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PubMed1993

Recombinant cytokines as immunological adjuvants.

This paper describes the bacterial expression and purification of bioactive recombinant ovine interleukin-2 (rovIL-2), interleukin-1 alpha (rovIL-1 alpha) and tumour necrosis factor alpha. These purified proteins had specific activities in appropriate bioassays of 1 x 10(7) 1 x 10(7) and 1 x 10(5) U/mg, respectively. Recombinant ovIL-1 alpha was assessed as an immunological adjuvant for the sheep response to the model protein avidin. When delivered either intradermally or intramuscularly in conjunction with avidin in aluminium hydroxide the rovIL-1 alpha significantly enhanced the secondary humoral response. Doses of 1, 10 or 100 micrograms per sheep enhanced the humoral response to a similar extent. Recombinant ovIL-1 beta had similar adjuvant activity in that it was demonstrated to significantly enhance the sheep humoral response to an experimental H. contortus antigen. This increase in specific antibody, however, did not correlate with enhanced protection against infection with third stage H. contortus larvae. In addition incorporation of rovIL-1 beta into the formulation was shown not to alter the isotype profile of H. contortus antigen specific antibody.

Adjuvants, Immunologic↗
PubMed1993

Production of vaccines against gastrointestinal nematodes of livestock.

Three international collaborations involving Australian research scientists are currently developing vaccines against Haemonchus, Trichostrongylus and Ostertagia parasites using recombinant DNA technology. The variety of protective antigens identified can be classified as 'conventional' (stimulate naturally acquired immunity) or 'novel'/'convert'/'concealed' (protective once immunity is induced by vaccination). To date, the most gratifying progress has resulted in 60-90% protection against Haemonchus and other blood-sucking parasites (e.g. ticks) using novel antigens, where high titres of serum antibody ingested by feeding worms leads to their demise. A great deal of research effort is unravelling the complexity of naturally acquired immunity so that conventional antigens, which may be the principal means of removing 'mucosal-browsing' parasites, may be formulated and delivered to achieve optimal efficacy. This work reveals that to remove early stages of parasites before they take up residence, deliberate induction of hypersensitivity responses akin to asthma, may be a desirable goal for vaccines and that the two models have much in common.

Animals↗
PubMed2002

Mechanisms of immunity to Haemonchus contortus infection in sheep.

In two separate experiments, sheep were immunized by nine to 12 weekly immunizing infections with 4000 Haemonchus contortus third stage larva (L3), drenched with anthelminthics and maintained free of H. contortus infection for a further 12 weeks. The anamnestic cellular immune responses in both the abomasal lymph node (ALN) and mucosa of the immunized sheep were examined 3 and 5 days post challenge with 50 000 H. contortus L3. Sheep in the two experiments clearly segregated out in two distinct groups, one in which challenge larvae were obviously present in the tissues of all 12 sheep at 3 and 5 days post challenge while no challenge larvae were detected in tissues of seven of the eight sheep in the other group. In sheep in which no tissue larvae were detected, very few changes were noted in either the ALN or mucosa. In contrast, dramatic changes were observed in the cellular profiles of the ALN and mucosa after challenge infection in sheep in which larvae were observed in the abomasal tissues. In the ALN, these changes were characterized by an increase in the relative percentage of gammadelta-TCR+ T cells and B cells and an increase in the proportion of CD4+ T cells coexpressing the activation markers MHC class II and CD25. In the abomasal mucosa, an increase in the number of infiltrating CD4+ and gammadelta-TCR+ T cells and B cells was observed by 3 days postinfection and these levels were further increased at 5 days postinfection. This infiltration of the abomasal mucosa by lymphocytes was accompanied by a dramatic increase in the number of infiltrating eosinophils, which were often in intimate association with the surface of H. contortus larvae. None of these changes occurred in the mucosa of the sheep that showed no sign of challenge larvae in the tissues; however, a transient increase in gammadelta T cells in the ALN and a drop in intraepithelial globule leucocytes were uniquely observed in these sheep at 5 days post challenge. These results suggest that two different types of immune responses can be generated after challenge infection of immunized sheep, one where tissue larvae are excluded from their tissue niche as observed previously and which is associated with changes in globular leucocyte population but no mobilization of the local immune system. In contrast, when challenge larvae reach their tissue niche, dramatic changes in the local immune system occur, including a pronounced infiltration of eosinophils. These two immune mechanisms may be associated with the rapid and delayed rejection of parasite infections in immune sheep.

Abomasum↗
PubMed2000

Induction of T helper 1- and T helper 2-type immune responses during Haemonchus contortus infection in sheep.

The production of cytokines by lymphoid cells, isolated from non-infected and Haemonchus contortus-infected lambs, was investigated. Particular attention was paid to differences in T helper 1- (Th1) and Th2-type immune profiles between genetically resistant and random-bred animal groups. Non-infected resistant and random-bred lambs produced equivalent levels of interferon-gamma (IFN-gamma) and interleukin-5 (IL-5), from isolated abomasal lymph node cells (ALN), mesenteric lymph node cells (MLN) and spleen cells (SC), in response to in vitro stimulation with T-cell mitogen (concanavalin A) or larval parasite antigen. ALN and MLN cells derived from infected resistant and random-bred lambs produced relatively lower levels of IFN-gamma, following in vitro stimulation with parasite antigen, when compared with their uninfected counterparts. In contrast, infected lambs of both groups showed enhanced mitogen- and antigen-stimulated production of IL-5, in comparison with uninfected controls, at days 5 and 28 postinfection (p.i.). Mitogen- and antigen-stimulated IL-5 responses were higher among resistant lambs compared with random-bred lambs, with the highest overall production of IL-5 by parasite antigen-stimulated ALN and MLN cells. Among day 28 p.i. lambs, levels of cell culture-derived parasite-specific immunoglobulin G1 (IgG1) and IgE antibodies were higher in resistant lambs than in random-bred lambs, following in vitro stimulation of SC or ALN cells with parasite antigen. Finally, after 28 days p.i., histological examination of abomasal tissue revealed higher densities of mast cells and eosinophils in the mucosa of resistant lambs than in random-bred lambs. Taken together, these data support the notion of a strong Th2-type immune response to Haemonchus infection in genetically resistant sheep, and support the claim for a Th1/Th2 dichotomy in ruminants.

Animals↗
PubMed1997

Vaccination against Haemonchus contortus with denatured forms of the protective antigen H11.

As part of a systematic examination of the protective epitopes on H11, groups of sheep were vaccinated with preparations of purified H11 used untreated (group A), or progressively denatured (linearized) by incubation with sodium dodecyl sulphate (SDS) (group B) or by boiling with SDS in the presence of dithiothreitol (group C). All the sheep developed antibodies which bound to the untreated H11. When challenged with 10,000 infective larvae of Haemonchus contortus the mean levels of protection relative to the mean values for adjuvant controls were 99.8%, 85% and 79% for faecal egg counts and 95%, 79% and 54% for worm burden at post-mortem for groups A, B and C respectively. The H11-specific antibodies inhibited the microsomal aminopeptidase activity of H11 in vitro up to 80%. The levels of inhibition by sera from individual animals correlated with levels of protection with r2, of 0.69-0.87.

Aminopeptidases↗
PubMed1998

Eosinophil-mediated killing of Haemonchus contortus larvae: effect of eosinophil activation and role of antibody, complement and interleukin-5.

Eosinophils have previously been shown to accumulate around the tissue invasive (L3) stage of sheep gastrointestinal parasites in vivo. In this study, eosinophils obtained from mammary washes of sheep, were shown to immobilize and kill H. contortus larvae in vitro in the presence of antibody specific against a defined L3 surface antigen. Eosinophils obtained from sheep primed by repeated infusion of H. contortus larvae were more effective than eosinophils obtained after a single infusion of parasite extract in Fasciola hepatica infected ewes suggesting the former were activated in vivo. The level of larval immobilization in the presence of antibody was significantly increased when complement was added to cultures containing activated eosinophils. The addition of interleukin-5 to larval cultures containing antibody and complement resulted in a significant increase in larval immobilization with unactivated eosinophils suggesting that eosinophil effector function is enhanced following priming with this cytokine. Ultrastructural analysis of the eosinophil/larvae interaction at 6 h of incubation revealed degranulation of adhering eosinophils onto the surface of larvae. By 24 h of incubation, many larvae showed signs of damage and most eosinophils had degenerated. These results suggest that eosinophil-mediated killing may be an effector mechanism for the elimination of L3 H. contortus larvae in immune sheep.

Animals↗
PubMed1999

Further immunization and biochemical studies with a protective antigen complex from the microvillar membrane of the intestine of Haemonchus contortus.

Immunization of sheep with a protective antigen complex from the intestinal cells of Haemonchus contortus in Freund's adjuvant stimulated individually variable antibody responses but still conferred significant protection against parasite infection. Correlation between antibody concentration and degree of protection was suggestive of antibody being the effector mechanism. The antigen is known as Haemonchus galactose-containing glycoprotein complex (H-gal-GP) because it binds to lectins with a specificity for N-acetyl-galactosamine. Polypeptide composition analysis by polyacrylamide gel electrophoresis indicated an apparent molecular weight of about 1000 kDa and SDS gels revealed four major polypeptides, containing between 2 and 5 disulphide linked subunits, nearly all being glycosylated. N-terminal amino acid sequence was obtained from 12 subunits, ten showing homologies with cDNAs from Haemonchus encoding either pepsin, metalloprotease or cysteine protease-like enzymes. pH optima, inhibitor and various substrate studies confirmed that the native complex possessed proteolytic activities in agreement with the sequence data. Although the cDNAs predicted water soluble enzymes, little of the complex was solubilized from worm membranes without the use of a detergent, such as Triton X-100. It is hypothesized that H-gal-GP is a gut membrane associated multiprotease complex which is involved in the digestion of the blood meal and which can be neutralized by specific antibodies with drastic consequences for the parasite.

Amino Acid Sequence↗
PubMed1999

Immunization with an affinity purified protein extract from the adult parasite protects lambs against infection with Haemonchus contortus.

Young lambs were immunized with membrane protein extracts from adult Haemonchus contortus which had been enriched for cysteine protease activity using Thiol-Sepharose chromatography. The resulting extract comprised several peptides including cysteine as well as serine and metallo-protease activities although the former predominated. A limited number of the peptide components were glycosylated. Following a single challenge infection with the same parasite, vaccinated lambs had substantially reduced faecal egg outputs and final worm burdens (overall means of 77% and 47%, respectively, from three trials) compared with challenge controls. Antibody in sera from vaccinated lambs was almost exclusively bound to the surface of the parasite gut indicating that protection may be mediated by the inhibition of parasite digestion.

Animals↗
PubMed2000

Vaccination of Manchego lambs against Haemonchus contortus with a somatic fraction (p26/23) of adult parasites.

A low molecular weight fraction from adult Haemonchus contortus containing two peptides (p26/23) was used to vaccinate Manchego female lambs between 3.5 and 5 months of age. Immunizing injections were given three times on days 0, 14 and 28 of the experiment. On day 43, lambs were challenged with 400 third stage larvae/kg live weight. Vaccination induced a lengthening of prepatent periods, significant reduction (> 60%) in mean faecal egg counts and smaller variations in packed cell volume values. At necropsy, average worm burden in the vaccinated lambs was significantly lower (61.6%) than that found in unvaccinated challenged animals. A clear correlation was found between protection and serum antibody response in immunized lambs.

Animals↗
PubMed2000

Evaluation of immunization with gut membrane glycoproteins of Ostertagia ostertagi against homologous challenge in calves and against Haemonchus contortus in sheep.

Peanut and ConA lectins were used as ligands to isolate glycoproteins from detergent extracts of adult Ostertagia ostertagi membranes. As judged by their profiles following SDS-PAGE, these fractions closely resembled the equivalents from Haemonchus contortus which are derived from the nematode intestinal cell microvillar membranes and which are highly protective when used as antigens. Groups of calves were immunized with the peanut and ConA binding fractions of Ostertagia, either as separate or pooled antigens mixed with QuilA as adjuvant. All calves, including controls immunized with adjuvant only, were challenged with a single dose of infective Ostertagia larvae and faecal egg counts were monitored for 5 weeks. In two experiments where the antigen fractions were pooled, moderate (30-50%), but statistically significant reductions in egg output were observed, but the number of worms was not diminished. No significant protection was observed in a third trial where groups of calves were immunized with peanut or ConA binding proteins given separately. Two further trials were conducted in sheep immunized with the same Ostertagia fractions but challenged with Haemonchus. Irrespective of whether they were administered separately or together, the Ostertagia antigens cross protected efficiently against Haemonchus reducing egg counts by between 81% and 97% and worm numbers by between 57% and 84%.

Adjuvants, Immunologic↗
PubMed2001

Cross-protection studies with gut membrane glycoprotein antigens from Haemonchus contortus and Teladorsagia circumcincta.

Gel profiles of the peanut and ConA lectin binding integral membrane glycoproteins of Teladorsagia circumcincta and Haemonchus contortus were compared and found to be considerably different. However, some of the Teladorsagia polypeptides were recognized by antisera specific for Haemonchus amino-, metallo- or aspartyl peptidases, enzymes which are known to be protective antigens for that parasite. As expected, an experimental vaccine containing these Haemonchus proteases was extremely effective against homologous challenge, reducing egg and worm counts by more than 99% and 92%, respectively, but it did not provide any useful cross-protection against either T. circumcincta, Trichostrongylus axei or Cooperiaoncophora. A reciprocal experiment, where sheep were immunized with the equivalent glycoproteins from T. circumcincta, showed that, while they were not protected against homologous challenge, there was some cross-protection against Haemonchus as measured by a significant reduction in worm egg output.

Animals↗
PubMed2001

The influence of protein supplementation on the immune response to Haemonchus contortus.

A major protective mechanism in lambs against the abomasal parasite Ostertagia (Teladorsagia) circumcincta appears to be the immunoglubulin (Ig)A-mediated suppression of worm growth and fecundity. The present study indicates that IgA may play a similar role in the control of another abomasal parasite Haemonchus contortus. Hampshire Down lambs were offered one of two diets: (i) a basal diet and (ii) a diet supplemented with additional protein. Lambs were then 'trickle' infected with H. contortus and killed 10 weeks after the start of infection. Those lambs on the supplemented diet had shorter adult worms and produced significantly more antiparasite IgA. There was a significant association between reduced female adult worm length and increased IgA against third-stage larvae. Most of the difference between the two groups in worm length could be accounted for by differences in IgA responses. Therefore, IgA may be the major mechanism controlling fecundity of H. contortus and the magnitude of the IgA response is influenced by the quality of the diet.

Animals↗
PubMed2003

Abomasal lymph node responses to Haemonchus contortus intestinal antigens established in kid goats by infection or immunization with intestinal antigens.

Immune responses to Haemonchus contortus intestinal antigens were evaluated using abomasal lymph node (ALN) lymphocytes from kid goats protected against challenge infection by immunization with parasite intestinal antigen, and from kids that were challenged after immunization with ovalbumin. ALN lymphocytes from the intestinal antigen-immunized group produced significantly higher antibody levels against intestinal antigens than the ovalbumin group, supporting the theory that immunization contributed to that ALN response. In contrast, intestinal lysates and membrane enriched preparations from intestinal cells stimulated significant proliferation of ALN lymphocytes in both groups. The proliferation was antigen-dependent, since intestinal antigens failed to stimulate proliferation in ALN lymphocytes from unimmunized and uninfected kids. For both the intestinal antigen and ovalbumin immunized groups, CD4+ T lymphocytes predominated in ALN lymphocytes that were stimulated to proliferate by intestinal antigens. The results indicate that H. contortus infection alone can induce ALN lymphocyte responses to intestinal antigens. In contrast to ALN lymphocyte responses, serum antibody against intestinal antigens was generally low to undetectable in ovalbumin-immunized kids following infection. Abomasal mucus from an H. contortus infected lamb was probed with a monoclonal antibody that binds to a periodate sensitive determinant on numerous H. contortus intestinal membrane and secreted proteins. Numerous bands of reactivity were detected, indicating that multiple parasite intestinal antigens were released into abomasal mucus during infection. The results, challenge the general concept that H. contortus intestinal antigens are 'hidden' from the host immune system during an infection. On the contrary, parasite intestinal proteins may be relatively abundant antigens presented to the host during infection. In addition, ALN T lymphocytes appear to provide a more sensitive measure than serum antibody to detect presentation of these antigens to the host immune system.

Abomasum↗
PubMed2003

Metalloendopeptidases from the intestinal brush border of Haemonchus contortus as protective antigens for sheep.

Substantial protection against the economically important nematode Haemonchus contortus has been achieved by immunizing sheep with a glycoprotein fraction isolated from the intestinal membranes of this parasite. This fraction has been termed Haemonchus galactose-containing glycoprotein complex (H-gal-GP) since it was originally isolated through its selective binding to lectins with a specificity for N-acetylgalactosamine. A major component of this highly protective antigen complex is a family of four zinc metalloendopeptidases, designated MEPs 1-4. Various combinations of these MEPs were evaluated in immunization-challenge trials in sheep. In two experiments a combination of all four MEPs, separated from the rest of the complex by gel filtration in 8 m urea, significantly reduced H. contortus egg counts by 45 and 50%, an effect not significantly different from that conferred by 8 m urea treatment of H-gal-GP itself. Similarly, MEP3 alone or MEPs 1, 2 and 4 in combination, electroeluted from the complex following SDS gel electrophoresis, each reduced egg counts by some 33%. The MEPs are therefore protective components of H-gal-GP and from previously published findings, it appears that MEP3 is the most effective member of this metalloendopeptidase family. However, there was no significant protection when sheep were immunized with fully reduced and denatured H-gal-GP or with bacterially expressed recombinant forms of MEP 1 or the principal domains of MEP3, suggesting that conformational epitopes on the MEPs are required for immunity.

Animals↗
PubMed2003

Immunization against ovine haemonchosis with three low molecular weight somatic antigens of adult Haemonchus contortus.

Individual bands (15) from electroblotted soluble extracts of adult Haemonchus contortus were excised and three peptides of molecular weight ca. 56 (F4), 39 (F8) and 18.5 kDa (F14) used to vaccinate 4-4.5-months-old lambs against the nematode. Immunizing doses from each peptide were administered in 1 ml Freund complete adjuvant (first 50 microg injection) and 1 ml Freund incomplete adjuvant (second and third 50 microg injections) to six lambs. Two weeks after last immunization, animals were challenged with 300 L-3/kg live weight (LW). Lambs were slaughtered 34 days after challenge. Immunization induced a strong antibody response estimated by enzyme-linked immunosorbent assay, whereas no peripheral lymphoproliferative response was observed. Lambs in the F8-vaccinated group showed on average delayed pre-patent period, lower faecal egg counts and reduction of abomasal worm burdens, although the differences were not statistically significant.

Animals↗
PubMed1998

Faecal egg counts are representative of digestive-tract strongyle worm burdens in sheep and goats.

The relationship between faecal egg counts and worm burdens in sheep and goats was studied in a large array of environments, from temperate (ewes, lambs or dairy-goats in France) or steppic (ewes in Middle-Atlas of Morocco) to Sahelian (young sheep and goats of Mauritania in West Africa) climates. The studied temperate worm communities were dominated by Teladorsagia and Trichostrongylus sp., and those from steppic areas by Teladorsagia, Marshallagia and Trichostrongylus sp.; Haemonchus contortus was highly predominant in the Sahelian regions. The fertility of worms depended on density (10 to 50% of variance) and presence of H. contortus to a lesser extent. For sheep and goats from several temperate and steppic areas, a good relationship between egg counts and worm burdens was established (r = 0.62). It was ameliorated when the percentage of H. contortus, the most prolific species was incorporated in the model. The predictive value of faecal egg count for assessing worm burden was only of interest for groups of hosts.

Age Factors↗
PubMed2002

Kinetics of antibody response by Dot-ELISA in rabbits immunized with adult Haemonchus contortus antigen.

Whole adult soluble extract of Haemonchus contortus as an antigen along with Freund's complete adjuvant, was used to immunize rabbits. Antisera from immunized rabbits were collected at intervals of 30, 60, 90, 120, 150 and 180 days. For the detection and titration of anti-H. contortus antibodies in these sera, Dot-ELISA was developed. Sera collected 30 days post-immunization exhibited a titre of 1:5,000 in all the rabbits except one, where a titre of 20,000 was recorded. Later, all the rabbits attained the highest titre of 40,000 at different periods of post-immunizations, which were maintained 150-180 days. These high titre sera can be of immense use in the identification and characterization of immunodominant antigens of adult H. contortus.

Animals↗
PubMedDate not supplied

Pathological and immunohistochemical study of the abomasum and abomasal lymph nodes in goats experimentally infected with Haemonchus contortus.

Histopathological changes and the distributions of T and B lymphocytes and IgG producing plasma cells were recorded in the abomasum and abomasal lymph nodes of goats 3, 7 and 21 weeks post-infection (wpi) after an experimental infection with H. contortus. The low rate of worm recovery by 3 wpi (5.6%) might have been due to larvae death as suggested by the presence of granulomas in the abomasal mucosa at 3 and 7 wpi, or simply due to a poor larval establishment. Marked increase in the secretion of mucus by mucous cells together with an abundant infiltration of eosinophils, mast cells, CD3+ T lymphocytes, CD79a+ B cells, IgG+ plasma cells and globule leukocytes were recorded in the abomasal mucosa, especially at 7 wpi. Except for the globule leukocytes, this reaction decreased substantially by week 21, suggesting this cell type may have been involved in rejection of adult nematodes. The abomasal lymph nodes showed marked hyperplasia, particularly of CD79a+ B cells and IgG+ plasma cells in all infected goats. These reactions may have been responsible for the reduction in the number of worms found in the abomasum between 3 and 7 wpi.

Abomasum↗