We have attempted, and continue to attempt, to aggregate all the science on the subject of helminthic therapy and related topics here. We have grouped the papers by topic, and since some papers fit more than one of our categories where a paper is repeated we include only the link to the full paper and to the abstract where it first appears on this page. In some cases we have linked the paper title to the online version so that you can purchase access to the full paper more easily.

Where particularly important papers exist that allow publication in their entirety on non-commercial sites we have included them on this site.

These are:

1. IBD Click to view

2. Inflammation Click to view

Locating Papers online:

PMID and DOI numbers can be used to locate a particular paper using any of the online publications dealing with medicine or science. In the absence of either of those numbers for a listing below (the appear below the Abstract) simply copy of the title of the paper listed below and use the search function on one of the sites below. The following is a partial list of sites where you can track down the full text or the papers referenced below. Simply enter the PMID or DOI in their search field to locate the paper.

1. 1.PubMed
   

2. 2.Blackwell-Synergy
   

3. 3.The Lancet
   

4. 4.BMJ (formerly the British Medical Journal)
   

5. 5.The New England Journal of Medicine
   

6. 6.Annals of Neurology
   

Research not focused on a particular disease

The beneficial helminth parasite?

McKay DM.

Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada. mckayd@mcmaster.ca.

Parasitology. 2006 Jan;132(Pt 1):1-12

Abstract: There is unequivocal evidence that parasites influence the immune activity of their hosts, and many of the classical examples of this are drawn from assessment of helminth infections of their mammalian hosts. Thus, helminth infections can impact on the induction or course of other diseases that the host might be subjected to. Epidemiological studies demonstrate that world regions with high rates of helminth infections consistently have reduced incidences of autoimmune and other allergic/inflammatory-type conditions. Here I review and assess the possible ways by which helminth infections can block or modulate concomitant disease processes. There is much to be learned from careful analysis of immuno-regulation in helminth-infected rodents and from an understanding of the immune status of acutely and chronically infected humans. The ultimate reward from this type of investigation will likely be a more comprehensive knowledge of immunity, novel ways to intervene in the immune response to alleviate autoimmune and allergic diseases (growing concerns in economically developed areas), and perhaps the development of helminth therapy for patients suffering from specific inflammatory, autoimmune or allergic disorders.

PMID: 16393348

Introduction to Immunology and Autoimmunity.

Dorinda A. Smith and Dori R. Germolec.  

Environmental Health Perspectives. 107, 5, 1999, 661-665

Abstract: Autoimmune disease occurs when the immune system attacks self-molecules as a result of a breakdown of immunologic tolerance to autoreactive immune cells. Many autoimmune disorders have been strongly associated with genetic, infectious, and/or environmental predisposing factors. Comprising multiple disorders and symptoms ranging from organ-specific to systemic, autoimmune diseases include insulin-dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, thyroiditis, and multiple sclerosis. There are also implications of autoimmune pathology in such common health problems as arteriosclerosis, inflammatory bowel disease, schizophrenia, and certain types of infertility. Largely of unknown etiology, autoimmune disorders affect approximately 3% of the North American and European populations, > 75% of those affected being women. This discussion provides a brief introduction to the immune system and tolerance maintenance, an overview of selected autoimmune diseases and possible mechanisms of immune autoreactivity, and a review of experimental autoimmune models.

Dose-ranging study for trials for therapeutic infection with
Necator Americanus in humans

Mortimer, A. Brown, J. Feary, C. Jagger, S. Lewis S, M. Antoniak, D. Pritchard and J. Britton.

Am. J. Trop. Med. Hyg., 2006, 75(5), 914-20.

Abstract: Epidemiological studies suggest that a hookworm infection producing 50 eggs/gram of feces may protect against asthma. We conducted a dose-ranging study to identify the dose of hookworm larvae necessary to achieve 50 eggs/gram of feces for therapeutic trials of asthma. Ten healthy subjects without asthma or airway hyperresponsiveness to inhaled methacholine received 10, 25, 50, or 100 Necator americanus larvae administered double blind to an area of skin on the arm. Subjects were seen weekly for 12 weeks and were then treated with mebendazole. Skin itching at the entry site and gastrointestinal symptoms were common at higher doses. Lung function did not change. Levels of blood eosinophils and IgE increased transiently, and levels of IgG increased progressively. All doses resulted in at least 50 eggs/gram of feces in the eight subjects who completed the study. Infection with 10 N. americanus larvae is well tolerated, elicits a modest host eosinophil response, and is potentially suitable for use in preliminary clinical therapeutic trials.

Molecular Pathology of hookworm infection

P. J. Hotez, J. M. Hawdon, M. Cappello, B. F. Jones and D. Pritchard,

Infect. Agents Dis., 1995, 4(2), 71-5.

Abstract: Within the past 2 years, progress has been made in the identification, isolation, and cDNA cloning of several macromolecules from hookworms. While the predicted amino acid sequences of some cDNAs resemble those from other nematodes, such as Caenorhabditis elegans, other cDNAs are unique to hookworms. Studies are under way to evaluate the function of these recombinant hookworm polypeptides with respect to the biology of hookworms in experimental animal models. The recombinant polypeptides are also under evaluation as vaccine targets and as natural products used in the treatment of human cardiovascular and autoimmune diseases.

Asthma & Allergy

Asthma and current intestinal parasite infection: systematic review

and meta-analysis

J. Leonardi-Bee, D. Pritchard and J. Britton.

Am. J. Respir. Crit. Care Med., 2006, 174(5), 514-23.

Abstract: RATIONALE: Epidemiologic studies suggest that intestinal parasite infections may protect against asthma. OBJECTIVES: A systematic review and meta-analysis of epidemiologic studies to determine whether total or species-specific current parasite infection is associated with a reduced risk of asthma or wheeze. METHODS: We searched MEDLINE, EMBASE, and CINAHL (up to January 2006); reviews; and reference lists from publications, with no language restrictions. We included studies that reported asthma or wheeze as an outcome measure and ascertained parasite infection by fecal examination. We estimated pooled odds ratios (OR) and 95% confidence intervals (CI) using data extracted from published papers, or where available, original data provided by authors, using random effect models. MEASUREMENTS AND MAIN RESULTS: Thirty-three studies met the inclusion criteria. Infection with any parasite was associated with a small, nonsignificant increase in asthma risk (OR, 1.24; 95% CI, 0.98-1.57; 29 studies). In species-specific analysis, Ascaris lumbricoides was associated with significantly increased odds of asthma (OR, 1.34; 95% CI, 1.05-1.71; 20 studies), while hookworm infection was associated with a significantly strong reduction (OR, 0.50; 95% CI, 0.28-0.90; 9 studies) that was directly and significantly related to infection intensity (p < 0.001; OR for highest tertile of infection, 0.34; 95% CI, 0.19-0.62). Other species had no significant effects on asthma. Infection effects on wheeze were derived from smaller numbers, but revealed a broadly similar pattern of results.

Independent Effects of intestinal parasites infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study

S. Scrivener, H. Yemaneberhan, M. Zebenigus, D. Tilahun, S. Girma, S. Ali, P. McElroy, A. Woodcock, D. Pritchard, A. Venn and J. Britton,

Lancet. 2011, 3:358 (9292), 1493-9

Abstract: Why asthma is rare in rural subsistence societies is not clear. We tested the hypotheses that the risk of asthma is reduced by intestinal parasites or hepatitis A infection, and increased by exposure to dust-mite allergen or organophosphorus insecticides in urban and rural areas of Jimma, Ethiopia. METHODS: From 12876 individuals who took part in a study of asthma and atopy in urban and rural Jimma in 1996, we identified all who reported wheeze in the previous 12 months, and a random subsample of controls. In 1999, we assessed parasites in faecal samples, Der p 1 levels in bedding, hepatitis A antibodies, serum cholinesterase (a marker of organophosphorus exposure), total and specific serum IgE, and skin sensitisation to Dermatophagoides pteronyssinus in 205 cases and 399 controls aged over 16 years. The effects of parasitosis, Der p 1 level, hepatitis A seropositivity, and cholinesterase concentration on risk of wheeze, and the role of IgE and skin sensitisation in these associations, were analysed by multiple logistic regression. FINDINGS: The risk of wheeze was independently reduced by hookworm infection by an odds ratio of 0.48 (95% CI 0.24-0.93, p=0.03), increased in relation to Der p 1 level (odds ratio per quartile 1.26 [1.00-1.59], p=0.05), and was unrelated to hepatitis A seropositivity or cholinesterase concentration. In the urban population, D pteronyssinus skin sensitisation was more strongly related to wheeze (9.45 [5.03-17.75]) than in the rural areas (1.95 [0.58-6.61], p for interaction=0.017), where D pteronyssinus sensitisation was common, but unrelated to wheeze in the presence of high-intensity parasite infection. INTERPRETATION: High degrees of parasite infection might prevent asthma symptoms in atopic individuals.

The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?

Sergio Romagnani (2004)

112 (3), 352-363. doi:10.1111/j.1365-2567.2004.01925.x

Center for Research, Transfer and High Education MCDNENT, University of Florence, Florence, Italy

Abstract: Allergic atopic disorders, such as rhinitis, asthma, and atopic dermatitis, are the result of a systemic inflammatory reaction triggered by type 2 T helper (Th2) cell-mediated immune responses against 'innocuous' antigens (allergens) of complex genetic and environmental origin. A number of epidemiological studies have suggested that the increase in the prevalence of allergic disorders that has occurred over the past few decades is attributable to a reduced microbial burden during childhood, as a consequence of Westernized lifestyle (the 'hygiene hypothesis'). However, the mechanisms by which the reduced exposure of children to pathogenic and nonpathogenic microbes results in enhanced responses of Th2 cells are still controversial. The initial interpretation proposed a missing immune deviation of allergen-specific responses from a Th2 to a type 1 Th (Th1) profile, as a result of the reduced production of interleukin-12 and interferons by natural immunity cells which are stimulated by bacterial products via their Toll-like receptors. More recently, the role of reduced activity of T regulatory cells has been emphasized. The epidemiological findings and the experimental evidence available so far suggest that both mechanisms may be involved. A better understanding of this question is important not only from a theoretical point of view, but also because of its therapeutic implications

Impaired T Helper 2 Response to Aeroallergen in Helminth-Infected Patients with Asthma - download full paper.

Maria Ilma A. S. Araujo,1,4,5 Bradford Hoppe,6 Manoel Medeiros, Jr.,1 Leda Alcaˆ ntara,2 Maria Cecı´lia Almeida,1

Albert Schriefer,1 Ricardo R. Oliveira,1 Ramon Kruschewsky,4 Joanemile P. Figueiredo,1 Alvaro A. Cruz,3,5

and Edgar M. Carvalho1,4,5 1

Servic¸ o de Imunologia, Hospital Universitario Professor Edgard Santos, 2Faculdade de Farma´ cia, and 3Centro de Enfermidades Respirato´ rias,

Universidade Federal da Bahia, and 4Escola Bahiana de Medicina e Sau´ de Pu´ blica, and 5Instituto de Investigac¸ a˜ o em Imunologia (iii)/Conselho

Nacional de Desenvolvimento Cientifico e Tecnolo´ gico, Salvador,Bahia,Brazil;6DivisionofInternationalMedicineandInfectiousDiseases,Weill        

Abstract: Helminthic infections have been shown to inhibit allergy skin-prick tests and to modify the course of asthma.  We evaluated Dermatophagoides pteronyssinus–specific immune responses in patients with asthma by measuring levels of T helper 2 (Th2) cytokines in peripheral blood mononuclear cell (PBMC) cultures. PBMCs from Schistosoma mansoni–infected patients with asthma living in an area of polyhelminthic endemicity produced lower levels of interleukin (IL)–5 and IL-4 in response to D. pteronyssinus antigen (Ag) 1 than did PBMCs from helminth-free patients with asthma. In contrast, D. pteronyssinus Ag 1–specific production of IL-10 was higher in helminth-infected patients than in helminth-free patients. The addition of recombinant

human IL-10 to D. pteronyssinus Ag 1–stimulated cultures of PBMCs from helminth-free patients led to down-modulation of production of IL-5. After helminth-infected patients with asthma received antihelminthic treatment, there was down-modulation of D. pteronyssinus Ag 1–specific production of IL-10 in vitro. S. mansoni–infected patients with asthma produce lower levels of Th2 cytokines than do helminth-free patients with asthma, and this modulation is likely done by IL-10

Intestinal Helminths Protect in a Murine Model of Asthma1

Kunihiko Kitagaki, Thomas R. Businga, Doina Racila, David E. Elliott, Joel V. Weinstock2 and Joel N. Kline3

Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242        

Abstract: Underdeveloped nations are relatively protected from the worldwide asthma epidemic; the hygiene hypothesis suggests this is due to suppression of Th2-mediated inflammation by increased exposure to pathogens and their products. Although microbial exposures can promote Th2-suppressing Th1 responses, even Th2-skewing infections, such as helminths, appear to suppress atopy, suggesting an alternate explanation for these observations. To investigate whether induction of regulatory responses by helminths may counter allergic inflammation, we examined the effects of helminth infection in a murine model of atopic asthma. We chose Heligosomoides polygyrus, a gastrointestinal nematode, as the experimental helminth; this worm does not enter the lung in its life cycle. We found that H. polygyrus infection suppressed allergen-induced airway eosinophilia, bronchial hyperreactivity, and in vitro allergen-recall Th2 responses in an IL-10-dependent manner; total and OVA-specific IgE, however, were increased by worm infection. Finally, helminth-infected mice were protected against eosinophilic inflammation induced by adoptive transfer of OVA-stimulated CD4+ cells, and transfer of cells from helminth-infected/OVA-exposed mice suppressed OVA-induced eosinophilic inflammation, suggesting a role for regulatory cells. Increased CD4+CD25+Foxp3+ cells were found in thoracic lymph nodes of helminth-infected/OVA-exposed mice. Helminthic colonization appears to protect against asthma and atopic disorders; the regulatory cytokine, IL-10, may be a critical player.

Pathogen induced regulatory cell populations preventing allergy through the Th1/Th2 paradigm point of view.

Roumier T, Capron M, Dombrowicz D, Faveeuw C. 

Immunol Res. 2008;40(1):1-17.

Abstract: Epidemiological studies have demonstrated an inverse correlation between prevalence of helminth infections and allergic diseases both associated to Th2 immune responses. On the other hand, such an inverse correlation has also been evidenced between allergies and bacterial infections, associated to Th1 responses. In this review, we will examine and compare the various mechanisms by which Th1- or Th2-inducing infectious agents regulate the development of atopic diseases. We will emphasize the key role of various regulatory cell populations associated to the immune responses toward pathogen.

PMID: 18193360

Anaphylaxis

Helminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells
(full text)

Niamh E. Mangan*, Rosemary E. Fallon*, Philip Smith, Nico van Rooijen, Andrew N. McKenzie and Padraic G. Fallon2, 

The Journal of Immunology, 2004, 173: 6346-6356

Abstract: Modulation of the immune system by infection with helminth parasites, including schistosomes, is proposed to reduce the levels of allergic responses in infected individuals. In this study we investigated whether experimental infection with Schistosoma mansoni could alter the susceptibility of mice to an extreme allergic response, anaphylaxis. We formally demonstrate that S. mansoni infection protects mice from an experimental model of systemic fatal anaphylaxis. The worm stage of infection is shown to mediate this protective effect. In vivo depletion studies demonstrated an imperative role for B cells and IL-10 in worm-mediated protection. Furthermore, worm infection of mice increases the frequency of IL-10-producing B cells compared with that in uninfected mice. However, transfer of B cells from worm-infected mice or in vitro worm-modulated B cells to sensitized recipients exacerbated anaphylaxis, which was attributed to the presence of elevated levels of IL-4-producing B cells. Worm-modulated, IL-10-producing B cells from IL-4-deficient, but not IL-5-, IL-9- or IL-13-deficient, mice conferred complete resistance to anaphylaxis when transferred to naive mice. Therefore, we have dissected a novel immunomodulatory mechanism induced by S. mansoni worms that is dependent on an IL-10-producing B cell population that can protect against allergic hypersensitivity. These data support a role for helminth immune modulation in the hygiene hypothesis and further illustrate the delicate balance between parasite induction of protective regulatory (IL-10) responses and detrimental (IL-4) allergic responses.

Autism & Psychiatric Disorders

Comment on this section: While none of these papers directly suggest that helminthic therapy could be of benefit to the conditions they focus on, the results of their studies all demonstrate an autoimmune and often inflammation component to the disorder they study. One does make the connection with the hygiene hypothesis, which was the theoretical basis for the exploration of helminthic therapy. It is not such a great leap then to wonder if these disorders, with mechanisms similar in some ways to those causing diseases which do respond to helminthic therapy, might also respond to helminthic therapy.

Autism, asthma, inflammation, and the hygiene hypothesis.

Becker KG

Med Hypotheses.

Gene Expression and Genomics Unit, RRB, TRIAD Technology Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. beckerk@grc.nia.nih.gov

Abstract: Inflammation and the genes, molecules, and biological pathways that lead to inflammatory processes influence many important and disparate biological processes and disease states that are quite often not generally considered classical inflammatory or autoimmune disorders. These include development, reproduction, aging, tumor development and tumor rejection, cardiovascular pathologies, metabolic disorders, as well as neurological and psychiatric disorders. This paper compares parallel aspects of autism and inflammatory disorders with an emphasis on asthma. These comparisons include epidemiological, morphometric, molecular, and genetic aspects of both disease types, contributing to a hypothesis of autism in the context of the immune based hygiene hypothesis. This hypothesis is meant to address the apparent rise in the prevalence of autism in the population.

PMID: 17412520

Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study.

Molloy CA, Morrow AL, Meinzen-Derr J, Dawson G, Bernier R, Dunn M, Hyman SL, McMahon WM, Goudie-Nice J, Hepburn S, Minshew N, Rogers S, Sigman M, Spence MA, Tager-Flusberg H, Volkmar FR, Lord C. 

Center for Epidemiology and Biostatistics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Ohio 45229-3039, USA. cynthia.molloy@cchmc.org

Abstract: A multicenter study of 308 children with Autism Spectrum Disorder (ASD) was conducted through the Collaborative Programs of Excellence in Autism (CPEA), sponsored by the National Institute of Child Health and Human Development, to compare the family history of autoimmune disorders in children with ASD with and without a history of regression. A history of regression was determined from the results of the Autism Diagnostic Interview-Revised (ADI-R). Family history of autoimmune disorders was obtained by telephone interview. Regression was significantly associated with a family history of autoimmune disorders (adjusted OR=1.89; 95% CI: 1.17, 3.10). The only specific autoimmune disorder found to be associated with regression was autoimmune thyroid disease (adjusted OR=2.09; 95% CI: 1.28, 3.41).

PMID: 16598435

Immunity, neuroglia and neuroinflammation in autism.

Pardo CA, Vargas DL, Zimmerman AW 

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. cpardo@jhmi.edu

Abstract: Autism is a complex neurodevelopmental disorder of early onset that is highly variable in its clinical presentation. Although the causes of autism in most patients remain unknown, several lines of research support the view that both genetic and environmental factors influence the development of abnormal cortical circuitry that underlies autistic cognitive processes and behaviors. The role of the immune system in the development of autism is controversial. Several studies showing peripheral immune abnormalities support immune hypotheses, however until recently there have been no immune findings in the CNS. We recently demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes. The role of neuroglial activation and neuroinflammation are still uncertain but could be critical in maintaining, if not also in initiating, some of the CNS abnormalities present in autism. A better understanding of the role of neuroinflammation in the pathogenesis of autism may have important clinical and therapeutic implications

PMID: 16401547

Autoantibodies associated with psychiatric disorders

Margutti P, Delunardo F, Ortona E. 

Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, Rome, Italy. ortona@iss.it.

Abstract: Growing evidence suggests that autoantibodies to neuronal or endothelial targets in psychiatric disorders exist and may be pathogenic. This review describes and discusses the possible role of autoantibodies related to the psychiatric manifestations in autoimmune diseases, autoantibodies related to the psychiatric disorders present in post-streptococcal diseases, celiac disease, chronic fatigue syndrome and substance abuse, and autoantibodies related to schizophrenia and autism, disorders now considered of autoimmune origin

PMID: 16719797

Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders.

Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. 

Department of Psychiatry, Indiana University School of Medicine, and James Whitcomb Riley Hospital for Children Indianapolis 46202-4800, USA.

Abstract: Increased prevalence of familial autoimmune disease is a common finding among probands with various autoimmune disorders. Autistic disorder (autism) is a highly genetic disorder with known immune and immunogenetic abnormalities. Previous research has found an increased frequency of autoimmune disorders in families with autistic probands. We further investigated this association by determining the frequency of autoimmune disorders in families that have probands with pervasive developmental disorders (PDDs), including autism, compared with 2 control groups. METHODS: Three well-defined study groups, including 1) families that have a child with a PDD, 2) families that have a child with an autoimmune disorder, and 3) families with a healthy control child, constituted the sample. A questionnaire inquiring about which first- and second-degree family members had received a diagnosis of having specific autoimmune disorders was completed by 101 families in each group. RESULTS: The frequency of autoimmune disorders was significantly higher in families of the PDD probands compared with families of both the autoimmune and healthy control probands. Autoimmunity was highest among the parents of PDD probands compared with parents of the healthy control subjects. Hypothyroidism/Hashimoto's thyroiditis and rheumatic fever were significantly more common in families with PDD probands than in the healthy control families. CONCLUSIONS: Autoimmunity was increased significantly in families with PDD compared with those of healthy and autoimmune control subjects. These preliminary findings warrant additional investigation into immune and autoimmune mechanisms in autism.

PMID: 14595086

Cardiovascular Disease

Can worms defend our hearts? Chronic helminthic infections may attenuate the development of cardiovascular diseases.

Magen E; Borkow G; Bentwich Z; Mishal J; Scharf S, 

Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot, Israel. elimgen2@netvision.net.il

Medical hypotheses

Abstract: The established risk factors for atherosclerosis fail to fully explain the extent and severity of coronary artery diseases in 50% of the patients. Thus, the causative agents and processes, which may be involved in the pathogenesis of atherosclerosis, are being sought. Notoriously, atherosclerosis and cardiovascular event rates are much lower in developing countries. Clinically, severe infections by intracellular pathogens are widespread mostly in developing countries with poor sanitation, nutrition and massive worm infections. A link between atherosclerosis and helminth infections has never been examined. Based on the present knowledge of immune and infectious mechanisms related to atherosclerosis, it is proposed that chronic helminthic infections can have a significant bearing on the epidemiology of cardiovascular diseases. How can helminthic infections affect the cardiovascular risk? (1) Helminths evade or suppress host immune responses, by producing anti-inflammatory and other immunomodulatory molecules. (2) Helminths induce chronic Th2 activation, which can modify cytokine profiles and immunological responses to heat shock proteins, Chlamydia pneumoniae and cytomegalovirus. (3) The chronic Th2 profile may modulate monocyte activation and chemotaxis to inflammatory sites (atherosclerotic plaques). (4) Chronic Th2 activation may lead to a cytokine profile that could be beneficial for attenuation of atherosclerosis development (upregulation of IL-4, IL-10 and IL-13 and downregulation of proinflammatory cytokines). (5) Helminthic infections may reduce plasma LDL level not only by affecting the host nutrition, but also via modulation of naturally occurring antibodies to cholesterol. Studies are needed to clarify these suggestions. If the hypothesis that helminthic infections impact atherosclerosis is correct, it should be taken into consideration in atherosclerosis immunomodulation therapy and especially in the design of vaccines and vaccine trials.

IBD

For a detailed explanation of the therapeutic role of helminths for Crohn’s, UC and Irritable Bowel go here.

Biologic therapy for inflammatory bowel disease

S. Ardizzone and G. Bianchi Porro

Drugs, 2005, 65(16), 2253-86

Abstract: Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.

Intestinal Helminths: A Clue Explaining The Low Incidence Of Inflammatory Bowel Diseases In Subsaharan Africa? Potential Benefits And Hazards Of Helminth Therapy.

Flassse, R., Latinne, D..

Drugs, 2005, 65(16), 2253-86

Abstract: In their review, the authors state that the very low incidence and prevalence of IBD in sub-Saharan Africa cannot be explained by genetic factors since in Black populations of the U.S.A. and U.K., the incidence of these diseases is approaching that of the white populations. Beside helminths whose intestinal infestation is frequent in sub-Saharan Africa, other micro-organisms such as atypical mycobacteria, lactobacilli, etc, might have been reduced in Western population. This is a new variant of the Hygiene hypothesis. After Rook et al., these micro-organisms were acting as adjuvants for induction of T regulatory cells which, associated with antigen-presenting cells secrete IL-10 and TGF-beta, inhibiting the maturation of CD4 T cells to Th1 and Th2 effector cells, and consequently reducing the occurrence of Th1-mediated diseases like Crohn's disease and Th2-mediated diseases like ulcerative colitis. The effects of intestinal helminths on host immunity have been studied in Ethiopian Jews emigrated to Israel. Thorough studies before and after deworming have demonstrated that chronic helminth infestation provokes a state of chronic immune activation with anergy, reversible after deworming. Administration of ova of Trichuris suis, an helminth non pathogenic in man, has given encouraging results in the treatment o Crohn's disease and ulcerative colitis with a good safety record but long-term trials are needed since the potentially harmful effects of helminths on immunity.

PMID: 17343086

Helminths and the modulation of mucosal inflammation

D. E. Elliott, R. W. Summers and J. V. Weinstock.

Curr. Opin. Gastroenterol., 2005, 21(1), 51-8.

Abstract: Inflammatory bowel disease is an emerging illness associated with socioeconomic development. The current epidemic of immune-mediated diseases may result from our loss of exposure to parasitic worms (helminths). This review summarizes some of the recent findings showing that helminths induce regulatory circuits that could prevent and treat inflammatory bowel disease. RECENT FINDINGS: Inflammatory bowel disease appears to result from a dysregulated immune response. Although genes influence the risk of inflammatory bowel disease, it seems that critical changes in our environment have permitted its expression. One such change is the eradication of helminths. Helminths can impede interleukin-12, interferon gamma, and tumor necrosis factor alpha release and promote interleukin-10, transforming growth factor beta, and regulatory T-cell production. Helminths can prevent and reverse intestinal inflammation in animal models of inflammatory bowel disease. In clinical studies of patients with inflammatory bowel disease, exposure to the helminth Trichuris suis reduces disease activity. SUMMARY: If harboring helminths protects against immune-mediated disease, then these animals must be viewed in a new light. Are there "good" helminths in addition to bad? Instead of being detestable objects marked for eradication, helminths should be viewed as useful animals that may produce important compounds helpful for therapy of human disease.

Recent advances in biological therapy for inflammatory bowel disease.

J. Kurtovic and I. Segal.

Trop. Gastroenterol., 2004, 25(1), 9-14.

Abstract: Immune system is a major determinant of pathophysiology of inflammatory bowel disease (IBD), and cytokines are well known mediators of immune system. Recently, informations on pro-inflammatory cytokines and their role in IBD have led to development of potential therapeutic approach to manipulate these cytokines and there by inhibiting inflammation in IBD. These therapeutic approaches include inhibitors of the tumour necrosis factor (TNF)-alpha lymphocyte trafficking, type 1 T helper (Th1) cell polarization and nuclear factor type beta; immunoregulatory cytokines and various growth factors. Studies on these therapies have documented variable results and the outcomes of many clinical trials are awaited. However, these potential therapies, if become real may revolutionise approach in patients with IBD. Analysis of the inflammed mucosa from patients with Crohn disease (CD) and ulcerative colitis (UC) have shown increased expression of certain proinflammatory cytokines such as interleukin-1 (IL-1), interleukin 6 (IL-6) and TNF-alpha. The latter is important in the recruitment of neutrophils into inflammed tissue, a process which results from three physiological steps: (i) rolling, (ii) adhesion, and (iii) transendothelial migration. Understanding of the biology of chronic inflammation has expanded the therapies available for IBD and particularly CD. At present, the biological therapies that are being used in clinical practice or investigated for the treatment of IBD are predominantly proteins, usually delivered intravenously or subcutaneously. The therapies used include: 1. TNF-alpha inhibitors: infliximab, CDP 571, etanercept, onercept, CNI- 1493 and thalidomide. 2. Inhibitors of lymphocyte trafficking: natalizumab, LPD-02 and ICAM-1. 3. Inhibitors of Th1 polarization: monoclonal antibodies for IL-12, interferon (IFN)-gamma and anti IFN-gamma. 4. Immunoregulatory cytokines: IL-10 and IL-11. 5.

Trichuris suis therapy in Crohn's disease

R W Summers1, D E Elliott1, J F Urban, Jr2, R Thompson1 and J V Weinstock1.

James A Clifton Center for Digestive Diseases, Department of Internal Medicine, University of Iowa Roy J and Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Nutrient Requirements and Functions Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland, USA

Abstract: Background: Crohn's disease is common in highly industrialised Western countries where helminths are rare and uncommon in less developed areas of the world where most people carry worms. Helminths diminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease.
Aims: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth Trichuris suis in the treatment of patients with active Crohn's disease.
Patients: Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index (CDAI)220 were enrolled in this open label study.
Methods: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response was defined as a decrease in CDAI of greater than 100.
Results: At week 24, 23 patients (79.3%) responded (decrease in CDAI >100 points or CDAI <150) and 21/29 (72.4%) remitted (CDAI <150). Mean CDAI of responders decreased 177.1 points below baseline. Analysis at week 12 yielded similar results. There were no adverse events.
Conclusions: This new therapy may offer a unique, safe, and efficacious alternative for Crohn's disease management. These findings also support the premise that natural exposure to helminths such as T suis affords protection from immunological diseases like Crohn's disease.
Abbreviations: CDAI, Crohn's disease activity index; 6-MP, 6-mercaptopurine; DNBS, ditrinitrobenzene sulphonic acid; TNBS, trinitrobenzene sulphonic acid

Will worms really cure Crohn's disease?

G L Radford-Smith.

Abstract: There are a wealth of data that support an immunoregulatory role for helminth infection in animal models and the human host.1-3 Recently, this concept has been utilised therapeutically for the treatment of patients with inflammatory bowel disease (IBD). Specifically, Summers and colleagues4 report the results of their open study of live Trichuris suis ova therapy in 29 patients with Crohn's disease (CD) in this issue of Gut(see page 87).4 Treatment with T suis appears safe and effective in the short term, even with concurrent immunosuppressive therapy. Extension of this concept into the "hygiene hypothesis"5 may seem increasingly attractive in terms of an explanation for some epidemiological observations in patients with IBD, in particular the north-south gradient for IBD prevalence in both North America and Europe, and the lack of IBD in developing nations.6-8

A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors

J Croese1, J O'Neil2, J Masson3, S Cooke3, W Melrose4, D Pritchard5 and R Speare6.

1 Department of Gastroenterology, Townsville Hosptial, Townsville, Australia
2 Department of Gastroenterology, Royal Brisbane Hospital, Brisbane, Australia
3 Department of Gastroenterology, Townsville Hosptial, Townsville, Australia
4 School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Australia
5 Boots Science Building, School of Pharmacy, University of Nottingham, Nottingham, UK
6 School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Australia

Abstract: Our pilot study has established a potential for Necator Americanus, already a fact of life for many millions, as a candidate parasite to inoculate those with autoimmune disease. The natural advantages are lifecycle and migration predictability, ability to control the size of and eliminate a colony, and the parasite's longevity. Inoculation proved safe, even in immune suppressed patients. Our hope that NA would suppress autoreactivity sufficiently to allow immune suppressive therapy to be stopped was unrealistic. Recent and compelling evidence has shown that IBD is self sustaining.10 It may be that after remission is achieved, endoparasites will offer an alternative or adjunct to immune suppressive therapy, a priority for some people with CD.

Helminths and harmony

J V Weinstock, R Summers and D E Elliott.

Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

Abstract: Environmental factors affect the worldwide distribution of IBD. Supported by a growing volume of both epidemiological and experimental data, it appears plausible that exposure to helminths is a factor that protects people from IBD (fig 1). As reported by Moreels and colleagues2 in this issue of Gut, helminths protect mice from experimental colitis. Many factors help initiate and maintain immunological diseases. Targeting one or just a few cytokines in most cases may not prove sufficient to permanently suppress disease activity. Helminths have broad immunoregulatory properties that evolved as part of the successful host-parasite interaction. Studying helminths and how they alter the host's immune response could lead to new and highly effective therapeutic strategies for human IBD. Such studies may also provide new insight into the pathogenesis of CD, UC, and other emerging immunological diseases.

13. Karin A. Saunders,1 Tim Raine,2 Anne Cooke,2 and Catherine E. Lawrence1

Liver Disease (Autoimmune)

An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection.

Aoyama H, Hirata T, Sakugawa H, Watanabe T, Miyagi S, Maeshiro T, Chinen T, Kawane M, Zaha O, Nakayoshi T, Kinjo F, Fujita J.

Division of Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. haaoyama-gi@umin.ac.jp

Abstract: A case-control study was undertaken to describe the prevalence of Strongyloides stercoralis infection among patients with autoimmune liver diseases, such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). This study covered 4,117 patients who were admitted to hospitals in Okinawa, Japan, between 1988 and 2006. During this period, 538 patients had the following chronic liver diseases: PBC, AIH, PSC, chronic viral hepatitis group, and alcoholic liver disease. The other 3,579 patients who were hospitalized and underwent parasitologic tests served as controls. The frequency of S. stercoralis infection in the autoimmune liver diseases group (1.0%) was lower than that found in the control group (7.0%; P = 0.0063). None of the female patients with PBC born before 1955 had S. stercoralis infection, which was also statistically significant (P = 0.045). We hypothesized that immunomodulation by S. stercoralis infection may lower the incidence of autoimmune liver disease.

PMID: 17488925

Multiple Sclerosis

Association between parasite infection and immune responses in multiple sclerosis

Jorge Correale, MD *, Mauricio Farez, MD.

Department of Neurology, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina

Abstract: Objective: To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS)

Methods: A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated eosinophilia. All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the eosinophilia was not present during the 2 previous years. Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF)-, and interferon- production by myelin basic protein-specific peripheral blood mononuclear cells were studied using enzyme-linked immunospot (ELISPOT). FoxP3 and Smad7 expression were studied by reverse-transcriptase polymerase chain reaction.

Results: During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein-specific responses in peripheral blood showed a significant increase in IL-10 and TGF- and a decrease in IL-12 and interferon--secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein-specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF- secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-.

Interpretation: Increased production of IL-10 and TGF-, together with induction of CD25+CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS. Ann Neurol 2007

Immunoregulation of CNS autoimmunity by helminth and mycobacterial infections.

Sewell DL, Reinke EK, Hogan LH, Sandor M, Fabry Z.

Department of Pathology, University of Wisconsin, Madison, WI 53706, USA.

Abstract: The 'hygiene hypothesis' has been proposed to explain apparent increases in autoimmune disease and allergy in areas of the world with improved health care and sanitation. This hypothesis proposes that the lack of serious childhood infections impairs development of an appropriately educated immune response. Imbalance of Th1 and Th2 responses and lack of regulatory T-cell populations are two of many proposed potential mechanisms for immune failures such as autoimmunity and allergy. We summarize the literature evidence for the influence of infectious organisms on autoimmunity with focus on helminth and mycobacterial infections. We also demonstrate that Schistosoma mansoni ova pretreatment, Mycobacterium bovis (BCG) infection, and lyophilized Mycobacterium tuberculosis all modify the course of clinical disease in mice induced for experimental autoimmune encephalomyelitis (a mouse model for human multiple sclerosis (MS)). Our data supports the applicability of the hygiene hypothesis to CNS autoimmune disease.

Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization.

Sewell D, Qing Z, Reinke E, Elliot D, Weinstock J, Sandor M, Fabry Z

Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.

Abstract: Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.

Type I Diabetes

Inhibition of Autoimmune Type 1 Diabetes by
Gastrointestinal Helminth Infection

1. Department of Immunology, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, United Kingdom
2. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom

Abstract: Gastrointestinal nematode infections are prevalent worldwide and are potent inducers of T helper 2 responses with the capacity to modulate the immune response to heterologous antigens. Parasitic helminth infection has even been shown to modulate the immune response associated with autoimmune diseases. Nonobese diabetic (NOD) mice provide a model for studying human autoimmune diabetes; as in humans, the development of diabetes in NOD mice has been linked to the loss of self-tolerance to beta cell autoantigens. Previous studies with the NOD mouse have shown that helminth and bacterial infection appears to inhibit type 1 diabetes by disrupting the pathways leading to the Th1-mediated destruction of insulin-producing beta cells. The aim of our study was to examine whether infection with the gastrointestinal helminths Trichinella spiralis or Heligmosomoides polygyrus could inhibit the development of autoimmune diabetes in NOD mice and to analyze the mechanisms involved in protection and the role of Th2 responses. Protection from diabetes was afforded by helminth infection, appeared to inhibit autoimmune diabetes by disrupting pathways leading to the destruction of beta cells, and was mediated by seemingly independent mechanisms depending on the parasite but which may be to be related to the capacity of the host to mount a Th2 response.

Inflammation

Parasitic worms and inflammatory diseases (full text available)

P. ZACCONE *, Z. FEHERVARI *, J. M. PHILLIPS, D. W. DUNNE & A. COOKE

Department of Pathology, Tennis Court Road, Cambridge, UK

Extract: THERAPEUTIC APPLICATION OF PARASITE PRODUCTS AND FUTURE PROSPECTS

Abstract: Helminths are exquisitely adapted to evading and modulating the mammalian immune response; and interestingly similar evasion mechanisms can be shared among distantly related species (see Table 4).
This begs the obvious question of whether this ability can ever be exploited for therapeutic purposes. The growing body of epidemiological and experimental data detailed above strongly suggests that a reduction in helminth infection is linked to rising rates of autoimmunity and atopy. This offers the real possibility that helminths applied in a controllable clinical setting, could relieve inflammatory disease yet minimize the adverse effects of the parasite. Indeed, several models of autoimmune disease have validated the potential of such an approach. Although still a very young field, limited clinical trials have already been carried out assessing the effects of the porcine whipworm, Trichuris suis, on IBD (Inflammatory Bowel Disease) (65). Initial pilot studies using oral ingestion of live T. suis ova at regular intervals hinted at a beneficial effect on IBD without any overt side-effects (62). Larger trials, including one double-blinded and placebo controlled, revealed effective relief of Crohn's disease in nearly 80% of patients but much more modest effects in the case of Ulcerative Colitis (62,66). It should be noted that the patients enrolled in these studies were refractory to standard interventions, so any beneficial effect should be welcomed, but larger trials with improved clinical scoring would be desirable (67). A similar trial, this time using the human hookworm Necator americanus, is also being carried out in Crohn's patients (68). The caveat of a live parasite approach is only too evident; even if the chosen parasite is unable to productively infect the host patient, as is the case with T. suis, there may still be some adverse side-effects, particularly when patients are challenged in conjunction with immunosuppressants, or in otherwise immunosuppressed individuals. In particular, parasite-mediated immunomodulation may compromise the anti-tumour responsiveness of the patient (69-71). Far more desirable then would be to mimic the beneficial effects of helminth infection by using non-infective products derived from them. Aside from the safety issues, the use of helminth products or their synthetic analogues may also allow a finer level of immunomodulatory control or even potency. Emerging proteomics data and the steady progress in the S. mansoni sequencing project will also surely illuminate the search for novel and efficacious immunomodulatory helminth-derived products (72,73).
One prediction of the Hygiene Hypothesis is that the rising rate of inflammatory disorders is due specifically to a paucity of infection during infancy, which in turn tunes the immune response in subsequent adulthood to a less pathogenic modality. This being the case, therapeutic dosing of a helminth (or products thereof) to relieve fulminant inflammatory disease in an adult may be relatively ineffective. The patient's immune repertoire, both adaptive and innate, has already been shaped by the absence of parasite antigens, and is subject to only relatively minor perturbations. This may explain the incomplete effects of the T. suis infections described above. A prolonged treatment regimen, infection with an attenuated host-specific helminth, or exposure during the supposed critical period of infancy may all potentially improve the efficacy of such an approach. In some not too distant futurity, there may come a day when we all take 'helminth supplements' along with our Omega 3 fatty acids, vitamins, and whatever else goes to make up a modern balanced diet.