The adjuvant system AS01 up-regulates neutrophil CD14 expression and neutrophil-associated antigen transport in the local lymphatic network.

The liposome-based adjuvant system AS01 is under evaluation for use in several vaccines in clinical development. We have shown previously that AS01 injected with hepatitis B surface antigen (HBsAg) induces a distinct cellular signature within the draining lymphatics that enhances local lymphocyte recruitment and antigen-specific humoral immunity. Here, we show that AS01-induced neutrophil recruitment is associated with increased expression of CD14 and enhanced antigen uptake capacity in neutrophils from both afferent and efferent lymphatic compartments during the first 48 h after vaccination. Significant and transient increases in CD14 expression on systemic neutrophils were also observed following primary and boost vaccination with HBsAg-AS01; however, they were not observed following additional encounter with HBsAg-alone or HBsAg-alum. These results show that following immunization with AS01, neutrophils expressing higher levels of CD14 are both more abundant and efficient at antigen uptake, warranting further investigation into the role of neutrophil-associated CD14 in the adjuvanticity of AS01.

Immunity to Haemonchus contortus and Vaccine Development.

Sheep are capable of developing protective immunity to Haemonchus contortus through repeated exposure to this parasite, although this immune protection is the result of a complex interaction among age, gender, physiological status, pregnancy, lactation, nutrition and innate and adaptive immunity in the host animal. There are multiple effectors of the protective immune response, which differ depending on the developmental stage of the parasite being targeted, and our understanding of the effector mechanisms has developed considerably in the 2000s. The rational design of vaccines based on 'natural' or 'exposed' antigens depends on an understanding of this exposure-induced immunity. However, the most effective current vaccines rely on protection via the induction of high circulating antibody levels to 'hidden' gut antigens of H. contortus. The success of this latter strategy has resulted in the launch of a vaccine, which is based on extracts of the parasite's gut, to aid in the control of Haemonchus in Australia. The development of recombinant subunit vaccines based on the components of the successful native vaccine has not yet been achieved and most of the recent successes with recombinant subunit vaccines have focussed on antigens unrelated to the gut antigens. The future integration of an understanding of the immunobiology of this parasite with advances in antigen identification, expression (or synthesis) and presentation is likely to be pivotal to the further development of these recombinant subunit vaccines. Recent progress in each of the components underpinning this integrated approach is summarized in this review.

Galectin-11: A novel host mediator targeting specific stages of the gastrointestinal nematode parasite, Haemonchus contortus.

Galectin-11 is released from epithelial cells of the gastrointestinal tract, specifically following infection with gastrointestinal parasites including the highly pathogenic nematode, Haemonchus contortus. The function(s) of galectin-11 are currently unknown but seem to be associated with the development of immunity by the host. The aim of the present study was to examine the interaction of galectin-11 with the different parasitic life cycle stages of H. contortus and determine any effects on parasite development. The results of this study showed that galectin-11 binds to the surface of the L4 and adult stages of the parasite but not to the exsheathed L3 stage. In addition, at a lower concentration, binding to the L4 was specifically localised to the pharynx region. Subsequent in vitro assays demonstrated significant inhibition of larval growth and development in the presence of recombinant galectin-11. These results indicate, to our knowledge for the first time, a functional role for galectin-11 in gastrointestinal nematode infection of ruminants and a mechanism of action of galectin-11, targeting the development and growth of the L4 and possibly the adult parasite stage.

Field vaccination of sheep with a larval-specific antigen of the gastrointestinal nematode, Haemonchus contortus, confers significant protection against an experimental challenge infection.

The availability of effective vaccines would add a valuable tool to the management of gastrointestinal nematode infections in livestock. While some experimental vaccines have shown protection in laboratory trials, few have been tested in the field. In the present study, eight month old sheep kept on pasture were treated with anthelmintic 8 weeks before vaccination with a larval surface antigen of the nematode parasite, Haemonchus contortus, under a commercially acceptable protocol, i.e. 2 immunizations using a commercial adjuvant; they were then given a controlled challenge infection 4 weeks later in indoor pens. Vaccination of sheep with 4 increasing doses of antigen resulted in significant reductions of 61% and 27% in cumulative faecal egg counts in the two highest dose groups, and a 69% reduction in worm burden in the highest dose group. Blood loss, as determined by packed cell volume, was also significantly reduced in the highest dose group of sheep. One outlier sheep showed an unusual increase in egg count without a concomitant increase in worm burden compared to the control sheep, indicating a vaccine-induced stress response. Antigen-specific serum antibody levels steadily increased in sheep while on pasture and decreased when transported to indoor pens. No difference in antibody levels could be detected between vaccinated and unvaccinated sheep, but all showed increased antibody levels compared to uninfected control sheep kept in indoors pens for 2-3 months, suggesting sheep were sensitized to the larval antigen either from low dose pasture contamination or cross reaction with pasture-related antigens. The results of these studies confirm the protective properties of the larval surface antigen and its protective effect when vaccinations are performed in the field.

Novel immunomic technologies for schistosome vaccine development.

Schistosomiasis remains one of the most common human helminthiases, despite the availability of an effective drug against the causative parasites. Drug treatment programmes have several limitations, and it is likely that a vaccine is required for effective control. While decades of vaccine development have seen the discovery and testing of several candidate antigens, none have shown consistent and acceptable high levels of protection. The migrating larval stages are susceptible to immunity, however few larval-specific antigens have been discovered. Therefore, there is a need to identify novel larval-specific antigens, which may prove to be more efficacious than existing targets. Immunomics, a relatively new field developed to cope with the recent large influx of biological information, holds promise for the discovery of vaccine targets, and this review highlights some immunomic approaches to schistosome vaccine development. Firstly, a method to focus on the immune response elicited by the important and vulnerable larval stage is described, which allows a targeted study of the immunome at different tissue sites. Then, two high-throughput arrays are discussed for the identification of protein and carbohydrate antigens. It is anticipated that these approaches will progress vaccine development against the schistosomes, as well as other parasites.

Galectin-11 induction in the gastrointestinal tract of cattle following nematode and protozoan infections.

Galectin-11 (LGALS11) has been suggested to play an important role in protective immunity against gastrointestinal nematodes in ruminants. However, in cattle, this molecule has not been characterized in detail. In the current study, it was shown that transcription of LGALS11 was highly inducible in the bovine abomasal mucosa after an Ostertagia ostertagi infection. LGALS11 protein expression was also increased in the abomasal mucosa following O. ostertagi infection and localized to the nucleus and cytoplasm of epithelial cells and the mucus. Using in vitro abomasal epithelial cell cultures, it was shown that LGALS11 induction was associated with the proliferative and dedifferentiated status of cells. However, LGALS11 was not induced following stimulation with O. ostertagi excretory-secretory products. These results suggest that LGALS11 induction in vivo may be an indirect rather than a direct effect of the parasite on the epithelium. In addition, LGALS11 transcript was also detected in the abomasal lymph nodes where it was shown to be transcribed in MHCII+ cells; however, transcription levels in the lymph nodes were not altered after O. ostertagi infection. In addition, LGALS11 was also induced in the small intestine by different types of parasites, including the nematode Cooperia oncophora and the protozoan parasite Giardia duodenalis.

Resistance to liver fluke infection in the natural sheep host is correlated with a type-1 cytokine response.

Indonesian thin-tail (ITT) sheep can resist infection with Fasciola gigantica but not F. hepatica and presents an ideal model to investigate the mechanisms of liver fluke resistance in a natural host. This study examines the local and systemic immune responses of sheep during Fasciola infection and demonstrates that different anatomical tissues display distinct cytokine profiles consistent with liver fluke migration. The study also reveals a significant difference in the cytokine and antibody profiles of ITT sheep infected with F. gigantica compared with F. hepatica, with a higher ratio of IL-4/IFN-γ mRNA expression and specific IgG1/IgG2 antibodies strongly correlating with pathology. Interestingly, the significant type-1 cytokine profile occurred in the lymph node closest to the site of infection at a time when the effective immune response against F. gigantica liver flukes is thought to occur. When the same F. gigantica infection in the resistant ITT sheep was compared with the susceptible Merino breed, the resistant type-1 phenotype against liver fluke infection was only observed in the ITT sheep. These studies provide the first evidence to suggest that the induction of an early type-1 immune response in this natural sheep host may be responsible for the ability to resist liver fluke infection.

Immune mechanisms of resistance to gastrointestinal nematode infections in sheep.

Infections with gastrointestinal nematode parasites are a major problem for the sheep industry in Australia and New Zealand and have been the subject of intensive research to define mechanisms of resistance. The ability to take continuous biopsy samples of infected organs and cannulate both afferent and efferent lymphatics of draining lymph nodes has been particularly useful in illuminating the kinetics of immune responses at the site of infection. Distinct localized immune responses were shown to occur within and between sheep breeds at different sensitization regimes, as well as at different developmental stages of the parasite within the host. Using localized antibodies derived from mucus and lymph nodes, two major antigens have been identified on the infective L3 stage, which may be responsible for inducing protection and have potential as vaccine targets. Recent advances in sheep genomics also offer the potential of gaining further insight into the underlying genetics of resistance to nematode infections.

The innate host defence against nematode parasites.

Nematode parasites cause significant infections in both humans and animals. They are complex, multicellular organisms that present unique challenges for the host, in particular with respect to the recognition of their unusual surface structures by the innate defence system. The innate immune system is now recognized to be a critical component in the development of an adaptive effector response as well as a driver of vaccine-induced immunity. This paper will give an overview of current research on the innate barriers and immune mechanisms, cells, and receptors involved in the innate host response to nematode parasites. It will also review the 'nematode-associated molecular patterns' that may be specifically recognized by the host, in addition to other signals, such as nervous stimulation and tissue damage, that may alert the innate system to parasite invasion.

Eosinophil interactions with Haemonchus contortus larvae in the ovine gastrointestinal tract.

Sheep were immunized by weekly oral infections with Haemonchus contortus for 9 weeks followed by anthelmintic treatment. They were challenged either 9 or 22 weeks later with PBS (sham controls) or one million exsheathed L3 surgically injected in the abomasum, and killed 24 h or 48 h later. Sheep challenged 9 weeks after immunization displayed varying degrees of tissue eosinophilia that showed a significant inverse relationship with the number of intra-epithelial mast cells (globule leucocytes). Close association of eosinophils with tissue larvae was observed mainly in the gastric pits (24 h) or on the mucosal surface (48 h). All L3-challenged sheep in this group had detectable globule leucocytes and tissue IL-4 mRNA, as measured by Southern blot RT-PCR. In contrast, sheep challenged 22 weeks after immunization had no detectable globule leucocytes or IL-4 mRNA and although they exhibited consistent tissue eosinophilia, eosinophils were not closely associated with tissue larvae. Scanning and transmission electron microscopy of sheep sensitized and rested for 9 weeks before challenge showed that L3 surrounded by eosinophils were at varying stages of damage and structural collapse. These studies strongly indicate that eosinophils can damage and probably kill gastrointestinal nematode larvae in vivo. In addition, they also suggest that effective killing by tissue eosinophils may depend on other microenvironmental factors such as intra-epithelial mast cells and IL-4.

Airway remodelling and inflammation in sheep lungs after chronic airway challenge with house dust mite.

BACKGROUND: Remodelling of airway walls is a significant morbidity factor in patients suffering from chronic asthma. The relationship between airway remodelling and the inflammatory response is not well defined. Sheep have been used extensively to model airway disease in humans and represent a suitable model to examine airway remodelling. OBJECTIVE: The aim of the present study was to develop a model for airway remodelling in sheep after repeated challenge with a relevant human allergen to assess the relationship of airway remodelling with inflammation. METHODS: Repeated challenges of house dust mite (HDM) extract or saline (control) were administered to local lung segments of sheep for a period of 6 months. After the last challenge, lung tissues from both challenged and unchallenged lung compartments of the same sheep were compared using morphometric image analysis and (immuno) histological studies. RESULTS: All HDM-challenged sheep developed significant bronchoalveolar lavage eosinophilia during challenge. At the end of the challenge period, significant increases in airway collagen and airway smooth muscle content were found in a proportion (3/7) of the HDM-challenged sheep. Hyperplasia of goblet cells and epithelial cells were observed in small bronchi and bronchioles exposed to allergen. Irrespective of airway remodelling changes, all HDM-challenged, but no saline-challenged sheep, displayed significant increases in mast cells in alveolar septa and airway walls of challenged lungs compared with untreated lung compartments of the same sheep. Significant increases were also observed in CD5 and gamma delta T cell subpopulations in all allergen-exposed lung parenchyma. CONCLUSION: A proportion of atopic sheep develop typical airway remodelling changes after chronic allergen challenge, which is not directly related to the level of allergic inflammation.

Local immune responses in sensitized sheep following challenge infection with Teladorsagia circumcincta.

Sheep were sensitized by weekly infections with Teladorsagia circumcincta over a 9-week period. After a 12-week rest, sheep were divided into four groups and killed without challenge or 3, 5 and 10 days post challenge (DPC) with 50000 L3. Recovery of challenge larvae from abomasal scrapings was highest at 3 DPC while no parasites were recovered by 10 DPC. Abomasal lymph nodes (ALN) of challenged sheep were significantly larger at 5 DPC, coinciding with an increase in the proportion of CD4 T cells and a decrease in CD21+ cells, probably reflecting the loss of CD21 from terminally differentiated antibody secreting cells. A significant increase was observed in gammadelta-TCR+ cells at 3 DPC in the ALN, while their number slightly decreased in the abomasal tissues throughout the challenge period. The number of tissue eosinophils was dramatically increased after challenge compared with the unchallenged controls, with a peak at 3 DPC, coinciding with the peak in larval recovery. CD4+ cells significantly increased in the abomasal tissues at 5 DPC, while no changes in globule leucocytes were observed until 10 DPC. Antibody-secreting cell probes (ASC-probes) generated from the ALN showed highest reactivity against larval antigens at 5 DPC. This reactivity was predominantly directed against regions between 90 and 100 kDa and 30-35 kDa in the L3 preparation and lower molecular weight antigens in the L4. No reactivity was observed against the adult extract. The 30-35 kDa antigen seemed to exist as a high molecular weight complex in L3 homogenate and was not susceptible to protease K treatment, suggesting it may be non-protein in nature.

Progress and new technologies for developing vaccines against gastrointestinal nematode parasites of sheep.

Despite the identification of highly effective native antigens for vaccination against Haemonchus contortus, particularly 'hidden' antigens derived from the intestine of adult worms, to date similar efficacy has not been shown with recombinant antigens. In addition, progress towards identification of protective antigens from other sheep gastrointestinal (GI) nematode species is limited. Coupled with this is an incomplete understanding of the mechanism of natural immunity to GI nematodes, making selection of appropriate immunization strategies and adjuvants for evaluation of candidate 'natural' antigens problematic. The current explosion in new high-throughput technologies, arising from human studies, for analysis of the genome, transcriptome, proteome and glycome offers the opportunity to gain a better understanding of the molecular pathways underlying pathogen biology, the host immune system and the host-pathogen interaction. An overview is provided on how these technologies can be applied to parasite research and how they may aid in overcoming some of the current problems in development of commercial vaccines against GI nematode parasites.

Induction of allergic inflammation in the lungs of sensitized sheep after local challenge with house dust mite.

BACKGROUND: Previous sheep models of asthma are based on sheep sensitized to nematode (Ascaris) allergens and these have been used to evaluate the physiological and pharmacological effects of potential anti-asthma agents. The immunological mechanisms associated with the allergic response in sheep lungs has not been examined in detail. OBJECTIVE: To develop an experimental sheep model of allergic lung inflammation based on a relevant major human allergen, house dust mite, and to define the immunological features of the allergic response in this model. METHODS: Sheep immunized subcutaneously with solubilized house dust mite extract were given a single bronchial challenge with house dust mite. Bronchoalveolar lavage (BAL) and peripheral blood leucocytes were collected before and after challenge for flow cytometry, and tissue samples were taken post-mortem (48 h post-challenge) for histology and immunohistochemical analyses. RESULTS: Immunizations with 50 microg house dust mite induced an allergen-specific IgE response in 50 to 60% of sheep (allergic sheep), with higher antigen doses increasing specific IgG1 but not IgE. Lung challenge of allergic sheep with house dust mite led to the initial recruitment of neutrophils (at 6 h post-challenge) followed by eosinophils and activated lymphocytes into the lung tissue and BAL, similar to the late-phase allergic response seen in human asthma. Eosinophil recruitment peaked at 48 h post-challenge, representing 10 to 33% of BAL leucocytes in allergen-challenged allergic sheep compared to 0 to 3% in allergen-challenged control (naïve) sheep. Lymphocytes recovered from the lung after allergen challenge were enriched for CD4+ T cells and were more activated than lymphocytes in blood. There was significant down-regulation of CD62L (L-selectin) and CD49d (VLA-4) expression after allergen challenge on BAL eosinophils and lymphocytes compared to blood. In addition, VCAM-1 (ligand for VLA-4) was up-regulated on blood vessels of allergen-challenged lungs. Eosinophils, CD4+ T cells and CD45R+ B cells were the most prominent leucocytes found in lung tissue 48 h after allergen challenge. CONCLUSION: This study demonstrates, for the first time, the ability of house dust mite to induce allergic responses in sheep lungs. This novel sheep model of allergic lung inflammation using relevant human allergens, exhibits similarities to human asthmatic disease and will be a useful tool for studies of the immunological and physiological mechanisms of allergic asthma.

Cellular kinetics of an allergic-type response in a sheep mammary gland model of inflammation.

BACKGROUND: Tissue recruitment of eosinophils and activated lymphocytes is a characteristic feature of allergic reactions. However, little is known about the involvement of specific adhesion molecules in the traffic of leucocytes during the allergic response. OBJECTIVE: To use a sheep mammary infusion model to characterize the kinetics of cell recruitment and expression of cellular adhesion molecules and activation markers on eosinophils and lymphocytes involved in an allergic-type response. METHODS: Mature non-lactating ewes were primed and challenged by direct infusion of the mammary glands with nematode larvae. Using a non-invasive method of saline infusion and 'milking' of the glands, large numbers of inflammatory cells were repeatedly sampled over 10 to 96 h following their migration into the mammary gland lumen, and analyzed by 2-colour flow cytometry. RESULTS: Leucocyte recruitment into the mammary lumen was characterized by two separate phases involving an acute neutrophilic response at 10 h post-challenge, followed by a dramatic reduction in neutrophils and appearance of eosinophils and activated lymphocytes. From 48 h post-challenge, eosinophils were predominant and represented 40 to 65% of leucocytes in the mammary lavage (MAL). Increases in activated CD4+ T cells and gammadelta+ T cells were also observed at this time-point. The kinetics of expression of cell surface molecules on eosinophils and lymphocytes in blood and MAL were compared during the course of the allergic-type reaction. Adhesion molecule expression on lymphocytes was modulated following allergen challenge and an activation of MAL vs. blood lymphocytes was seen during the later stages of the allergic response. Eosinophil expression of VLA-4 and l-selectin was down-regulated compared with blood at all time-points examined. There were high levels of expression of CD11b and CD44 on eosinophils during the early compared to the late-phase of the allergic reaction. CONCLUSION: These results indicate the existence of two separate mechanisms of eosinophil recruitment during the allergic inflammatory response.

Pathological and immunological changes after challenge infection with Pasteurella multocida in naive and immunized calves.

Challenge infections of calves with Pasteurella multocida were established to characterize the local inflammatory response and determine the effect of previous exposure to live bacteria on the post-challenge immune response. Experimental infections were established by intratracheal inoculation of P. multocida in both naive calves and calves that had been previously vaccinated with two subcutaneous (s.c.) injections of live bacteria. Histological, immunohistological and cytokine expression studies were performed on bronchoalveolar lavage (BAL) samples, lung parenchymal tissues and lung lymph nodes (LN). In comparison to uninfected control animals in which no lung lesions were observed, a patchy to confluent bronchopneumonia was observed following infection of naive calves, characterized by abscess formation, haemorrhage, oedema and suppurative consolidation. Cellular analysis following infection of naive animals was characterized by an influx of neutrophils in the BAL, with macrophages and dendritic cells observed in the lesion perimeter. A significant increase in the number of CD8(+) blasts expressing MHC (major histocompatibility) II was also observed in the BAL of infected calves. Decreased expression of interleukin (IL)-1 beta and increased expression of IL-8 compared to naive unchallenged controls was apparent in lung LN. In comparison, a more limited pathology was observed in vaccinated animals post-challenge, indicating partial protection conferred by the s.c. immunization with live bacteria. Studies of vaccinated animals showed the presence of bronchial-associated lymphoid tissue (BALT) in the lung tissue and an increase in the number of B-cells and CD4(+) T-cells expressing MHCII in the lung LN after challenge. In contrast to primary infection, there was no significant influx of neutrophils in the BAL. Instead, a population of newly recruited monocytes/macrophages was observed. Increased IL-2 expression and decreased IL-8 expression was observed in the LN, while IL-1 beta expression was not detected. The reduced neutrophil and increase monocyte response in the vaccinated calves may be associated with significant changes in the gamma delta T lymphocyte population in the BAL.

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.

Isolation, characterisation and expression of mRNAs encoding the ovine CC chemokines, monocyte chemoattractant protein (MCP)-1alpha and -2.

CC chemokines are important mediators of immune responses, orchestrating the differential recruitment of various leukocyte populations. Despite the large number of known CC chemokines in other species, no cDNA encoding ovine CC chemokines have been isolated. A homology cloning strategy was utilised to isolate the cDNA of ovine CC chemokines. Full-length monocyte chemoattractant protein (MCP)-1alpha and -2 cDNA have been isolated. The predicted ovine MCP-1alpha amino acid sequence shares 87 and 75% identity with bovine MCP-1alpha and porcine MCP-1, respectively. The predicted ovine MCP-2 amino acid sequence shares 92 and 85% identity with bovine and porcine MCP-2, respectively. Northern blot analysis of MCP-1alpha revealed that it is strongly expressed in cells isolated from mammary lavage fluid (MAL) of ewes given intramammary infusions of Haemonchus contortus. Weak signals were detected in mammary and abomasal tissue. Southern blot analysis of reverse transcriptase-polymerase chain reaction (RT-PCR) products indicates that MCP-1alpha mRNA levels increase in abomasum after challenge with H. contortus. MCP-1alpha mRNA levels were also increased in bronchoalveolar lavage (BAL) cells and lung tissue after house dust mite extract (HDME) challenge. Similarly, MCP-2 mRNA was detected by Northern blot analysis at high levels in MAL cells after H. contortus intramammary infusion, and increased in BAL cells and lung tissue in HDME-challenged sheep. MCP-2 mRNA was not detected by Northern blots in whole mammary or abomasal tissue, but Southern blot analysis of RT-PCR products also indicates that MCP-2 mRNA increases in abomasal tissue after challenge with H. contortus. Hence, two ovine CC chemokine mRNA have been isolated that are up-regulated in response to parasite infection and allergen challenge. Ultimately the isolation of these and other ovine CC chemokines will help elucidate a wide variety of immune responses in sheep.

Comparative T-cell responses during pregnancy in large animals and humans.

PROBLEM: Placentation in different large animal species shows a remarkable diversity in the level of trophoblast invasion into the maternal endometrial tissues. We wish to determine the influence of implantation on T-cell responses during pregnancy. METHOD OF STUDY: Review of the literature and current data. RESULTS: alphabeta-TCR+ T cells are only prominent during early pregnancy in species with relatively non-invasive placentation (pig and horse) but are rapidly downregulated in species with more invasive placentae. gammadelta-TCR+ T cells are prominent in species with moderate trophoblast invasion (ruminants) where they increase dramatically during mid and late pregnancy. gammadelta-TCR+ T cells remain prominent during late gestation in species with highly invasive placentation (humans) and, in addition, a distinct gammadelta T-cell population is present in first trimester decidua where it may play a regulatory role in controlling natural killer cell activity. The gammadelta-TCR+ population present in both ruminants and humans shows large granular morphology and contains antimicrobial proteins, suggesting their function may be to protect the uterine environment from infection during pregnancy and parturition. CONCLUSION: The comparative analysis of T-cell responses during pregnancy in different large animal species supports an increasing role for cells of the innate immune response (NK and gammadelta T cells) and a downregulation of the adaptive immune response with increasingly invasive placentation.