;11). IBD became prevalent in
developed countries as improved hygienic practices decreased helminth exposure. While
helminths are nearly eradicated from developed countries, they remain common in lesserdeveloped countries.
Figure 1. The global prevalence of IBD.
Helminths and the Immune Response (The theoretical basis for TSO®)
Helminths are parasitic worms. There are many different species of helminths. People
acquire helminths naturally through contact with contaminated food, water or soil. Colonization
is most common in children living in tropical areas with poor sanitation.
To be successful, helminths must influence the immune system. People with helminths
have modulated immune responses characterized by decreased
production of IFNγ and diminished delayed-type hypersensitivity
responses (12-14). This alteration in the immune response
occurs through induction of regulatory cytokines such as IL4,
IL10, and TGFβ (13;15).
Helminths also alter immune
responses in animal experiments showing that this is a general
feature of these organisms (12;16;17) (18-20).
Helminth-mediated modulation of the immune system
can prevent inappropriate responses that cause disease (10;11).
There is excellent epidemiologic data showing that helminths
protect from development of asthma and atopy (21;22). This
may be due to induction of immuno-regulatory IL10 (23).
Animal models also show that helminths protect against
excessive inflammation. Helminths inhibit onset of autoimmune
diabetes in mice (24;25). In murine experimental autoimmune Figure 2. Mice exposed to
encephalitis (a model of multiple sclerosis), helminths inhibit helminths are protected from
disease (26;27).
Importantly, helminths prevent onset of developing TNBS colitis.
spontaneous colitis in IL10 deficient mice (10), and protect mice Adapted from Elliott, et.al., Amer. J.
and rats from developing severe colitis in response to Physiol. 284:G385, 2003.
dinitrobenzene sulfonic acid or trinitrobenzene sulfonic acid (28-30), see Figure 2.
Helminths and humans co-evolved. Until the twentieth century, people routinely carried
helminths. Our immune systems are adapted for helminths. It is likely that loss of exposure to
these organisms has affected our immune systems permitting development of excessive immune
responses that cause IBD.
The choice of Trichuris suis.
As detailed above, there is a strong basis for using helminths as natural immune
modulators to treat IBD. Such a treatment strategy requires use of a helminth suited for
medicinal application. Some helminths have significant potential to cause disease that hinders
their therapeutic use. Others reproduce in ways that could permit inadvertent colonization of
others. An medicinal helminth should, 1) produce self-limited colonization in humans, 2) have
no potential to cause human disease, 3) not replicate in the host, 4) not be transmissible, and 5)
be free of other contaminating agents or organisms.
Trichuris suis, the active component in TSO®, meets these requirements. Trichuris suis
is the porcine whipworm (Figure 3). It is related to, but distinct from, Trichuris trichiura, the
human whipworm (31). T. suis can colonize people but the worms are short-lived and
colonization is self-limited. Although many farmers are exposed to T. suis, this helminth does
not cause disease in people. T. suis cannot increase their numbers (replicate) in people. T. suis
ova require a 3 to 6 week incubation in moist soil to mature. Thus, inadvertent spread to others
is highly unlikely. Finally, as described below, T. suis can be isolated and purified free of other
agents and organisms.
T. suis is acquired by ingesting developed ova. The ova are nearly microscopic
measuring 24 µm x 54 µm. Once ingested, the egg hatches to release a single T. suis larva. Over
two months, the larvae mature, migrating from the small bowel to the cecum and ascending
colon. The body of adult worms is about 1 cm in length. They have a thin hair-like appendage
that attaches to the host giving them a
“whip-like” appearance.
Like most helminths, T. suis
cannot mature outside of a host. At
Ovamed, we colonize young pigs with T.
suis to obtain adult worms. Once the
worms are mature, they are removed from
the pig, washed, and then grown in the
laboratory to obtain ova. Ova then are
processed and extensively tested to assure
uniformity.
Figure 3. Adult Trichuris suis worms
T. suis for treatment of IBD.
Researchers have performed clinical trials with T. suis to treat Crohn’s disease and
ulcerative colitis. They found that T. suis is a safe and effective treatment for IBD (32). This
treatment was found safe even in patients using steroids and/or azathioprine/6-mercaptopurine.
Figure 4 shows response profiles for IBD patients treated with T. suis ova. In these
examples, the patients were treated with a single dose of 2500 ova then observed for 12 to 15
weeks. The patient with Crohn’s disease responded to the first dose with a drop in the Crohn’s
Disease Activity Index (CDAI) to below 150. The CDAI is a standard index of clinical
symptoms and signs for determining how
Crohn’s disease responds to treatments (33).
CDAI scores less than 150 indicate clinical
remission. After about 8 weeks, the effect
waned and the patient relapsed. This likely
correlates with the fairly rapid loss of the T. suis
in human hosts. The patient began maintenance
treatment at week 16 receiving 2500 ova every
3 weeks. With maintenance treatment, the
patient went back into remission. The lower
chart in Figure 4 shows the response profile of
an ulcerative colitis patient treated with T. suis.
This study used the Simple Clinical Colitis
Activity Index (SCCAI) (34) to measure
ulcerative colitis disease activity. The patient
with ulcerative colitis received a dose of 2500
ova. The patient improved and did not relapse
before entering maintenance treatment. With T.
suis maintenance therapy the patient achieved
remission.
These and other studies have
demonstrated that T. suis therapy is safe and
effective in IBD. The studies show that T. suis Figure 4. Response profiles of a Crohn’s
causes no symptoms as compared to placebo. T. disease patient and an ulcerative colitis
suis is safe at doses up to at least 2500 ova patient treated with T. suis ova. Adapted from
every 2 weeks. Concurrent immune suppression Summers, et. al., Amer. J. Gastro. 98:2034, 2003
with prednisone, azathioprine, and/or 6mercaptopurine does not hinder response to or safety of T. suis. It takes about 6-8 weeks for
most patients to respond to T. suis therapy. Because the helminth is short-lived in people,
repeated dosing is required to maintain response.
TSO® - INSTRUCTIONS FOR USE
TSO® contains viable Trichuris suis ova that are the active agent. TSO® is not
metabolized and does not circulate in the body. The T. suis ova are extensively tested for
uniformity and safety. TSO® is used for immune-mediated inflammatory conditions like IBD
that may result from loss of natural helminth exposure.
Response time and use of concomitant medications:
Response to ImmNova® can require several weeks. Therefore, TSO® is not indicated
for fulminate colitis or conditions that may require urgent surgical correction. TSO® is useful
for active or quiescent disease, and can be used in combination with other therapies. TSO®
appears safe to use in patients on moderate or low-dose corticosteroids, and/or azathioprine or 6mercaptopurine. TSO has not been extensively tested in patients treated with infliximab
(Remicade®), cyclosporin A, or methotrexate. If a patient that requires corticosteroids to remain
in remission begins TSO®, it is recommended that they remain on TSO® for 8 weeks before
attempting to slowly taper the steroids.
Administration:
Most patients are started at 500 ova/dose. They receive TSO® orally every 1 to 3 weeks
on an “empty stomach”. If the patient has not responded to TSO within 8 weeks (4 treatments)
the dose is increased to 1000 ova/dose. The current maximal recommended dose of TSO is 2500
ova every 2 weeks.
To take TSO®, gently agitate the vial to disperse the ova. Pour the contents into a
disposable cup containing dilute juice or a non-acidic electrolyte re-hydration (sports) drink.
Add a small amount of water or juice to the vial, agitate, and pour the contents again into the
disposable cup. Avoid mixing TSO® with hot drinks (eg. coffee or tea). Avoid mixing TSO®
with alcoholic beverages (eg. beer, wine, or liquor). The patient should drink the contents of the
cup then dispose of the cup into a waste container. Do not let others drink from the cup that
contains TSO®.
Storage and handling:
Because TSO® contains living organisms, it must be protected from high temperatures or
freezing. Do not expose TSO® to temperatures greater than 40°C. TSO® should be refrigerated
at 4° to 10°C. Do not freeze TSO®. It should not be stored below 4°C due to the risk of
freezing. Do not place the vials directly on freezer packs or in ice that could be below 0°C.
Contraindications and adverse events:
TSO® is contra-indicted in patients known to be hypersensitive to Trichuris or
compounds made from Trichuris. If an adverse reaction to the agent is suspect, treatment with
albendazole (400 mg) will eliminate the agent.
Patient acceptability of TSO®:
TSO® is a natural way to modify inappropriate mucosal immune responses. Patients are
very accepting of the therapy when they understand the principles supporting this treatment.
Patients take TSO® orally every 1 to 3 weeks. Patients are relieved to know that they ingest
almost microscopic eggs and do not find (see) worms or eggs in the stool. The therapy does not
appear to cause side effects or complications. The therapy can be given alone or in conjunction
with other standard medications for inflammatory bowel disease.
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