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Chymase inhibitor ameliorates eosinophilia in mice infected with Nippostrongylus brasiliensis.

BACKGROUND: Chymase is a chymotrypsin-like serine protease primarily stored in mast cells. Infection with helminth parasites is known to increase the level of mast cell chymase in the jejunum and serum in mice. The aim of the present study is to elucidate the role of chymase in helminth infection. METHODS: Chymase inhibitor SUN-C8257 was administered to mice infected with the nematode Nippostrongylus brasiliensis, and the number of eosinophils in the blood, serum IgE levels and fecal egg counts were determined. RESULTS: Administration of SUN-C8257 significantly inhibited blood eosinophilia in BALB/c mice infected with N. brasiliensis. The effect of SUN-C8257 was specific for eosinophils, in that it affected neither the number of total leukocytes nor serum IgE levels. SUN-C8257 did not alter the fecal egg counts in this model, showing that SUN-C8257 has no effect on infectivity and expulsion of the nematode. N. brasiliensis infection induced eosinophilia in mast cell-deficient mice (W/W(v)) as well as their littermates (+/+), and SUN-C8257 inhibited the eosinophilia in +/+ mice but not in W/W(v) mice. These results suggest that the eosinophil number may be regulated by different mechanisms in W/W(v) and +/+ mice, and that the effect of SUN-C8257 on nematode-induced eosinophilia is probably due to chymase inhibition. CONCLUSIONS: Chymase released by activated mast cells may play a role in helminth-induced eosinophilia.

Animals↗

Anthelmintics.

This article describes the drugs used in helminthic infections and their therapeutic indications, mode of action, toxicity and other details of each of the recommended drugs, and discusses the nature and treatment of infection by helminths important in human medicine. Infestation due to the roundworms Enterobius vermicularis, Ascaris lumbricoides and the hookworms, Ancylostoma duodenale and Necator americanus can all be treated effectively with pyrantel pamoate. For Enterobius vermicularis, however, a newer drug, mebendazole, is equally as effective. The advantage of these drugs in the indicated circumstances is that they can be administered in a single dose. Unfortunately, pyrantel pamoate is not a panacea and in the case of Necator it is not as effective as in the other roundworms. In that situation the use of tetrachlorethylene is preferable. For treatment of Strongyloides stercoralis, and important human parasite, because it can become disseminated and lead to fatal infections in immunoincompetent hosts, the only effective drug is thiabendazole. In treatment of Trichuris trichiura infection, mebendazole, administered over a period of 3 days, is the most effective available drug. For the roundworms inhabiting tissues--either as aberrant infections of man or as the normal part of their life cycle in man--therapy tends to be largely non-specific. For example, in visceral larva migrans, caused by the dog roundworm Toxocara canis, only palliative therapy with systemic anti-inflammatory agents and corticosteroids may be helpful. Cutaneous larva migrans, caused by the dog hookworms Ancylostoma brasiliensis and Ancylostoma caninum, is also treated primarily with symptomatic measures, but there is a suggestion that thiabendazole may kill the larvae and thus be effective. Trichinella spiralis may cause severe, even fatal infections in man, but only symptomatic therapy can be offered. Therapy for filarial infections is regrettably complicated and not completely effective. Diethylcarbamazine remains the best available drug, but in some of these infections local surgical excision may also be used. It is important to bear in mind that release of antigens from dying or dead worms may cause systemic inflammatory and allergic reactions that may require therapy with corticosteroids. Therapy for Cestodes is achieved most effectively with niclosamide, but the antimicrobial agent paromomycin has also been effective. For the aberrant cestode infections of man, such as echinococcal cysts or Taenia solium cycticerci, treatment is surgical if the affected areas are accessible. Treatment of schistosomal infections is quite toxic and, therefore, it is mandatory to determine viability of the worms before recommending therapy. If therapy is required, then Schistosoma mansoni infections are treated with stibophen and S. japonicum with antimony potassium tartrate, taking care in both of these instances to watch for the early signs of antimony toxicity; therapy of S. haematobium infections is based on administration of niridazole...

Anthelmintics↗

Helminth fauna of the stoat (Mustela erminea Linneaus, 1758) and the weasel (M. nivalis Linnaeus, 1758) in Belorussian Polesie.

Helminthological examinations of 30 stoat and 31 weasel carcasses were carried out in Belorussian Polesie (southern part of Belarus, Brest and Gomel regions) between 1980 and 1999. The total rate of helminth infection of these animals was 78.7%. A total of 23 stoats and 25 weasels were infected by helminths. The animals were hosts for 20 species of helminths.

Acanthocephala↗

Complexity and function of cytokine responses in experimental infection by Echinococcus granulosus.

Cytokines are important in the regulation of the immune system and are secreted by a variety of cells in response to self and non-self stimuli. Communication within cells, in the same or distant anatomical sites, occurs via cytokines which determine the quality and intensity of inflammatory and adaptive immune responses. Infection by helminths is characterized by a dominant secretion of type-2 cytokines; IL-4, IL-5, IL-10 (among others), which down-regulates the induction and functions of type-1 cytokines. The molecular mechanisms involved in the polarization of type-2 responses and their biological significance in helminthic infections are unknown, and probably depends on each host-parasite system. Understanding these issues may contribute to immune therapy against parasitic infections. Here we summarize our data obtained in Echinococcus granulosus experimental infection regarding type-2 cytokine induction and its putative role in the host-parasite interaction. Results suggest that induction of cytokine responses at different stages of infection is complex and depends on several parameters. In addition, they support the hypothesis that early IL-10, secreted by B cells in response to non-proteic antigens, may favour parasite survival and the establishment of a polarized type-2 cytokine response.

Animals↗

[Eosinophilic granulocytes: from common residents in normal gastrointestinal mucosa to aggressive agents of eosinophilic gastroenteritis].

Because of their biological affinity for normal gastrointestinal (GI) mucosa, eosinophilic granulocytes are "normal residents" in the mucosa. This physiological GI eosinophilia translates into a state of "permanent normal inflammation", which means that the mucosa's local immune system is constantly confronted by dietary proteins and indigenous microorganisms. This eosinophilic infiltration of the GI mucosa is increased, reactively, in the course of local inflammatory processes, collagenosis, infections (especially helminthic infections), vasculitis, neoplasms and IgE-dependent allergic reactions to food. Lastly, GI eosinophilia that is clearly aggressive, both because of its intensity and its persistence, is what characterizes eosinophilic gastroenteritis. In the present article, we summarize the ethiopathogenic and clinico-epidemiological features of this process, as well as its position within the field of immunopathologic food intolerance.

Eosinophilia↗

Tissue parasitic diseases in Korea.

Parasitic disease is still important subject in the field of infectious diseases in Korea considering it's number and morbidity. Recently there was conspicuous reduction of parasitic disease in terms of soil-transmitted nematodiasis, but parasitism affecting organs other than intestinal tract is still a considerable problem. This survey covers the parasitic diseases cross-sectioned at a pathology laboratory of a referral hospital, trying to elucidate the significance of its relative frequency and also to describe some histopathological changes made by different parasites. Entire pathological materials of parasitic diseases, that were referred, examined and confirmed at the Department of Pathology, Seoul National University Hospital from 1968 to 1987, were used for the study. There was a total of 594 cases of tissue parasitic diseases. This number accounted for 0.33 per cent of total accessions of surgical pathology. There occurred average 30 cases of tissue parasitic disease each year at this Hospital. Protozoal diseases were constituted of 15 cases of amebiasis, 7 cases of leishmaniasis (imported) and 5 cases of Pneumocystis carinii infections. Among helminthic infections cysticercosis was the most common (425 cases), and was followed by paragonimiasis (35 cases), sparganosis (31 cases), clonorchiasis (32 cases) and ascariasis (16 cases). In addition there were 4 cases of anisakiasis, 2 cases of fascioliasis, 2 cases of echinococcosis (imported) and a case of strongyloidiasis and a case of metagonimiasis respectively. It is emphasized that imported parasitic diseases such as leishmaniasis and hydatid disease become steadily found nowadays. Schistosomiasis is another possible imported disease, but not found in this series. And certain cestodiasis particularly cysticercosis and sparganosis should be the subjects of epidemiologic re-evaluation in view of steady occurrence of their morbidity.

Adult↗

Helminth-induced immunoregulation of an allergic response to food.

Work from our laboratory has shown that an enteric helminth infection can act as an adjuvant to prime for a Th2-biased response to a typically tolerogenic form of dietary antigen. Helminth infection did not, however, prime for an allergic response. Using a model in which systemic anaphylactic symptoms and antigen specific IgE are induced in C3H/HeJ mice by repeated intragastric administration of peanut antigen with the mucosal adjuvant cholera toxin we showed that an enteric helminth infection protects against the development of food allergy. Helminth-dependent protection against allergy was abrogated when the helminth-infected, allergen-sensitized mice were treated with neutralizing antibodies to IL-10. Recent work from our laboratory and others has implicated helminth induced immunoregulatory cells in protection against allergy. We will discuss the characteristics of the immunoregulatory cell populations that have been described and the mechanism(s) by which they may function in the suppression of allergy.

Animals↗

Low dose daily iron supplementation improves iron status and appetite but not anemia, whereas quarterly anthelminthic treatment improves growth, appetite and anemia in Zanzibari preschool children.

Iron deficiency and helminth infections are two common conditions of children in developing countries. The consequences of helminth infection in young children are not well described, and the efficacy of low dose iron supplementation is not well documented in malaria-endemic settings. A 12-mo randomized, placebo controlled, double-blind trial of 10 mg daily iron and/or mebendazole (500 mg) every 3 mo was conducted in a community-based sample of 459 Zanzibari children age 6-71 mo with hemoglobin > 70 g/L at baseline. The trial was designed to examine treatment effects on growth, anemia and appetite in two age subgroups. Iron did not affect growth retardation, hemoglobin concentration or mild or moderate anemia (hemoglobin < 110 g/L or < 90 g/L, respectively), but iron significantly improved serum ferritin and erythrocyte protoporphyrin. Mebendazole significantly reduced wasting malnutrition. but only in children <30 mo old. The adjusted odds ratios (AORs) for mebendazole in this age group were 0.38 (95% CI: 0.16, 0.90) for weight-for-height less than -1 Z-score and 0.29 (0.09, 0.91) for small arm circumference. In children <24 mo old, mebendazole also reduced moderate anemia (AOR: 0.41, 0.18, 0.94). Both iron and mebendazole improved children's appetite, according to mothers' report. In this study, iron's effect on anemia was limited, likely constrained by infection, inflammation and perhaps other nutrient deficiencies. Mebendazole treatment caused unexpected and significant reductions in wasting malnutrition and anemia in very young children with light infections. We hypothesize that incident helminth infections may stimulate inflammatory immune responses in young children, with deleterious effects on protein metabolism and erythropoiesis.

Anemia, Iron-Deficiency↗

Genetic influences on plasma cytokine variation in a parasitized population.

The soil-transmitted helminths are the most common helminthic infections, affecting about one-fourth of the world's population. There is a significant genetic component to susceptibility to infection with these organisms. Substantial changes in plasma cytokine levels are associated with helminthic infections, and there may be significant genetic components to this cytokine variation. Six plasma cytokine levels were assessed for 367 members of a single pedigree from the Jirel population of eastern Nepal. This population experiences moderate rates of infection with geohelminths. Sex, age, helminthic infection, infection with Giardia, and presence of a household latrine were considered as covariates in all analyses of the cytokine data. The analyses of the single Jirel pedigree revealed significant heritabilities for IFN-gamma (h2 = 0.654+/-0.096), TNF-alpha (h2 = 0.458+/-0.101), IL-2 (h2 = 0.583+/-0.101), IL-4 (h2 = 0.700+/-0.095), IL-5 (h2 = 0.676+/-0.087), and IL-10 (h2 = 0.597+/-0.093). The ratios of IL-4 to IFN-gamma and of IL-10 to IFN-gamma were used as indicators of the degree of type 2 bias in immunological response; analyses of these variables indicated that approximately 40-60% of the variation (h2 = 0.400-0.577) in these derived measures of relative type 2/type 1 response is due to genetic factors.

Agriculture↗

Biology of soil-transmitted helminths: the massive infection.

Soil-transmitted helminth infections when light-to-moderate usually are well tolerated, but heavy-to massive infections invariably cause disease. A massive infection with Ascaris lumbricoides may cause intestinal obstruction, liver abscess, or some other condition requiring surgical treatment; more regularly, however, ascaris disease is a form of malnutrition. Trichuris trichiura causes diarrhea and dysentery and, at times, rectal prolapse. The hookworms, Necator americanus and Ancylostoma duodenale, cause blood-loss from the intestine resulting in anemia. Necator infection is acquired percutaneously, and is more frequently massive than is that of Ancylostoma which may be acquired percutaneously or orally. Estimates of egg output in the feces, based on egg-counts by dilution, direct smear, or thick-film techniques, provide a reliable index of light, medium, or heavy infection. Acquisition of heavy infection with Ascaris and Trichuris depends on favorable qualities of the soil, and on the sorting action of rain which transports and concentrates the eggs of helminths in locations where survival and transmission are favored. The high frequency of heavy hookworm infection in southeastern United States and probably elsewhere may depend largely on the presence of feces-burying dung beetles. Human infection with soil-transmitted helminths of dogs and cats has become a serious public health problem attributable to the persistence of rural mores in the urban setting.

Animals↗

Ecdysteroids in urine of African patients infected with helminths.

The insect molting hormone and related compounds (ecdysteroids) have been found in patients infected with helminths. To investigate this phenomenon, we quantified and analyzed the urinary ecdysteroids in Malian subjects suffering from various helminthiases, as well as in Europeans. Very high titers (up to 100 nM) were found in some patients, whereas healthy persons had a basic level of 4 nM only. The high RIA activity was mainly due to two compounds. One of them was remarkable for being present in all the positive samples; it comigrated with the 20-hydroxyecdysone standard, both in HPLC and in TLC. The origin and the physiological significance of these compounds are questionable, since there was no clear relationship between their levels and the severity of the diseases. Numerous patients who were heavily infected had normal titers. Nevertheless, there is no doubt that high concentrations of ecdysteroid-like compounds in human urine indicate a pathological condition.

Adolescent↗

Enteric infection acts as an adjuvant for the response to a model food antigen.

Oral administration of soluble protein Ags typically induces Ag-specific systemic nonresponsiveness. However, we have found that feeding a model food protein, OVA, to helminth-infected mice primes for a systemic OVA-specific Th2 response. In this report we show that, in addition to creating a Th2-priming cytokine environment, helminth infection up-regulates costimulatory molecule expression on mucosal, but not peripheral, APCs. To examine the consequences of mucosal infection for the T cell response to orally administered Ag, we adoptively transferred transgenic, OVA-specific, T cells into normal mice. We found that helminth infection enhances the expansion and survival of transgenic T cells induced by Ag feeding. Transfer of 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled donor cells showed that T cell proliferation in response to Ag feeding takes place primarily in the mesenteric lymph nodes. Upon subsequent peripheral exposure to Ag in adjuvant, the proliferative capacity of the transferred transgenic T cells was reduced in noninfected mice that had been fed OVA. Helminth infection abrogated this reduction in proliferative capacity. Our data suggests that enteric infection can act as an adjuvant for the response to dietary Ags and has implications for allergic responses to food and the efficacy of oral vaccination.

Adjuvants, Immunologic↗

Prevalence and distribution of soil-transmitted helminth (STH) infections in urban and indigenous schoolchildren in Ortigueira, State of Paranà, Brasil: implications for control.

Soil-transmitted helminth (STH) infections represent a major public health problem in poor and developing countries. During the period September-October 1998 we conducted an epidemiological survey of STH infections in schoolchildren of an urban area (group A) and an indigenous reserve (group B), in the Municipality of Ortigueira, State of Paranà, Brazil, to assess potential benefits of mass treatment. Stool samples were examined for helminth eggs by quantitative (Kato-Katz) technique to determine the prevalence and intensity of intestinal parasitic infection. Moreover, we examined the relationship between prevalence and intensity of STH infections and housing/hygienic factors (by means of a 7-item questionnaire). 236 schoolchildren aged 5-15 years were enrolled, 136 in group A and 100 in group B. The prevalence of STH infections was significantly higher in group B (93%) than in group A (22%) (P < 0.001). Detected parasites were: A. lumbricoides (16.1% prevalence in group A, 88% in group B, P < 0.001), hookworms (5.8% in group A, 52% in group B, P < 0.001) and T. trichiura (5.1% in group A, 2% in group B, P = 0.2). Heavy infections were detected in 2.9% and 23% of the children in group A and B, respectively (P < 0.001). Housing/hygienic indicators were significantly poorer in group B. A statistically significant correlation was observed between total prevalence of STH infections and prevalence of high-intensity infections with most housing/hygienic variables. On the basis of these results, mass treatment and educational interventions were suggested for the indigenous community, whereas target treatment and educational interventions were suggested for the urban community. Even in a geographically homogeneous area different epidemiological realities can be found, which in turn can influence infection levels and control programmes.

Adolescent↗

The cellular IgE response of rodents to infection with Nippostrongylus brasiliensis, Trichinella spiralis and Schistosoma mansoni.

The IgE response at the cellular level to helminthic infection was studied in BALB/c mice inoculated with the infective larvae of the nematodes Nippostrongylus brasiliensis (Nb) or Trichinella spiralis (Ts) or with the cercariae of the trematode Schistosoma mansoni (Sm). Changes in mesenteric lymph node (MLN) cell number, cell surface(s) IgD, IgM, IgE and Thy-1.2 and intracytoplasmic (c) IgE were recorded. In addition, a comparable study was conducted in rats infected with Nb. At 11 days after infection (DAI) of mice with Nb or Ts, or rats with Nb, there was a 3-fold increase in cell number in the MNL. There was a marked increase in cell number in the MLN of mice infected with Sm at 7 weeks after infection (WAI) and in the spleens of Sm-infected mice at 4 WAI. The percentage of cIgE+ cells increased from undetectable levels in uninfected mice and rats to as high as 0.5-1.3% in the MLN of helminth-infected mice and rats. Analysis of cell surface molecules with a fluorescence activated cell sorter (FACS) showed that Nb and Ts infection induced slight increases in the percentages of B cells and slight decreases in the percentage of T cells. More remarkably, the percentage of sIgE+ cells in the MLN of both Nb- and Ts-infected mice rose from undetectable levels in uninfected mice to 33 and 27%, respectively, at 15 DAI. This rise was stimulated in Ts-infected mice predominantly by adult Ts. In the MLN of Nb-infected rats, the percentage of cells that were sIgE+ was greater than 50% at 15 DAI. However, there was no detectable increase in sIgE+ cells in the spleen and MLN of Sm-infected mice until 5 WAI; peak levels of approximately 20% sIgE+ cells were reached at 8 WAI. Treatment of MLN cells from mice infected with Nb, Ts or Sm and rats infected with Nb, with pH 4.0 acetate buffer for 1 min (acid treatment) removed all detectable sIgE from greater than 90% of the sIgE+ cells, but did not remove sIgD or sIgM from cells with these surface isotypes. The effect of acid treatment on sIgE was similar even after a secondary infection of mice or rats with nematode larvae. These data show that helminthic infection, in general, is a potent stimulator of the IgE system at the cellular level and that almost all of the sIgE+ cells that arise have acquired cytophilic sIgE.

Animals↗

IgE memory: persistence of antigen-specific IgE responses years after treatment of human filarial infections.

BACKGROUND: The human immune response to helminth infections is characterized by elevated serum levels of antigen-specific IgE. Although it is well established that IgG humoral immunity can persist for years, as yet there have been no longitudinal studies of antigen-specific IgE responses to helminth infection in the absence of re-exposure to pathogen. OBJECTIVE: We sought to determine the presence of filaria-specific IgE responses years after treatment of human filarial infections in patients no longer living in a region endemic for filariasis. METHODS: Filaria-specific IgE levels were measured in 34 filaria-infected patients before and 11 to 178 (median = 33) months after anthelmintic therapy. Frequencies of filaria-specific IgE-producing cells and measures of filaria-specific IgE-mediated histamine and IL-4 release from basophils were measured in subsets of these patients. RESULTS: At follow-up, all patients were asymptomatic without evidence of active infection, and none had traveled to filaria-endemic regions since initial evaluation. Although frequencies of Brugia malayi antigen (BmAg)-specific IgE-producing cells and serum levels of BmAg-specific IgE decreased significantly over time, both remained detectable in the majority of patients years after initial treatment. Six of 10 patients' basophils released histamine in response to BmAg after treatment (vs 7 of 10 before treatment). Basophils also continued to release IL-4 after stimulation with BmAg years after treatment. CONCLUSION: These results demonstrate that filaria-specific IgE production and filaria-specific IgE-mediated basophil release of histamine and IL-4 persist for years after treatment of human filarial infections. CLINICAL IMPLICATIONS: These findings suggest that (1) absolute allergen avoidance may not result in the loss of allergy, and (2) parasite-specific IgE-inducing vaccines, if effective, could potentially induce longstanding protection.

Animals↗

Relationship between the degree of poverty and the IgE response to Ascaris infection in slum children.

We examined a group of urban slum children in Caracas, Venezuela, and demonstrated the relationship that exists between poverty, conditions of hygiene and the prevalence of helminth infection. Concordant with the high prevalence of helminth infection in these children, the total serum levels of immunoglobulin E (IgE) and blood eosinophilia were elevated and were directly related to the degree of poverty and lack of sanitary facilities. However, in contrast, the reverse pattern was observed for the specific allergic response to these parasites. Thus, the immediate hypersensitivity skin test reactivity to Ascaris antigens, and the serum levels of specific anti-Ascaris IgE antibody, were lowest in the poorest children, who had the highest prevalence of helminth infection and the highest total IgE levels. As allergic-type reactions may participate in protective mechanisms against helminths, these results suggest that poverty and poor sanitary conditions may, by influencing the IgE response, compromise the resistance of such children to parasitic infections.

Animals↗

[Helminths detected in some laboratory animals by fecal examinations.].

Fecal specimens obtained from 505 rats, 317 mice, 128 rabbits and 52 guinea pigs were examined for helminth infections. In general, 38.02% of rats and 83.59% of mice were infected with one or more helminth species. The percentage of Syphacia muris and Syphacia obvelata were 32.48% and 12.67%, respectively, in rats, and the percentage of Aspiculuris tetraptera, S. obvelata and Hymenolepis nana were 79.18%, 10.72% and 15.45%, respectively, in mice. Passalurus ambiguus was found only in one rabbit (0.78 %). No helminth infections were detected in guinea pigs.

English Abstract↗