Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

Liu, Qian; Sundar, Krishnan; Mishra, Pankaj Kumar; Mousavi, Gity; Liu, Zhugong; Gaydo, Andrew; Alem, Farhang; Lagunoff, David; Bleich, David; Gause, William C.

doi:10.1128/iai.01170-08

Cited by 121 publications

(121 citation statements)

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“…In addition, clinical trials in humans examining effects of helminth products on disease severity in autoimmune diseases have shown promising results, as well as showing the safety of these helminth-derived immunomodulators for use as therapeutic agents. Although there is evidence to show that helminth infection can prevent T1DM in mice, 11,13,[23][24][25] there are no reports to support this hypothesis in humans. Epidemiologic studies carried out in southern India have shown reduced prevalence of LF after mass drug administration.…”

Section: Discussionmentioning

confidence: 88%

“…10 Experimentally, a number of helminthic parasites, including the trematode Schistosoma mansoni 11 and the nematodes Litomosoides sigmodontis, Heligmosomoides polygyrus, and Trichinella spiralis , prevent the onset or suppress the severity of T1DM in non-obese diabetic mice. 12,13 Several studies have found that persons infected with chronic parasitic worm infections have lower rates of autoimmune diseases than persons without these infections. 14,15 Currently, trials are under way using Trichuris suum and Necator americanus infection for the treatment of T1DM, multiple sclerosis, inflammatory bowel disease, asthma, and food allergies.…”

Section: Introductionmentioning

confidence: 99%

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Decreased Prevalence of Lymphatic Filariasis Among Subjects with Type-1 Diabetes

Aravindhan¹,

Mohan²,

Surendar³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Several animal studies have shown a protective effect of helminth infections against type-1 diabetes mellitus (T1DM). However, epidemiologic studies demonstrating this protective relationship with T1DM are largely lacking, although an inverse correlation between the prevalence of lymphatic filariasis (LF) and prevalence of allergies and autoimmunity has been shown. A cross-sectional study was undertaken in southern India to assess the baseline prevalence of seropositivity of LF among persons with T1DM (n = 200) and normal glucose tolerant (NGT) persons (n = 562). The prevalence of LF was 0% among persons with T1DM and 2.6% among NGT persons (P = 0.026). The percentage of persons who were positive for filarial antigen-specific IgG4 (but not antigen-specific IgG) was also significantly lower in persons with T1DM (2%) compared with NGT persons (28%) (P < 0.001). Thus, there appears to be a striking inverse relationship between the prevalence of LF and T1DM in southern India.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Decreased Prevalence of Lymphatic Filariasis Among Subjects with Type-1 Diabetes

Aravindhan¹,

Mohan²,

Surendar³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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“…1C, 1D). Although separated, the spleen and the gut are still in relative proximity, and Th2 responses to H. polygyrus can be detected in the spleen (28). To increase the distance between the site of worm infestation and the secondary infection, we delivered BCG in the footpad.…”

Section: H Polygyrus Infection Impairs Priming Of Mycobacteria-specimentioning

confidence: 99%

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Obieglo

Feng

Bollampalli

et al. 2016

The Journal of Immunology

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Helminth infections have been suggested to impair the development and outcome of Th1 responses to vaccines and intracellular microorganisms. However, there are limited data regarding the ability of intestinal nematodes to modulate Th1 responses at sites distal to the gut. In this study, we have investigated the effect of the intestinal nematode Heligmosomoides polygyrus bakeri on Th1 responses to Mycobacterium bovis bacillus Calmette–Guérin (BCG). We found that H. polygyrus infection localized to the gut can mute BCG-specific CD4+ T cell priming in both the spleen and skin-draining lymph nodes. Furthermore, H. polygyrus infection reduced the magnitude of delayed-type hypersensitivity (DTH) to PPD in the skin. Consequently, H. polygyrus–infected mice challenged with BCG had a higher mycobacterial load in the liver compared with worm-free mice. The excretory–secretory product from H. polygyrus (HES) was found to dampen IFN-γ production by mycobacteria-specific CD4+ T cells. This inhibition was dependent on the TGF-βR signaling activity of HES, suggesting that TGF-β signaling plays a role in the impaired Th1 responses observed coinfection with worms. Similar to results with mycobacteria, H. polygyrus–infected mice displayed an increase in skin parasite load upon secondary infection with Leishmania major as well as a reduction in DTH responses to Leishmania Ag. We show that a nematode confined to the gut can mute T cell responses to mycobacteria and impair control of secondary infections distal to the gut. The ability of intestinal helminths to reduce DTH responses may have clinical implications for the use of skin test–based diagnosis of microbial infections.

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“…This protective effect could also be adoptively transferred with either regulatory T (Treg) cell [31], or B-cell transfer [32], in both cases in an IL-10 independent manner. Together with a number of other studies on H. polygyrus infection in allergy [33,34], colitis [35][36][37] and diabetes [38,39], it is clear that this helminth downregulates multiple effector pathways of the adaptive immune response [40].Therapy of human immune pathologies with live helminth parasites continues to be evaluated, but will remain an empirical process. Moreover, permitted doses of live parasites are minimal due to ethical and logistical constraints [41], such that exposure levels and duration do not approach those seen in endemic populations.…”

mentioning

confidence: 99%

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminthHeligmosomoides polygyrus

McSorley

O'Gorman

Blair³

et al. 2012

Eur J Immunol

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Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4 + CD25 + Foxp3 − ) to regulatory (CD4 + Foxp3 + ) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL-5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase-1 and RELM-α (resistin-like molecule-α). Although HES contains a TGF-β-like activity, similar effects in modulating allergy were not observed when administering mammalian TGF-β alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat-treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat-stable and heat-labile immunomodulatory molecules, which modulate pro-allergic adaptive and innate cell populations.Keywords: Allergy r Eosinophils r IgE r Infection r Macrophages IntroductionAllergic asthma has dramatically increased in prevalence in developing countries, exceeding 5% of the Western European and North American populations [1]. This contrasts with much lower asthma incidence in tropical countries that have significant levels of parasite infections, and these observations have stimulated research into the effects of parasitic organisms on human allergy [2][3][4]. From these studies, it has emerged that allergic diseases are least common in parts of the world with high helminth endemicity, and that within endemic populations the prevalence of atopy is significantly lower in individuals with chronic worm infections [5][6][7][8][9][10].Correspondence: Dr. Rick M. Maizels e-mail: rick.maizels@ed.ac.ukWhile a causal link between human helminth infections and reduced allergy has yet to be proven [2], chemotherapeutic clearance of intestinal helminths can result in accentuated atopic responsiveness [11][12][13] and helminth infection blocks overt allergy in a number of animal models [14][15][16][17]. The degree to which helminths may influence allergy, however, is clearly variable between different parasite species [18], and is probably dependent upon the duration and intensity of infection [2,19], each factors that need to be taken into account in assessing this interaction.The concept that helminths may act in a beneficial way for therapy of immunological disorders is one that has been gaining * These author contributed equally to this work. Eur. J. Immunol. 20...

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Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

Cited by 121 publications

References 48 publications

Decreased Prevalence of Lymphatic Filariasis Among Subjects with Type-1 Diabetes

Decreased Prevalence of Lymphatic Filariasis Among Subjects with Type-1 Diabetes

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminthHeligmosomoides polygyrus

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