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In many helminth infected hosts the number of eosinophils increases dramatically, often without any concurrent increases in the number of other leukocytes, so that eosinophils become the dominant cell type. Many experimental investigations have shown that the eosinophilia is induced by interleukin-5 (IL-5) but its functional significance remains unclear. Mice genetically deficient in IL-5 (IL-5-/-) have been used to evaluate the functional consequences of the IL-5 dependent eosinophilia in helminth infected hosts. Host pathology and level of infection were determined in IL-5-/- and wild type mice infected with a range of species representative of each major group of helminths. The effects of IL-5 deficiency were very heterogeneous. Of the six species of helminth examined, IL-5 dependent immune responses had no detectable effect in infections with three species, namely the cestodes Mesocestoides corti and Hymenolepis diminuta and the trematode Fasciola hepatica. In contrast, IL-5 dependent immune responses were functionally important in mice infected with three species, notably all nematodes. Damage to the lungs caused by migrating larvae of Toxocara canis was reduced in IL-5-/- mice. Infections of the intestine by adult stages of either Strongyloides ratti or Heligmosomoides polygyrus were more severe in IL-5-/- mice. Adult intestinal nematodes were clearly deleteriously affected by IL- 5 dependent processes since in its presence there were fewer worms which had reduced fecundity and longevity. The implications of these results for the viability of using inhibitors of IL-5 as a therapy for asthma are considered.

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Plasma-borne factors prime leukocytes from both infected and uninfected rats for radical generation in response to N. brasiliensis. The concentration of these factors is increased following infection and reaches maximal levels on day 8 post-infection (p.i.) as demonstrated by the striking ability of plasma from infected rats to prime leukocytes from uninfected rats to produce free radicals in response to adult worms. The cytokines, gamma-interferon and tumour necrosis factor (TNF) can be detected in plasma during infection with a variety of organisms and several lines of immunological and pathophysiological evidence, including radical generation, weight loss, anaemia and diarrhoea, implicate generation of these proteins in response to infection with N. brasiliensis. We therefore investigated whether gamma-interferon and TNF were detectable in the plasma of rats infected with N. brasiliensis and whether the presence of these cytokines correlated with the ability of plasma to enhance radical generation in response to N. brasiliensis. However, gamma-interferon was not detected in the plasma of rats at any time after infection with N. brasiliensis and neutralizing monoclonal antibody to rat gamma-interferon had no effect on the ability of plasma to prime free radical generation. TNF was detected in the plasma of heavily-infected rats but only at very low levels (< 1 ng/ml), though copius in vivo synthesis of TNF could be induced by treatment of the infected rats with lipopolysaccharide (LPS). However, neither parasite-induced nor parasite plus LPS-induced plasma TNF correlated with the ability of plasma to enhance radical generation in response to N. brasiliensis.(ABSTRACT TRUNCATED AT 250 WORDS)

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The course of primary infections with Nippostrongylus brasiliensis was followed in nude (CBH/R nu/nu) and heterozygote (CBH/R nu/+) rats. In both nude and heterozygote rats peak egg production by N. brasiliensis occurred on days 7 and 8 post-infection. However, whereas in heterozygote rats egg production declined rapidly thereafter and ceased completely by day 14 post-infection, in nude rats high numbers of N. brasiliensis eggs were still seen on day 27 post-infection, when the experiment was terminated. In comparison with the nude rats, heterozygote rats had a 5-fold greater loss of weight by day 9 post-infection and a 4-fold higher incidence of diarrhoea. Furthermore, infected heterozygote rats became anaemic whereas uninfected rats and infected nude rats showed no evidence of anaemia. Free radical generation was measured in infected (9 days) and uninfected rats. Leucocytes from infected heterozygote rats were able to generate copious quantities of free radicals in response to N. brasiliensis whereas leucocytes from infected nude rats produced only slightly more free radicals than uninfected rats. Thus, worm rejection, weight loss, diarrhoea, anaemia and free radical generation in response to N. brasiliensis infection are all T-cell dependent events.

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Primary infection of rats with Nippostrongylus brasiliensis was associated with alterations in host protein, carbohydrate and lipid metabolism. Infected rats fed ad libitum were compared with uninfected, weight matched, pair fed rats. Metabolic changes detected were related to the level of infection (larvae/g body weight) and also the time course of development of the parasite. The intestinal stage of the infection was associated with marked catabolism of skeletal muscle which did not appear to be mediated by increased secretion of corticosteroids. Plasma concentrations of protein in infected rats were altered even at the lowest dose (27 l/g), and in a biphasic manner corresponding to larval and adult stages of the parasite. Plasma globulin concentrations were increased on Day 2 after infection while from Days 5-10 after infection, plasma concentrations of both globulin and albumin were much reduced. Hypoglycemia developed on Days 8-9 after infection in rats given a dose of greater than or equal to 39 l/g. Infected rats had increased plasma concentrations of non-esterified fatty acids and in marked contrast with their pair fed partners, plasma triglyceride concentration increased dramatically with both the dose of parasites given and the duration of infection. The responses of the rat to infection with N. brasiliensis are compared with host responses to other helminths and microorganisms, and suggestions are made as to their possible functions and significance.

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The physiological responses of well-nourished rats to primary infection with the intestinal nematode Nippostrongylus brasiliensis were examined. Infected rats fed ad libitum were compared with uninfected control rats fed ad lib. and with uninfected rats which were pair-fed to the infected rats. Following infection with N. brasiliensis rat food intake was reduced from day 2 post infection (pi) and there were two periods of minimal food intake (days 2 to 3 and 8 to 9 pi). The water intake of infected rats was only reduced on days 2, 3 and 9 pi and not to the same extent as food intake. Muscle catabolism in infected rats was more severe than could be explained on the basis of their food intake reduction. The rectal temperature and rate of oxygen consumption per g body-weight of rats was not significantly altered by the infection. Host responses to N. brasiliensis are compared with those seen in microbial infections and some of them are found to be considerably different.

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Plasma concentrations of gastrointestinal hormones were measured by radioimmunoassay in fasted rats 9 days after infection with a range of doses of Nippostrongylus brasiliensis. Values for infected rats fed ad libitum were compared with those of weight matched, pair fed, uninfected rats to control for the possible effects of dose-dependent reductions in food intake associated with infection. The plasma concentrations of some of the gastrointestinal hormones in infected rats were very different from those of their pair fed partners. The magnitude and direction of the changes varied according to the hormone being examined. Plasma concentrations of gastrin and pancreatic polypeptide were similar in pair fed and infected rats at all doses used. For the other hormones assayed, infection was associated with dose-related changes. The plasma concentrations of cholecystokinin and insulin were slightly but significantly reduced in infected rats. In contrast, secretin, enteroglucagon, and pancreatic glucagon concentrations were markedly increased. At the highest dose given (52 larvae/g body wt), the plasma levels of secretin and enteroglucagon in infected rats were elevated 9 X and 15 X, respectively. A comparison of the changes seen in N. brasiliensis-infected rats with those reported for other helminth infections revealed striking differences. The possible etiology of alterations in plasma gastrointestinal hormone concentrations and their contribution to the pathological changes seen in animals infected with helminths are discussed.

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The pattern of daily food intake of well-nourished rats infected with Nippostrongylus brasiliensis included 2 distinct phases when food intake was much less than that of uninfected controls (days 0-4 and days 6-10 p.i.). These phases were separated by a period (days 4-6) of still reduced but relatively constant food intake. From day 10 p.i. food intake increased so that between days 12 and 17 infected rats ate more than uninfected controls. In each of the phases of reduced food intake there was a threshold dose above which food intake was further decreased as dose increased. In contrast to the obvious relationship between food intake and dose, food intake could not easily be related to the size of the adult Nippostrongylus population, as judged by egg and worm counts. The relationship appears to be complicated by host variability in susceptibility to infection and to the pathological effects of infection. Effects of N. brasiliensis on the daily pattern of food intake can be explained with respect to stages in the development of the parasite and host responses directed against the adult worms.

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