Waiting for the Cure » helminth immunology

Another Article proving Worms are Key

Tue, 15 Jun 2010 15:07:10 +0000

Here’s a new article from the University of Manchester, finding worms are a key part of a well orchestrated immune system. Is it just me, or are you getting a little tired of the avalanche of proof while we wait patiently suffering, unable to afford or receive our worms? We want worms and we want them NOW.

http://www.the-scientist.com/blog/display/57492/#ixzz0r7JuTFKP

http://www.manchester.ac.uk/aboutus/news/display/?id=5841

From the articles:

“A new class of organisms may be cutting in on the classic, co-evolutionary, immune system-boosting tango between mammals and the beneficial bacteria that inhabit their guts: parasitic worms.”

Trichuris muris eggs with Escherichia coli
Image courtesy of Kelly Hayes, University of
Manchester

“Importantly, the work also showed that the presence of worms and bacteria altered the immune responses in a way that is likely to protect ourselves, the bacteria and the worms.

Intestinal roundworm parasites are one of the most common types of infection worldwide, although in humans increased hygiene has reduced infection in many countries. High level infections by these parasites can cause disease, but the natural situation is the presence of relatively low levels of infection. The team’s work suggests that in addition to bacterial microflora, the natural state of affairs of our intestines may well be the presence of larger organisms, the parasitic roundworms, and that complex and subtle interactions between these different types of organism have evolved to provide an efficient and beneficial ecosystem for all concerned.

Professor Roberts says: “The host uses its immune system to regulate the damage caused by the bacteria and the worms. If the pathogens are missing, the immune system may not give the right response.”

Professor Grencis adds: “The gut and its inhabitants should be considered a complex ecosystem, not only involving bacteria but also parasites, not just sitting together but interacting.”

Some worms capable of passing on pathogens

Tue, 23 Mar 2010 14:50:28 +0000

http://www.ehjournal.net/content/8/S1/S17

I don’t know how this relates to hookworms or whipworms, but the thought before was that no pathogens could be transmitted from the parasites. This study shows that even when washed in an anti-microbial solution, certain pathogens remained and were capable of being passed on to an infected host.

It mentions mycobacteria avium was isolated from parasites that had fed on an infected host. Considering a theory that Crohn’s is often associated with MAP, one might be a little hesitant in sharing one’s infection with other parties if you have Crohn’s. Since there is little way to get testing for this organism at this time.

How does one assure oneself that the hookworms or whipworms are pathogen free, if an anti-microbrial buffer only washes the outside of the organism? I guess this is why TSO was chosen; pathogen free pigs. I wonder how Nottingham got past this, and how often and for what infections the resevoir donor is tested for?

For those DIY’ers, something to consider. And for those buying the parasites, something to ask about.

Worm Proteins Ameliorated Inflammation in Mice

admin — Mon, 08 Mar 2010 13:32:11 +0000

ISSN 1007-9327 CN 14-1219/R World J Gastroenterol 2010 February 14; 16(6): 703-712

Schistosoma mansoni proteins attenuate gastrointestinal motility disturbances during experimental colitis in mice

http://www.wjgnet.com/1007-9327/16/703.asp

Injecting worm proteins into mice given colitis resulted in decreased gastric motility (less bowel movements) and amelioration of inflammation. Pretty good stuff. This means that worm proteins will eventually be the next Prednisone, and the live worm won’t be necessary. I wonder how often we would have to take them? Will they be a shot, a pill, or an enema? Can we get out of the mice model into some human studies before those with IBD lose their colons in waiting?

Abstract

AIM: To investigate the therapeutic effect of Schistosoma mansoni (S. mansoni) soluble worm proteins on gastrointestinal motility disturbances during experimental colitis in mice.

METHODS: Colitis was induced by intrarectal injection of trinitrobenzene sulphate (TNBS) and 6 h later, mice were treated ip with S. mansoni proteins. Experiments were performed 5 d after TNBS injection. Inflammation was quantified using validated inflammation parameters. Gastric emptying and geometric center were measured to assess in vivo gastrointestinal motility. Peristaltic activity of distal colonic segments was studied in vitro using a modified Trendelenburg set-up. Cytokine profiles of T-lymphocytes isolated from the colon were determined by real time reverse transcriptase-polymerase chain reaction.

RESULTS: Intracolonic injection of TNBS caused severe colitis. Treatment with S. mansoni proteins significantly ameliorated colonic inflammation after 5 d. TNBS did not affect gastric emptying but significantly decreased the geometric center and impaired colonic peristaltic activity 5 d after the induction of colitis. Treatment with S. mansoni proteins ameliorated these in vivo and in vitro motility disturbances. In addition, TNBS injection caused a downregulation of effector T cell cytokines after 5 d, whereas a S. mansoni protein effect was no longer observed at this time point.

CONCLUSION: Treatment with S. mansoni proteins attenuated intestinal inflammation and ameliorated motility disturbances during murine experimental colitis.

Nottingham Hookworm Results for Allergies and Asthma

admin — Wed, 20 Jan 2010 16:58:24 +0000

Disappointing. 10 hookworms didn’t really work statistically for asthma or allergies, but there were immune changes. I wonder what “mimic most closely natural infection” means (last line of abstract for asthma study)? Less at once, more often? Or more than 10? I am feeing extraordinarily lucky that 10 hookworms caused such a pronounced change in me; first for the worst, then for the better. I started with 10 hookworms De. 2007, got edema, arthritis, a fever, diarrhea. By month 4 I was in remission, but added 2-3 worms a week for a total of 37. Then I lost them somehow by September 2008 and lost efficacy.

I got 10 new hookworms in February 2009, then 10 more in late September 2009. My last egg count was 1400 epg. My CRP (measure of inflammation) has been normal since March 2009. So 20 worms are working for me. Weight’s been normal since March, I can eat most foods but still get diarrhea from too much fiber. Now my hormones are causing anxiety/depression, but I’m assuming that’s un-worm related. I’m almost 38 years old.

I wish we knew the ideal dosing number and dosing schedule. It seems that those with the best response are getting at least 20-30 hookworms, though I also know of Crohns patients who had to terminate because 20-25 worms were way too much at once. I wish these studies were faster since we’re just dosing in the dark.

The asthma study:

http://www.ncbi.nlm.nih.gov/pubmed/20030661

Experimental hookworm infection: a randomized placebo-controlled trial in asthma.

Feary JR, Venn AJ, Mortimer K, Brown AP, Hooi D, Falcone FH, Pritchard DI, Britton JR.

Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.

Summary: Background Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma. Objectives :To determine the effects of experimental hookworm infection in asthma. Methods “Thirty-two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD(20)AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects. Results Mean PD(20)AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: -1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated. Conclusions” Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non-significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken

And the allergy one:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728895/?tool=pubmed

Clin Exp Allergy. 2009 Jul;39(7):1060-8. Epub 2009 Apr 20.

Safety of hookworm infection in individuals with measurable airway responsiveness: a randomized placebo-controlled feasibility study.

Feary J, Venn A, Brown A, Hooi D, Falcone FH, Mortimer K, Pritchard DI, Britton J.

Division of Epidemiology and Public Health, University of Nottingham, UK. johanna.feary@nottingham.ac.uk

BACKGROUND: Epidemiological evidence suggests that hookworm infection protects against asthma. However, for ethical and safety reasons, before testing this hypothesis in a clinical trial in asthma it is necessary to establish whether experimental hookworm infection might exacerbate airway responsiveness during larval lung migration. OBJECTIVE: To determine whether hookworm larval migration through the lungs increases airway responsiveness in allergic individuals with measurable airway responsiveness but not clinical asthma, and investigate the general tolerability of infection and effect on allergic symptoms. METHODS: Thirty individuals with allergic rhinoconjunctivitis and measurable airway responsiveness to adenosine monophosphate (AMP) but not clinically diagnosed asthma were randomized, double-blind to cutaneous administration of either 10 hookworm larvae or histamine placebo, and followed for 12 weeks. The primary outcome was the maximum fall from baseline in provocative dose of inhaled AMP required to reduce 1-s forced expiratory volume by 10% (PD(10)AMP) measured at any time over the 4 weeks after active or placebo infection. Secondary outcomes included peak flow variability in the 4 weeks after infection, rhinoconjunctivitis symptom severity and adverse effect diary scores over the 12-week study period, and change in allergen skin test responses between baseline and 12 weeks. RESULTS: Mean maximum change in PD(10)AMP from baseline was slightly but not significantly greater in the hookworm than the placebo group (-1.67 and -1.16 doubling doses; mean difference -0.51, 95% confidence interval -1.80 to 0.78, P=0.42). Symptom scores of potential adverse effects were more commonly reported in the hookworm group, but infection was generally well tolerated. There were no significant differences in peak-flow variability, rhinoconjunctivitis symptoms or skin test responses between groups. CONCLUSION: Hookworm infection did not cause clinically significant exacerbation of airway responsiveness and was well tolerated. Suitably powered trials are now indicated to determine the clinical effectiveness of hookworm infection in allergic rhinoconjunctivitis and asthma.

To the Medical Community, or Dear Dr. Weinstock

admin — Tue, 29 Sep 2009 16:20:31 +0000

Article after article extolling the virtues of helminths’ ability to prevent allergies and autoimmune diseases always end in quotes like this:

“The hope is that the work could aid the development of new treatments which work in the same way as gut parasites, by dampening down or rebalancing the immune system so that the body does not respond to allergens and trigger asthma attacks.”

“Here, the view is presented that assessment of the immunophysiological response to helminths could identify that infection with specific parasites would be therapeutically useful (although many helminths could not fulfil this role) and lead to precise knowledge of the immune events following infection, to identify ways to intervene in disease processes (in the absence of infection per se) that can be used to treat, and eventually cure, inflammatory and autoimmune disease.”

Dr. Joel Weinstock, one of the leaders in helminth therapy, criticizes operations like AIT for going ahead and giving out helminths before the research comes in:

“It is a legitimate field, but it’s been bootlegged,” said Dr. Joel Weinstock, a professor of medicine at Tufts University who’s studied parasitic treatment and is working to test the therapy. “The question is, what are you actually buying [from these companies]?”

Weinstock told ABC that selling parasites online “hurts the science, and when people do this it makes people skeptical.”

I would like these researchers to think about this deeply. How many years away is your medicine that mimics the worms’ effects? How accessible is the one helminth treatment that is sanctioned by Dr. Weinstock? How many trials are currently available that one can participate safely in helminth research?

I cannot answer the first question; my guess is at least a decade. Even 5 years is too long. The second question: TSO costs well over $10,000 a year for a therapeutic dose, and when I tried to get it in 2007, it was blocked importation by the FDA. For trials? There is currently 1; TSO for MS at the University of Minnesota. There will be another one at University of Nottingham for MS, but it’s not even recruiting. And that’s it. According to Weinstock, and most other researchers, we must wait until the overwhelming science proves that helminths do indeed dampen the inflammatory cascade that leads to the suffering caused by autoimmune diseases.

I have Crohn’s disease. I’ve had it for 21 years. I’ve already had 1/4 of my colon cut out and resectioned. I have a narrowed ileal-cecal valve that pains me often. I’ve failed every available medication on the IBD market; the only medicine I haven’t tried is Tysabri, with a 1 in 1000 chance of a fatal brain disorder. The risks of helminths are…anemia in large numbers. But you can control the numbers if you use hookworms, or whipworms. I suppose there is risk of coinfection, and a risk that the companies doling out helminths aren’t giving us what they say.

But I’ve seen hookworm eggs under my microscope and other patients have confirmed O&P’s for hookworm ova. Whipworms can be seen in a colonoscopy. My eosoniphils have risen after infection with hookworms, and I experienced all of the side effects that are usual for hookworms. I have taken blood tests to rule out the commonest co-infections. And a small dose of hookworms lowered my inflammation to 0, since I’ve been taking monthly blood tests before and after being infected. Do you need more proof?

If I waited for your molecule, let me describe my life. Emaciation, night sweats, eating a small handful of blended foods. Bedridden, unable to care for my children, in terrible pain, bowel blockages nightly, diarrhea so uncontrollable it spewed out on the floor as I ran to the bathroom every night. 10 + bowel movements a day. Depends for underwear, anemia, weakness, fever, and fatigue. Perhaps Tysabri would work, but after suffering near fatal neutropenia from 6MP, an allergic reaction to Humira, the fear of progressive multifocal leukoencephalopathy is strong. Would my children enjoy watching their mother die?

I understand the criticism. I understand the concern. I tried to get a helmith immunologist to study my effects from the hookworms at UCSF. I was willing to do before and after colonoscopies, monthly blood tests, tissue samples, to research the immunological effects of hookworms on my well-established Crohn’s. We were rejected by the ethics committee. What more can I do?

I’ve published this blog, been interviewed by CBS, have written to Dr. Prtichard and Dr. Weinstock, tried to spur the movement of connecting us experimenters with researchers, and have been rejected, time and time again. We are willing to do things in a controlled setting, but UCSF is not. I’ve asked for help with quantifiying egg counts, to no avail. My doctor says I am the expert in this therapy, which is a joke. There are immunologists who when interviewed, say this therapy has much merit. But go to your doctor and they will not sanction this. “It’s premature. You must wait for the research. Here, try Tysabri. I hope you don’t die.”

If you moved a little faster. If you had multiple trials for people to sign up and get a safe infection from a well-respected institution, then I wouldn’t balk so much. Study after study is pouring in, in the mouse model, in huge population studies, scientists are proving that the helminth is a key player in a well-orchestrated immune system.

Please don’t be so dismissive. We are suffering horribly. And you are taking far too long.

eosinophilia: significance?

Wed, 11 Feb 2009 14:56:40 +0000

There are very few studies on the effect of helminths on humans. As a patient trying this therapy, there are few immune markers we have on hand to check immune response. We have measures of inflammation, like CRP and SED rates, but only in the research setting can one measure IL-10, the T 1 and T2 arms, etc. All we have is eosinophilia and standard stool tests to assess worm burden.

Eosinophils rise in response to hookworm infection, seeming to peak between weeks 3-10. This study describes that eosiniphils peak between days 38-64 :

http://www.ajtmh.org/cgi/content/abstract/37/1/126

Peaks between weeks 3-9:

http://www.ajtmh.org/cgi/content/full/75/5/914#F5

Starts to be elevated at days 14-21, peaked on day 42 and declined to
a persistently elevated level:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1809522

Peaked week 5, declined by week 20:
“In the CD cohort, blood eosinophilia developed from week 5 (mean
2.60×109/l (1.89) v week 1 0.18×109/l (0.10) v week 20 0.59 (0.20)). ”

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1856386

But my favorite study, the MS study in Argentina, where they tracked 12 MS patients already infected with helminths and compared them to 12 other MS patients over a 4.6 year period, only recruited the helminth infected patients if their eosinophelia was high, (800-1800 mm3) and it stayed that way for the duration of the study. Their quantitative egg counts were also high: between 1,180 and 9,340 eggs/gram.

Eosinophils reflect parasitic infection, and the higher the number, usually the larger the worm burden. One indication that one has lost their worm infection would be having an elevated EOS for an extended length of time, then having it fall to baseline. Obviously, stool tests would confirm this, as well as symptom regression. In the dose-ranging trial, the higher doses resulted in higher EOS counts, though they did not test longer than 12 weeks.

I only tested my EOS at baseline and 18 weeks, so I never tracked a rise and fall. Baseline values were 74 cells/mcL and only rose to 192 post infection. (Normal is 15-550). Remember, I added worms from weeks 10-18, which may have provoked an immune response that curtailed the new worms from attaching, and possibly displaced some of the first 10, like this capsule endoscopy study shows. So by week 18, perhaps I had very few worms…

I will be testing EOS at weeks 3, 6, 9, and 12 to see how they respond to 10 larvae. I don’t think 10 hookworms are going to be enough to cause persistent eosinophilia. And like the MS study, it seems important to get and maintain a large enough worm burden to stimulate eosinophilia, and maintain a higher egg count. I’m very curious what my results will be this time…

3 Review Articles on the Hygiene, or Old Friends’ Hypothesis

Fri, 06 Feb 2009 15:02:30 +0000

3 new reviews in Immunology on how helminths are part of the missing link epidemiologically, along with certain other infections, and are probably the reason for the rise in autoimmunity, allergies, certain cancers, depression, nuerological diseases, and atherosclerosis. Click on the HTML or PDF link and you can read them in full.

Rook GAW; Review series on helminths, immune modulation and the hygiene hypothesis: The broader implications of the hygiene hypothesis. Immunology Volume 126 Issue 1, Pages 3-11. December 8 2008

Cooke A; Review series on helminths, immune modulation and the hygiene hypothesis: How might infection modulate the onset of type 1 diabetes? Immunology Volume 126 Issue 1, Pages 12-17. December 8 2008

Jackson JA, Friberg IM, Little S, Bradley JE: Review series on helminths, immune modulation and the hygiene hypothesis: Immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies? Immunology Volume 126 Issue 1, Pages 18-27. December 8 2008

Helminthic Patents

Tue, 30 Dec 2008 15:48:23 +0000

Two patents on helminthic therapy:

http://www.wipo.int/pctdb/en/wo.jsp?IA=WO2006%2F014907&WO=2006%2F014907&DISPLAY=\
STATUS

http://www.freepatentsonline.com/EP1749534.html

Who needs Humira when you can have worm shots?

Wed, 10 Dec 2008 14:07:38 +0000

Worm proteins injected intraperitoneally (shot in the abdomen) ameliorate colitis in mice.

http://www3.interscience.wiley.com/journal/121530207/abstract?CRETRY=1&SRETRY=0

“Conclusions: Treatment with proteins of S. mansoni and A. caninum ameliorated TNBS-induced colitis in mice. S. mansoni proteins increased mRNA expression of regulatory cytokines while suppressing expression of proinflammatory cytokines. Therefore, we suggest a therapeutic potential for helminth proteins in the treatment of IBD.”

This is probably the way helminth therapy will go. A shot every 2 weeks in the abdomen. No icky worms to think about. All sterile and in a nice box in the fridge. No worries about worm death…I wonder if it will hurt as much as Humira…