Immunostimulation, PCV-2 and PMWS.
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Animals↗
Biomedical subjects
S Krakowka
Publications and source records attributed to S Krakowka.
B-cell function in canine X-linked severe combined immunodeficiency.
Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma (gammac) subunit of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors and has a similar clinical phenotype to human XSCID. We have previously shown that the block in T-cell development is more profound in XSCID dogs than in genetically engineered gamma c-deficient mice. In this study we evaluated the B-cell function in XSCID dogs. In contrast to the marked decrease in peripheral B-cells in gamma c-deficient mice, XSCID dogs have increased proportions and numbers of peripheral B-cells as observed in XSCID boys. Canine XSCID B-cells do not proliferate following stimulation with the T-cell-dependent B-cell mitogen, pokeweed mitogen (PWM); however, they proliferate normally in response to the T-cell-independent B-cell mitogen, formalin-fixed, heat-killed Staphylococcus aureus. Canine XSCID B-cells are capable of producing IgM but are incapable of normal class-switching to IgG antibody production as demonstrated by in vitro stimulation with PWM and immunization with the T-cell-dependent antigen, bacteriophage PhiX174. Similar results have been reported for XSCID boys. Thus, it appears that gamma c-dependent cytokines have differing roles in human and canine B-cell development than in the mouse making the XSCID dog a valuable model for studying the role of these cytokines in B-cell development and function.
Animals↗
PCV-2-associated PDNS in Northern Ireland in 1990. Porcine dermatitis and nephropathy syndrome.
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Animals↗
Experimental infection of colostrum deprived piglets with porcine circovirus 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) potentiates PCV2 replication.
Experimental infection of colostrum-deprived (CD) pigs with a combined inoculum of porcine circovirus 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) potentiated the replication and distribution of PCV2 virus, when compared with pigs inoculated with PCV2 alone. The replication and distribution of PRRSV in dually infected pigs was not enhanced, when compared to pigs inoculated with PRRSV alone. The mechanisms involved in the potentiation of PCV2 replication in PCV2/PRRSV and PCV2/porcine parvovirus (PPV) dually infected pigs may relate to the fact that monocyte/macrophage cell types are common targets of these 3 viruses.
Animals↗
A sequential study of experimental infection of pigs with porcine circovirus and porcine parvovirus: immunostaining of cryostat sections and virus isolation.
The sequential tissue distribution of virus was investigated using virus isolation and immunofluorescence tests in 1-day-old piglets inoculated with porcine circovirus 2 (PCV2) and/or porcine parvovirus (PPV). Enlarged mesenteric lymph nodes were seen in the pig inoculated with PCV2 alone and killed at 26 days post-inoculation (PI). One of the pigs inoculated with PCV2 and PPV and killed at 21 days PI had an enlarged liver. The pig killed at 26 days PI in this group had enlarged liver, kidneys and heart. Histopathological changes were seen in lymphoid tissues of the pigs inoculated with PCV2 alone and killed at 14 and 26 days PI. Similar, but more severe, lesions were observed in the pigs infected with PCV2 and PPV and killed from 10 days PI onwards. Histological lesions of nephritis, pneumonia and hepatitis were also apparent in these animals. Mild nephritis was also seen in the pigs infected with PPV alone and killed at 14 and 26 days PI. Moderate amounts of PPV antigen were detected in tissues from the pigs inoculated with PPV alone and killed at 14 days PI. Low levels of PCV antigen were detected, mainly in lymphoid tissues, in the pigs inoculated with PCV alone and killed at 14 days PI. Low to moderate amounts of PCV antigen were detected in a wider range of tissues in the pig in this group killed at 26 days PI. In the pigs inoculated with both viruses, PPV antigen was detected in tissues of pigs killed from 3 to 26 days PI with maximal amounts detected between 6 and 14 days PI. PCV2 antigen was detected in low to moderate amounts in the tissues of pigs killed at 14 days PI. Large amounts of PCV2 antigen were detected in most of the tissues from pigs in this group killed between 17 and 26 days PI. Virus isolation results for PCV2 generally correlated well with the results for immunofluorescent staining. PPV was isolated from almost all tissues from pigs inoculated with PCV2 and PPV, a much higher incidence of positive tissues than observed for immunofluorescent staining.
Animals↗
Reproduction of lesions of postweaning multisystemic wasting syndrome by infection of conventional pigs with porcine circovirus type 2 alone or in combination with porcine parvovirus.
Post-weaning multisystemic wasting syndrome (PMWS) has recently emerged as an important disease of pigs in North America, Europe and Asia. Porcine circovirus type 2 (PCV2) and porcine parvovirus (PPV) have been isolated from affected pigs. To investigate the pathogenicity of these isolates, groups of colostrum-deprived conventional pigs were inoculated with PCV2 alone (n=4), PPV alone (n=3) or dually with PCV2 and PPV (n=7) and examined post mortem between 21 and 26 days post-infection (dpi). Two control pigs were inoculated with an uninfected cell culture lysate. All pigs that received both viruses became dull at approximately 10-12 dpi and six of these animals subsequently developed jaundice. Hepatomegaly and enlarged kidneys were prominent post-mortem findings in these animals. Histopathological examination revealed severe macrophage infiltration, syncytia formation and numerous cytoplasmic and nuclear amphophilic inclusion bodies in lymphoid tissues. Granulomatous lesions were apparent in liver, lung, kidney, pancreas, myocardium, intestines, testis, brain and salivary, thyroid and adrenal glands. Abundant PCV2 antigen was detected in affected tissues. Only one of the four pigs inoculated with PCV2 alone developed clinical signs, but they all had histopathological lesions which, although less severe, were similar to those in the dually infected animals. The control pigs and those infected with PPV alone remained clinically normal and did not have gross lesions. The only histopathological lesion seen in these animals was mild interstitial nephritis in the pigs infected with PPV alone. These results indicate that lesions of PMWS can be induced by inoculating pigs with PCV2 alone, thereby fulfilling Koch's postulates. Concurrent infection with PPV increased the severity of the lesions, suggesting that co-factors are important in the pathogenesis of PMWS.
Animals↗
Coinfection by porcine circoviruses and porcine parvovirus in pigs with naturally acquired postweaning multisystemic wasting syndrome.
Postweaning multisystemic wasting syndrome (PMWS) is an emerging disease in swine. Recently, the disease has been reproduced with inocula containing a newly described porcine circovirus (PCV), designated PCV 2, and porcine parvovirus (PPV). In order to determine if these viruses interact in naturally acquired PMWS, affected tissues from field cases were examined by immunohistochemistry (IHC) and polymerase chain reaction (PCR) for PCV 2 and PPV, as well as by PCR for the other recognized porcine circovirus, PCV 1. Porcine circovirus 2 was detected by PCR or IHC in affected fixed or frozen tissues from 69 of 69 cases of PMWS collected over 3 years from 25 farms. Porcine parvovirus was detected in 12 of the same cases, and PCV 1 was detected in 9 of 69; however, an apparent decrease was found in the sensitivity of the PCRs used to detect the latter 2 viruses when fixed tissue from the same cases were compared with the use of frozen tissues. Porcine circovirus 2 was not detected by PCR in affected tissues from 16 age-matched pigs that had Streptococcus suis-associated disease. Electron microscopic examination of plasma pooled from 15 pigs with PMWS revealed the presence of PCV and PPV, whereas these viruses were not observed in pooled plasma from 5 age-matched clinically normal pigs. These results confirm and extend previous findings documenting a consistent association of PCV 2 with PMWS. As well, infection by PPV or PCV 1 or both may be an important cofactor in the pathogenesis of some, but apparently not all, cases of PMWS.
Animals↗
Viral wasting syndrome of swine: experimental reproduction of postweaning multisystemic wasting syndrome in gnotobiotic swine by coinfection with porcine circovirus 2 and porcine parvovirus.
One-day-old gnotobiotic piglets were inoculated intranasally with in vitro passaged porcine circovirus 1 (PCV-1), PCV-2, and porcine parvovirus (PPV) alone or in combination (PCV-1/PCV-2, PCV-1/PPV, and PCV-2/PPV). Piglets were evaluated for 1) the development of porcine postweaning multisystemic wasting syndrome (PMWS), 2) distribution of viral antigens by immunochemistry, and 3) viremia and the presence of viral DNA in nasal and ocular secretions and feces. All single agent-infected piglets and piglets infected with PCV-1/PCV-2 or PCV-1/PPV were clinically asymptomatic. They were transiently viremic and seroconverted to homologous virus(es). At termination of the study on postinfection day (PID) 35, microscopic lesions were restricted to focal inflammatory cell infiltrates in livers and myocardia. One piglet given PCV-1/PPV was PPV viremic for 2 weeks after infection and had lymphangiectasia of the spiral and descending colon associated with granulomatous inflammation. All four PCV-2/PPV-inoculated piglets developed PMWS, characterized by sudden onset of depression and anorexia, icterus, and submucosal edema. One piglet became moribund on PID 27, and the remaining three piglets were euthanatized between PID 27 and PID 30 because of severe disease. Lymph nodes were small and the livers were mottled. Disseminated angiocentric granulomatous inflammation was present in all tissues examined except the brain. Multiple lightly basophilic intracytoplasmic inclusion bodies were identified in macrophages and histiocytes. PCV-2 antigen was widely distributed within macrophages; PPV antigen was sparse. Hepatocellular necrosis and bile retention were prominent. PCV-2 DNA was identified in ocular, fecal, and nasal secretions. Terminal sera contained antibodies to PPV (4/4) and PCV-2 (3/ 4). Production of PMWS in gnotobiotic swine appears to require PCV-2 and additional infectious agents such as PPV for full disease expression in gnotobiotic piglets.
Animals↗
FR145715, a novel histamine H2 receptor antagonist, with specific anti-Helicobacter pylori activities.
The pharmacological profile of N-[3-[2-[N'-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-ace tamide (FR145715), a novel histamine H2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with ranitidine. In isolated guinea-pig atria, FR145715 antagonized the effect of histamine on heart rate with approximately three times more potent activity than ranitidine. In in vivo experiments, intraduodenal FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED50 value of 18.4 mg/kg, which was comparable to that of ranitidine (30.5 mg/kg). FR145715 also inhibited histamine-stimulated acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED50 values of 0.59 and 2.72 mg/kg, respectively. Ranitidine displayed more potent activity having respective ED50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral FR145715 dose-dependently inhibited gastrin-stimulated acid secretion with respective ED50 values of 0.12 and 0.32 mg/kg, which were similar to those of ranitidine (0.09 and 0.33 mg/kg). In gastric ulcer models, FR145715 dose-dependently inhibited water immersion restraint stress- and acidified aspirin-induced gastric lesions with ED50 values of 3.2 and 15.1 mg/kg (p.o.), respectively. The comparative compound, ranitidine, also showed beneficial effects on stress-induced gastric ulcers with an ED50 value of 1.5 mg/kg (p.o.). However, it failed to inhibit acidified aspirin-induced gastric ulcers. FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with indomethacin abolished its beneficial effects, suggesting that FR145715 has a so-called cytoprotective effect which is dependent on endogenous prostaglandin production. In addition to its atypical profile as a histamine H2 receptor antagonist, FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori (H. pylori) with a mean minimal inhibitory concentration value of 0.32 microg/ml. Moreover, FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori, FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of inflammation, when treated orally for 10 days. These data demonstrate that FR145715 is a novel histamine H2 receptor antagonist having potent and selective anti-H. pylori activities as well as cytoprotective properties. The present data suggest that FR145715 might be useful for the patients suffering from ulcer relapse, since the drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause ulcer recurrence in humans.
Animals↗
Canine X-linked severe combined immunodeficiency.
Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma (gamma c) subunit of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. The most striking clinical feature is a failure to thrive or 'stunted' growth. Recurrent or chronic infections begin at the time of decline of maternal antibody, usually between six and eight weeks of age. Affected dogs rarely survive past three to four months of age. The major pathologic feature of canine XSCID is a small, dysplastic thymus. Grossly identifiable lymph nodes, tonsils, and Peyer's patches are absent in XSCID dogs. During the neonatal period, XSCID dogs have few, if any, peripheral T cells and increased number of peripheral B cells. Some XSCID dogs do develop phenotypically mature, nonfunctional T cells with age, however, the absolute number of peripheral T cells remain significantly decreased compared to age-matched normal dogs. An interesting finding is that as soon as T cells begin to appear in XSCID dogs they rapidly switch from a CD45RA+ (naive) phenotype to a CD45RA- (activated or memory phenotype). One of the characteristic findings in XSCID dogs is an absent or markedly depressed blastogenic response of T cells in response to stimulation through the T cell receptor and when the necessary second messengers for cellular proliferation are directly provided that by-pass signals delivered through ligand-receptor interaction. The proliferative defect is due to the inability of T cells to express a functional IL-2 receptor. Canine XSCID B cells do not proliferate following stimulation with T cell-dependent B cell mitogens, however, they proliferate normally in response to T cell-independent B cell mitogens. Canine XSCID B cells are capable of producing IgM but are incapable of class-switching to IgG antibody production following immunization with the T cell-dependent neoantigen, bacteriophage phiX174. The number of thymocytes in the XSCID thymus is approximately 0.3% of the thymocytes present in the thymus of age-matched normal dogs. The proportion of CD4-CD8- thymocytes in XSCID dogs is increased 3.5-fold and the CD4+CD8+ population is decreased 2.3-fold. These findings demonstrate that (1) a functional gamma c is required for normal B and T cell function, (2) early T cell development is highly dependent upon a functional gamma c, and (3) B cell development can occur through a gamma c-independent pathway.
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Whole body hyperthermia: effects upon canine immune and hemostatic functions.
In this study, the effects of induced whole body hyperthermia (WBH; 42.3 degrees C for 90 min) on peripheral blood mononuclear cell (PBMC) phenotype distribution, in vitro blastogenic responsiveness and selected parameters of hemostasis were determined in dogs. Hyperthermia was induced by heating venous blood during extracorporeal circulation (EC); induction of WBH by peritoneal lavage (PL) and perfusion without heating (i.e. euthermic EC and euthermic PL) were used as controls. Whole body hyperthermia was associated with lymphopenia and thrombocytopenia that persisted throughout the eight-day post-treatment observation interval. The lymphopenia was selective in that CD5-positive T lymphocytes were more sensitive than were sIg-positive B cells and, within the T-cell compartment, suppressor (CD8-positive) cells were more sensitive to hyperthermic stress than helper (CD4 positive) lymphocytes. Lymphopenia was also observed in EC and PL euthermic controls, although that lymphopenia was transient and nonselective. Persistent suppression of T-cell phytomitogen-induced blastogenesis was induced by WBH in contrast to transient suppression in euthermic controls. For all treatment groups, lymphopenia and suppressed blastogenesis were correlated to elevated plasma cortisol levels. Induction of WBH by EC resulted in coagulopathy characterized by thrombocytopenia, increased plasma fibrin degradation products, prolonged clotting times, and evidence of spontaneous bleeding. These hemostatic alterations were correlated temporally to increased serum levels of liver enzymes. However, there was no evidence of hepatic injury when WBH was induced by PL, where transient thrombocytopenia was the only significant hemostatic alteration. These results indicate that 42.3 degrees C whole body hyperthermia can be well-tolerated and, although associated with suppression of general indexes of immunocompetence, is not associated with opportunistic infections.
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The effects of extracorporeal whole body hyperthermia on the functional and phenotypic features of canine peripheral blood mononuclear cells (PBMC).
In this study the effect of transient 42.3 degrees C whole body hyperthermia (WBH) on the distribution of PBMC phenotypes and in vitro blastogenic responsiveness was determined in dogs. Hyperthermia (n = 6) was induced by heating venous blood during extracorporeal circulation (venous perfusion WBH); perfused non-heated dogs (n = 4) were used as controls. Both euthermic and hyperthermic perfusion produced transient lymphopenia which normalized in controls after perfusion but persisted in hyperthermic animals throughout the 8-day post-perfusion observation interval. The transient lymphopenia in control dogs was non-selective. In contrast, WBH-associated lymphopenia was selective, in that CD5+ T lymphocytes were more sensitive to hyperthermia than sIg+ B cells and, within the T cell compartment, suppressor (CD8+) cells were more sensitive to hyperthermic stress than helper (CD4+) lymphocytes. Functional analyses showed that WBH caused persistent suppression of PBMC blastogenesis in response to T cell phytomitogens. Increased plasma cortisol levels were correlated to peak lymphopenia and hyporesponsiveness to phytomitogens. Despite these alterations, high grade WBH was well tolerated and there was no evidence of opportunistic infection.
Animals↗
Oral use of interferon.
Interferon-alpha (IFN-alpha) given orally has biological activity in humans and other animals. The dose providing the most benefit delivers IFN-alpha to the oral mucosa in a concentration (10(2)-10(3) IU), similar to that naturally produced in the nasal secretions during respiratory infections. In contrast, conventional IFN therapy employs parenteral doses of > 10(6) IU and, for this reason, orally administered IFN therapies have been called low-dose treatments. Efficacy in both animal disease models and human studies has been reported, and the mechanisms whereby oral administration has a systemic effect are under active study in a number of laboratories.
Administration, Oral↗
Natural human interferon-alpha administered orally as a treatment of bovine respiratory disease complex.
Natural human interferon-alpha (nHuIFN-alpha) from three sources was given orally to 368 calves experiencing a natural outbreak of bovine respiratory disease complex (BRDC). In one study, 200 calves were given one treatment daily for 3 days of placebo or 20, 200, or 2,000 IU of nHuIFN-alpha before shipment. Calves treated with 20 or 200 IU had a significant (p < 0.05) weight gain benefit for the first 21 days in the feedlot, if they had rectal temperatures <40 degrees C when treated with nHuIFN-alpha. In a second trial, 168 mixed-breed calves (five groups randomized to 31-36 calves/group) were treated with one dose of placebo or 200 or 400 IU of nHuIFN-alpha after shipment to the feedlot. Using this regimen, a dose of 200 IU per calf significantly (p < 0.08) decreased the number of sick calves per group and delayed development of BRDC. Results of these studies demonstrate that oral administration of nHuIFN-alpha, which may partially mimic the nasally secreted IFN response reported during BRDC, may be beneficial in cattle.
Administration, Oral↗
flaA mRNA transcription level correlates with Helicobacter pylori colonisation efficiency in gnotobiotic piglets.
In-vivo passage of the gastric pathogen Helicobacter pylori in gnotobiotic piglets results in a greater colonisation efficiency in subsequent infections. The rate of colonisation steadily increases with the number of passages. To determine if this increased efficiency is related to the level of expression of flaA, a gene which encodes the major subunit of flagella, this study evaluated the level of flaA expression at five points during serial in-vivo passage of strain 26695. Semi-quantitative reverse transcriptase polymerase chain reaction and Northern dot-blot analysis of flaA mRNA levels (expressed as a ratio to the level of ureA mRNA) revealed a positive correlation between flaA expression and colonisation efficiency; flaA mRNA levels increased incrementally with in-vivo passage as did colonisation rates. Immunoblots of outer-membrane vesicles from pig-passaged and laboratory-passaged strains also demonstrated marked differences in the amount of flagellin present in poor and efficient colonisers.
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Reproduction of lesions of postweaning multisystemic wasting syndrome in gnotobiotic piglets.
Neonatal gnotobiotic piglets were inoculated with tissue homogenates and low- and high-passage cell culture material to determine if the lesions of the newly described porcine postweaning multisystemic wasting syndrome (PMWS) could be reproduced. For this, 17 3-day-old gnotobiotic piglets were inoculated intranasally with pelleted chloroform-treated, filtered extracts from cell cultures, filter-sterilized homogenates of lymphoid tissue from PMWS-affected piglets, or control materials. Piglets were maintained in germ-free isolators for up to 5 weeks after infection prior to euthanasia and collection of samples for analysis. All piglets inoculated with the viral inocula developed lesions typical of PMWS, including generalized lymphadenopathy, hepatitis, nephritis, interstitial pneumonia, myocarditis, and gastritis. Porcine circovirus (PCV), as well as porcine parvovirus (PPV), was detected in tissues by virus reisolation, polymerase chain reaction analysis, or immunohistochemistry. All infected piglets developed moderate to high titers of antibody to PCV and moderate titers to PPV. No lesions, virus, or virus-specific antibodies were detected in sham-inoculated or uninoculated control piglets. These studies demonstrate that the lesions of PMWS can be experimentally reproduced in gnotobiotic piglets using filterable viral agents derived from pigs with PMWS and provide an experimental basis for further investigation into the pathogenesis and control of this emerging infectious disease in swine.
Animals↗
Myocarditis and abortion associated with intrauterine infection of sows with porcine circovirus 2.
Porcine circovirus 2 (PCV2) is a recently identified agent that has been associated with postweaning multisystemic wasting syndrome (PMWS) in swine populations. In this report, the potential spectrum of disease associated with PCV2 is expanded by evidence of vertical transmission and associated reproductive failure. PCV2 was isolated from a litter of aborted piglets from a farm experiencing late-term abortions and stillbirths. Severe, diffuse myocarditis was present in 1 piglet associated with extensive immunohistochemical staining for PCV2 antigen. Variable amounts of PCV2 antigen were also present in liver, lung, and kidney of multiple fetuses. The presence of other agents that have been associated with fetal lesions and abortion in swine, including porcine parvovirus, porcine reproductive respiratory syndrome virus, encephalomyocarditis virus, and enterovirus, could not be established.
Abortion, Veterinary↗
Vaccination of gnotobiotic piglets against Helicobacter pylori.
To determine the effect of oral adjuvant-assisted and parenteral vaccination, germ-free piglets were vaccinated orally with and without labile toxin adjuvant or parenterally and challenged with viable Helicobacter pylori. All prechallenge vaccination regimens induced anti-H. pylori antibodies and suppressed bacterial colonization, but no vaccination regime completely prevented infection. Parenteral vaccination given after infection had no effect on bacterial colonization. Lymphocytic gastritis was present in all piglets challenged with live bacteria regardless of vaccination status. Neutrophilic gastritis was present in vaccinated challenged piglets but not in infected, unvaccinated piglets. Gastritis was not present in uninfected control piglets regardless of vaccination status. In gnotobiotic piglets, vaccination suppresses but does not prevent infection by H. pylori, and parenteral vaccination does not cure infected piglets. Vaccination does not ameliorate gastritis due to H. pylori in piglets but does induce neutrophilic gastric inflammation in some infected piglets.
Administration, Oral↗