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This work identifies the protein “macrophage infectivity potentiator” of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.

Abstract Background Viral infections can reduce early cancer development through enhancement of cancer immunosurveillance. This study was performed to analyse this effect of viral infection in a mouse model of solid tumor. Methods The experimental model used was the effect of BALB/c mouse infection by lactate dehydrogenase-elevating virus on AB1 mesothelioma cancer development. Results Acute infection with lactate dehydrogenase-elevating virus strongly reduced in vivo early AB1 mesothelioma growth and death resulting from cancer development. This effect was not due to a direct cytolytic effect of the virus on AB1 cells, but to an in vivo activation of natural killer cells. Gamma-interferon production rather than cytotoxic activity against AB1 cells mediated this protective effect. This gamma-interferon production by natural killer cells was dependent on interleukin-12 production. Conclusions Together with other reported effects of infectious agents on cancer development, this observation may support the hypothesis that enhancement of innate immunosurveillance against tumors may result from infection with common infectious agents through modulation of the host immune microenvironment.

Coccidioides meningitis (CM) is a challenging infection, given the limited penetration to the cerebrospinal fluid of conventional antifungals, resulting in a high risk of recurrence. We present the first case of a successfully treated persistent CM with voriconazole and adjuvant INF-γ 1b.

The research shows analysis of respiratory infections rates in adolescent athletes, the dynamics of the level of gamma-interferon at different periods of the annual cycle of athletes’ trainings during respiratory diseases prevention using of interferons inducer Kagocel. The high clinical efficacy of the inclusion of this drug in respiratory infections preventive programs is shown.

Background: Viral infections can reduce early cancer development through enhancement of cancer immunosurveillance. This study was performed to analyse this effect of viral infection in a mouse model of solid tumor. Methods: The experimental model used was the effect of BALB/c mouse infection by lactate dehydrogenase-elevating virus on AB1 mesothelioma cancer development. Results: Acute infection with lactate dehydrogenase-elevating virus strongly reduced in vivo early AB1 mesothelioma growth and death resulting from cancer development. This effect was not due to a direct cytolytic effect of the virus on AB1 cells, but to an in vivo activation of natural killer cells. Gamma-interferon production rather than cytotoxic activity against AB1 cells mediated this protective effect. This gamma-interferon production by natural killer cells was dependent on interleukin-12 production. Conclusions: Together with other reported effects of infectious agents on cancer development, this observation may support the hypothesis that enhancement of innate immunosurveillance against tumors may result from infection with common infectious agents through modulation of the host immune microenvironment. [ABSTRACT FROM AUTHOR]

Background: Infection with the Gram-negative bacterium Burkholderia pseudomallei is an important cause of community-acquired lethal sepsis in endemic regions in southeast Asia and northern Australia and is increasingly reported in other tropical areas. In animal models, production of interferon-gamma (IFN-gamma) is critical for resistance, but in humans the characteristics of IFN-gamma production and the bacterial antigens that are recognized by the cell-mediated immune response have not been defined. Methods: Peripheral blood from 133 healthy individuals who lived in the endemic area and had no history of melioidosis, 60 patients who had recovered from melioidosis, and 31 other patient control subjects were stimulated by whole bacteria or purified bacterial proteins in vitro, and IFN-gamma responses were analyzed by ELISPOT and flow cytometry. Findings: B. pseudomallei was a potent activator of human peripheral blood NK cells for innate production of IFN-gamma. In addition, healthy individuals with serological evidence of exposure to B. pseudomallei and patients recovered from active melioidosis developed CD4(+) (and CD8(+)) T cells that recognized whole bacteria and purified proteins LolC, OppA, and PotF, members of the B. pseudomallei ABC transporter family. This response was primarily mediated by terminally differentiated T cells of the effector-memory (T(EMRA)) phenotype and correlated with the titer of anti-B. pseudomallei antibodies in the serum. Conclusions: Individuals living in a melioidosis-endemic region show clear evidence of T cell priming for the ability to make IFN-gamma that correlates with their serological status. The ability to detect T cell responses to defined B. pseudomallei proteins in large numbers of individuals now provides the opportunity to screen candidate antigens for inclusion in protein or polysaccharide-conjugate subunit vaccines against this important but neglected disease.

Plasmodium falciparum parasites are the primary cause of malaria across Africa. The problem of drug resistance to malaria is ever growing and novel therapeutic strategies need to be developed, particularly those targeting the parasite and also the host or host-pathogen interaction. Previous studies have shown that the development of cerebral malaria (CM) is related to dysregulation of the immune system in a murine malaria model of experimental cerebral malaria. It involves a complex interaction of events and interferon-gamma seems to be the unifying factor. Therefore, the antiplasmodial activity targeting the parasite and immunomodulatory strategies that reduce overall host inflammation, with IFN-γ in focus, could delay CM onset and prove beneficial in malaria infection therapy. Phyllanthus niruri is used to treat fever and other symptoms of malaria in Nigeria. Its modes of action as an anti-malarial remedy have not been exhaustively investigated. This study therefore examined the aqueous extract of P. niruri (PE) for its antiplasmodial activity in vitro using the Plasmodium falciparum HB3 strain. Furthermore, in vivo murine malaria model using the Plasmodium berghei ANKA strain was used to investigate its anti-malarial effects. We showed that PE has multiple anti-malarial effects, including anti-parasitic and host immunomodulatory activities. Co-culture of P. falciparum with PE and some of its phytoconstituents drastically reduced parasite number. PE also decreased parasitemia, and increased the survival of infected mice. We also observed that the integrity of the blood-brain barrier was maintained in the PE-treated mice. The results confirmed that PE showed moderate antiplasmodial activity. In vivo murine malaria model using P. berghei ANKA for experimental cerebral malaria revealed that PE suppressed parasite growth, and modulate the production of interferon-gamma. The findings demonstrate that PE affects malaria progression, targeting parasites and host cells. [Display omitted] • Medicinal plants affect pathogenic organisms as well as the host's immune response. • Phyllanthus niruri possesses antiplasmodial activity both in vitro and in vivo. • P. niruri modulates the expression of IFN-γ by inhibiting NF-κB activation. • P. niruri could suppress ECM development by reducing the BBB disruption. [ABSTRACT FROM AUTHOR]

The role that cytokines play in the induction of Lyme arthritis is gradually being delineated. We showed previously that severe arthritis developed in a T-cell-driven murine model, even in mice lacking interleukin-17A (IL-17A) and administered anti-gamma-interferon (IFN-γ) antibody. Increased levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two pro-inflammatory cytokines, were detected in cultures of popliteal lymph node cells obtained from these mice. We hypothesized that concomitantly administered anti-IL-6, anti-TNF-α and anti-IFN-γ antibodies would inhibit the development of arthritis in IL-17A-deficient mice. Our results showed that swelling of the hind paws and histopathological changes consistent with arthritis were significantly reduced in IL-17A-deficient mice that administered the three anti-cytokine antibodies. These results suggest that treatment with multiple anti-cytokine antibodies can abrogate the induction of Lyme arthritis in mice. [ABSTRACT FROM AUTHOR]

The immune mechanisms responsible for development of Lyme arthritis are partially understood with interleukin-17 (IL-17) and gamma-interferon (IFN-γ) playing a generally accepted role. Elevated levels of IL-17 and/or IFN-γ have been reported in samples from human Lyme arthritis patients and experimental mice. In addition, IL-17 and IFN-γ have been implicated in the onset of arthritis in Borrelia-primed and -infected C57BL/6 mice. Recently, we showed that IL-17-deficient mice developed swelling and histopathological changes consistent with arthritis in the presence of high levels of IFN-γ. We hypothesized that neutralization of IFN-γ in IL-17-deficient mice would inhibit Borrelia-induced arthritis. Our results, however, showed that swelling of the hind paws and histopathological changes of arthritis did not differ between Borrelia-primed and -infected IL-17-deficient and wild-type mice with or without neutralization of IFN-γ. We also found higher levels of tumor necrosis factor alpha (TNF-α) and IL-6 in the popliteal lymph node cells of Borrelia-primed and -infected IL-17-deficient mice after neutralization of IFN-γ. These results suggest that multiple cytokines interact in the development of Borrelia-induced arthritis. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical significance of serum eosinophil cationic protein(ECP), Interleukin-2 (IL-2), IL-4, IL-5 and gamma interferon(IFN-γ)in children with acute attack of bronchial asthma. Methods A total of 40 cases of children with bronchial asthma treated in the pediatric asthma outpatient and ward of the hospital in Xiamen Hospital of Beijing University of Chinese Medicine from January 2015 to June 2017 were selected as the observation group,30 healthy children of the same age were selected as the control group. Levels of above five serum inflammatory cytokines were detected before treatment and 2 weeks after treatment in the two groups.the correlation between serum inflammatory cytokines and asthma severity in children with asthma were analyzed. Results (l)The levels of serum ECP, IL-2, IL-4, IL-5, IFN-γ before treatment in the observation group were compared with those in the control group, the differences were statistically significant P<0.05); (2)The levels of serum IL-2.IFN-γ in asthmatic children were negatively correlated with the severity of asthma (rs =— 0.940, — 0.938, P<0.05), but ECP,lL-4 and IL-5 were positively correlated with the severity of asthma(rs = 0.944, 0.920, 0.915, P<0.05);(3)After two weeks treatment, the levels of ECP, IL-4 and IL-5 in the observation group were decreased, while the levels of IL-2 and INF-γ were increased, the differences were statistically significant P<0.05). Conclusion The combined detection of ECP, IL-4, IL-5, IL-2,IFN-γ is helpful for the diagnosis of bronchial asthma, and judging the change of the disease. [ABSTRACT FROM AUTHOR]

This work identifies the protein "macrophage infectivity potentiator" of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Radwanska, de Lemos Esteves, Linsen, Coltel, Cencig, Widart, Massart, Colson, Di Paolo, Percier, Ait Djebbara, Guillonneau, Flamand, De Pauw, Frère, Carlier and Truyens.)

O diagnóstico presuntivo da tuberculose bovina é baseado na análise da resposta imune celular a antígenos micobacterianos. Procedeu-se à simulação experimental de sensibilização por Mycobacterium bovis e Mycobacterium avium inativados em bovinos a fim de acompanhar a resposta imune a partir do teste cervical comparativo e da evolução da produção específica de interferon-gama, além de identificar a interferência de reações inespecíficas por M. avium nos resultados dos testes. Verificou-se que os animais desencadearam resposta de hipersensibilidade tardia contra os bacilos inativados, e que ambos os testes diagnósticos da tuberculose bovina foram eficientes na identificação dos animais sensibilizados com M. bovis e na discriminação das reações geradas pela inoculação dos bovinos com M. avium.The presumptive diagnosis of bovine tuberculosis is based on analysis of the immune response to micobacterial antigens. This experimental simulation of sensibilization by Mycobacterium bovis and Mycobacterium avium in cattle aimed to verify the immune response by both the cervical comparative test and the evolution of the specific production of gamma-interferon, and also to identify interference of unspecified reactions by M. avium on the test results. The results support that the experimental animals started a response of delayed hypersensitivity to the inactivated bacilli, and that both diagnostic tests for bovine tuberculosis were efficient for the identification of animals sensitized with M. bovis and for discrimination of reactions generated by inoculation of cattle with M. avium.

In bovine tuberculosis (bTB) eradication programmes, especially where prevalence is low, sensitivity of testing in infected herds must be maximised to reduce the possibility of recrudescence of prior infection and the risk to other herds via animal movement. The gamma-interferon (γ-IFN) assay applied in parallel with intradermal tuberculin testing has been shown to increase test sensitivity. The aim of this work was to substantiate this effect in the field. A retrospective observational study was conducted on 239 New Zealand cattle breeding and dairy herds with bTB infection between 1 July 2011 and 1 September 2015 to evaluate the outcomes of new policy introduced in 2011. The investigation defined the number and proportion of reactors (animals testing positive and slaughtered) found with lesions of bTB in intradermal caudal fold testing (CFT) and parallel γ-IFN testing, at the breakdown test or first whole herd test after breakdown, WHT(1), and at the final or projected final whole herd test, WHT(F). Parallel γ-IFN testing was used in 26.8% of the 239 herds at WHT(1), and 430 animals in 49 herds were deemed reactors. One hundred and sixty (37.2%) of these reactors from 32 herds were found to have bTB lesions, despite having been negative to caudal fold testing. These 160 infected animals accounted for 29.6% of all infection found at WHT(1). At WHT(F), parallel γ-IFN testing was conducted on 93 herds and detected a total of 122 reactors in 49 herds, in addition to those found by CFT. Twenty-one of these reactors, from 13 herds, had bTB lesions at slaughter, accounting for 67.7% of all reactors found with bTB at WHT(F). Eleven of these 13 herds would have had their movement restrictions revoked based on a negative herd CFT alone, and could potentially have caused outward transmission of bTB to other herds, as well as experiencing recrudescent breakdowns. We conclude that γ-IFN testing in infected herds, in parallel with intradermal tuberculin testing, is a valuable tool in a bTB eradication programme, as it enables higher test sensitivity at both herd and animal level. The use of the γ-IFN test over a risk cohort early in a breakdown assists in removal of early infection and some cases of anergy to intradermal tuberculin testing. Parallel γ-IFN with compulsory slaughter of reactors should be considered in breeding and dairy herds in conjunction with tuberculin testing before movement control is revoked, and will assist in achieving TB freedom on a herd level and nationally. [ABSTRACT FROM AUTHOR]

Background: Fusarium species are ubiquitous environmental fungi that occasionally provoke serious invasive infections in immunocompromised hosts. Among Fusarium species, Fusarium ramigenum, belonging to the Fusarium fujikuroi species complex, has thus far never been found to cause human infections. Here we describe the first case of invasive fusariosis caused by Fusarium ramigenum in a human and also identify immunological deficiencies that most likely contributed to invasiveness.Case Presentation: A 32-year-old Caucasian male with a seemingly insignificant medical history of mild respiratory illness during the preceding two years, developed invasive pulmonary fusariosis. Detailed immunological assessment revealed the presence of common variable immunodeficiency, complicated by a severe impairment of the capacity of T-cells to produce both gamma-interferon and interleukin-17. In-depth microbiological assessment identified the novel human opportunistic pathogen Fusarium ramigenum as cause of the infection.Conclusion: This report demonstrated that an opportunistic invasive fungal infection may indicate an underlying cellular immune impairment of the host. The unexpected invasive infection with Fusarium ramigenum in this case unmasked a complex combined humoral and cellular immunological deficiency. [ABSTRACT FROM AUTHOR]

The hallmark of chronic Chagas' disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens (Cunha-Neto et al. (1996) Journal of Clinical Investigation, 98: 1709-1712). Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas' cardiomyopathy. The bulk of evidence points to a significant production of IFN-g and TNF-a which may be linked to T. cruzi-induced IL-12 production

The procedures for gaining, maintaining, suspending, withdrawing or re-gaining official bovine tuberculosis free herd status and for certification for intra-Union trade are based on the results of tuberculin skin tests. The skin test has a number of drawbacks, therefore the suitability of the gamma interferon test and other tests to be included by EU legislation was assessed. Suitability means that the test has a sensitivity equivalent or superior to the standard test currently used in the European Union and specificity not lower than that of the standard test with the lowest specificity used in the EU. Furthermore, there should be no foreseeable practical difficulties that could compromise test performance. It was concluded that purified protein derivative based gamma interferon tests can be included amongst the official tests for the purpose of demonstrating freedom. However, some results suggest that the specificity of the purified protein derivative based gamma interferon tests may not always be as high as the single intradermal tuberculin test. In case the test is included, the protocols for its use for this purpose should be harmonised in the EU. Based on the reviewed information, other tests should not yet be considered for inclusion in the official tests for the purpose of granting and retaining official tuberculosis free herd status. Further evaluation of the suitability of the gamma interferon tests test should study the influence of factors such as the presence of environmental mycobacteria, prevalence of bovine tuberculosis in the herd, the age type and bovine tuberculosis test history of the animals all of which may affect test specificity and hence the suitability of the test for demonstrating freedom from bovine tuberculosis in different situations.

Previous reports from this group have indicated that the immunoinhibitory programmed death (PD)-1 receptor and its ligand, PD-L1, are involved in the mechanism of immune evasion of bovine chronic infection. However, no functional analysis of bovine PD-L2 in cattle has been reported. Thus, in this study, the molecular function of bovine PD-L2 was analyzed in vitro. Recombinant PD-L2 (PD-L2-Ig), which comprises an extracellular domain of bovine PD-L2 fused to the Fc portion of rabbit IgG1, was prepared based on the cloned cDNA sequence for bovine PD-L2. Bovine PD-L2-Ig bound to bovine PD-1-expressing cells and addition of soluble bovine PD-1-Ig clearly inhibited the binding of PD-L2-Ig to membrane PD-1 in a dose-dependent manner. Cell proliferation and IFN-γ production were significantly enhanced in the presence of PD-L2-Ig in peripheral blood mononuclear cells (PBMCs) from cattle. Moreover, PD-L2-Ig significantly enhanced IFN-γ production from virus envelope peptides-stimulated PBMCs derived from bovine leukemia virus-infected cattle. Interestingly, PD-L2-Ig-induced IFN-γ production was further enhanced by treatment with anti-bovine PD-1 antibody. These data suggest potential applications of bovine PD-L2-Ig as a therapy for bovine diseases. [ABSTRACT FROM AUTHOR]

Background & objective Severe asthma exacerbations during pregnancy are a common complication leading to poor health outcomes for both the mother and the baby. Asthma exacerbations are caused most frequently by respiratory viruses. A balance between antiviral and inflammatory immune responses is critical during pregnancy; the balance may be altered by asthma and respiratory virus infection. Methods Peripheral blood mononuclear cells ( PBMCs) were isolated from (i) non-pregnant healthy controls, (ii) pregnant non-asthmatics, (iii) post-partum non-asthmatics, (iv) non-pregnant asthmatics (v) pregnant asthmatics, and (vi) post-partum asthmatics. Cells were cultured in vitro with the mitogen phytohaemagglutinin or with a strain of the 2009 pandemic swine influenza. Interferon (IFN)-γ, interleukin ( IL)-10 and IL-17 protein were measured from culture supernatant. Neutrophil counts were obtained in samples from pregnant and post-partum women. Results Following the phytohaemagglutinin stimulation of PBMCs, pregnant asthmatics had significantly higher IL-17 and significantly lower IFN-γ responses compared with healthy non-pregnant women. Following infection with influenza, a significant reduction was also observed in IFN-γ and IL-10 production from PBMC of pregnant asthmatics. The IL-17 response to phytohaemagglutinin correlated with the neutrophil percentage. Differences in IFN-γ, IL-10 and IL-17 were found to persist for at least 6 months post-partum. Conclusions A reduction in antiviral and regulatory immunity with increased inflammation during pregnancy occurs in PBMC from pregnant women with asthma. This novel information may relate to the increased susceptibility and disease severity to respiratory virus infections observed during pregnancy. [ABSTRACT FROM AUTHOR]

Abstract: Interferon (IFN)-β therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-β therapy. The MBP-elicited IFN-γ-, TNF-α- and IL-10 production decreased during therapy (p <0.007–0.03), while the IL-6 production increased (p <0.03). No significant change was observed in the MBP-induced CD4+ T cell proliferation, or in the production of IL-4, IL-5 and brain-derived neurotrophic factor. In comparison, IFN-β therapy reduced IFN-γ and IL-4 responses to TT (p <0.003 and p <0.04). Thus, IFN-β inhibits IFN-γ production in general, presumably alleviating the detrimental influence of IFN-γ in MS. However, the increase in proinflammatory IL-6 and the decrease in anti-inflammatory IL-10 responses suggest that IFN-β has more diverse effects than previously assumed. [Copyright &y& Elsevier]

Abstract: Purpose: Granulomatous diseases are defined by specific histological features, following the local recruitment of macrophages and lymphocytes. Many infections can lead to the development of granuloma. Current knowledge and key points: Microorganisms responsible for granuloma include mainly mycobacteria, many viral and fungal species, as well as schistosoma in endemic areas. Nevertheless, almost all microorganisms can lead to granuloma, especially if their clearance needs macrophages pathway. New immunosuppressive drugs such as tumor necrosis factor antagonists are associated with a high risk of infectious granulomatous complications. All patients with granuloma must be carefully screened to find a potential underlying infection, since an immunosupressive therapy could be otherwise considered. We here review the general diagnostic process with a specific glance to the main organs. Future prospects and projects: Without clinical or epidemiological clue, diagnosis can be very tedious. New molecular tools now assist classical microbiological and histological techniques. Their specificity and sensitivity have recently been better characterized, and their use will probably increase in the near future for the diagnosis of infectious granuloma. They may also lead to discover new infectious aetiologies of granulomatous diseases formerly considered as idiopathic. We describe here the main microorganisms that can be responsible for granuloma, with a specific focus on the use of new diagnostic tools. [Copyright &y& Elsevier]

Viruses are associated with the development of autoantibody-mediated blood autoimmune diseases. A two-step mechanism could explain virus involvement in the development of experimental hemolytic anemia. Immunization of normal mice with rat erythrocytes results in an autoantibody production that could be enhanced by viral infection, without erythrocyte destruction. Inoculation of the same virus when autoantibodies are at high levels triggers clinical anemia. This results from macrophage activation by gamma-interferon, leading to exacerbated erythrophagocytosis. Thus the development of anemia during the course of viral infection may require two independent stimuli, in which the first triggers autoantibody production and the second enhances the pathogenicity of these autoantibodies. [ABSTRACT FROM AUTHOR]

Summary: This article will review traditional and newer microbiological techniques for the diagnosis of mycobacterial respiratory infections. It will concentrate on the diagnosis of infections due to Mycobacterium tuberculosis, the main mycobacterium causing respiratory infections of clinical and public health importance. The diagnosis of respiratory disease associated with non-tuberculous mycobacteria (NTM), particularly in children with underlying airway pathology such as cystic fibrosis (CF) or bronchiectasis, will be briefly discussed. With respect to the diagnosis of tuberculosis (TB), the review will concentrate on the diagnosis of patients with symptoms and/or signs of clinical disease, rather than the detection of exposure or asymptomatic infection. It will not specifically address the assessment of pre-test probability based on clinical or epidemiological factors, the use of radiological investigations or the investigation of extrathoracic lymph node disease or chest wall disease. The role of newer diagnostic modalities including nucleic acid detection (NAD) and gamma-interferon assays in paediatric practice will be reviewed, and suggestions made as to how they may fit into contemporary diagnostic algorithms. [Copyright &y& Elsevier]

Summary: Interferon-γ is the most important cytokine in resistance to mycobacterial diseases and common variants of interferon-γ gene could be related to tuberculosis susceptibility. We tested the hypothesis that the interferon-γ+874T–A polymorphism is associated with tuberculosis disease, and affects the interferon-γ reponse. We determined by pyrosequencing the distribution of the interferon-γ+874T–A polymorphism in a Turkish population of 319 patients with pulmonary tuberculosis, 42 children with severe forms of tuberculosis and 115 healthy donors. We also analysed whether any correlation exists between this polymorphism and interferon-γ response to Mycobacterium tuberculosis antigens by ELISPOT in 58 pulmonary tuberculosis cases, and the results were analysed according to the genotypes. We found that the minor allele (T) frequency was significantly lower in patients with pulmonary tuberculosis when compared to controls (P=0.024, OR=0.7), a similarly significant decrease in the frequency of TT genotype was observed in patients with pulmonary tuberculosis, compared to the control group (P=0.02, OR=0.49). IFN-γ responses to PPD antigen in TT genotype was found to be significantly higher than the AA group (P>0.001). Non-parametric correlation analysis of ELISPOT data showed significant reverse correlation in PPD, CFP10 and ESAT6 values and IFN-γ +874 genotypes. These results show that the IFN-γ +874T-A polymorphism is related to the IFN-γ response and the magnitude of the response decreases during transition from TT- to TA and to AA genotypes. Our data suggest that similar to various Caucasian populations, in a Turkish population the IFN-γ+874 T–A polymorphism is also associated with tuberculosis disease and affects the magnitude of the IFN-γ response. [Copyright &y& Elsevier]

Abstract: Oral delivery of lipid-encapsulated BCG represents an effective method for vaccination against tuberculosis (Tb). This method establishes live, replicating BCG in the lymphatic tissues of the alimentary tract, and promotes systemic-level cell-mediated immunity (CMI) and consequent protection against virulent mycobacterial challenge. Here, we investigated the effects of reducing or eliminating the BCG load on CMI responses in mice. Mice receiving a standard immunising dose of approximately 107 BCG (range, 1–5×107) developed mycobacterial antigen-specific lymphocyte transformation (LT) responses, as well as interleukin-2 (IL-2) and gamma-interferon (IFN-γ) secretion, at 8 and 18 weeks post-oral vaccination. These responses were concurrent with establishment of viable, replicating BCG in the alimentary tract lymphatics in over 90% of cases. Reducing the immunising dose by 10-fold reduced the magnitude of CMI, concurrent with abridged establishment of BCG in the lymphatics; reducing the dose 100-fold ablated BCG establishment, and diminished the production of IFN-γ by antigen-stimulated lymphocytes of these mice. In mice immunised using the standard dose, replicating BCG were eliminated from the alimentary tract lymphatics using selective antibiotics. Interestingly, while lymphocyte transformation and interleukin-2 responses remained largely unaltered in these mice, levels of IFN-γ produced by antigen-stimulated lymphocytes were shown to be reduced significantly. This study identifies a dosage threshold for effective oral vaccination using lipid-encapsulated BCG, and furthermore highlights the requirement of on-going intra-lymphatic BCG replication for the maintenance of strong IFN-γ production, above other indicator CMI responses. [Copyright &y& Elsevier]

Abstract: The strategic use of the gamma-interferon (IFN-γ) assay (Bovigam®) can provide a means for the early identification of Mycobacterium bovis infected cattle, thus ensuring their removal from an infected herd. When used in parallel with the tuberculin test, it is capable of identifying infected cattle, which might otherwise not be detected until later, if at all. The early detection and removal of these animals reduces the risk that they will become a source of infection for other cattle. When targeted in herds of high prevalence the benefits to the herd owner directly concerned can be considerable as the assay provides a means of shortening the period of restriction for such herds. This serves to generate confidence among herd owners and other stakeholders that effective schemes, based on sound scientific principles, can be developed to eradicate tuberculosis from infected cattle populations. [Copyright &y& Elsevier]

Sendai virus C protein interacts with the signal transducer and activator of transcription (STAT) 1. This interaction is believed to be essential for the Sendai virus inhibition of the interferon (IFN) response. We here analyzed CF170S (a C protein mutant with the F170S mutation) with no STAT1-binding ability. CF170S lacked the ability to inhibit the IFN-α response, but retained the ability to inhibit the IFN-γ response. IFN-γ stimulation caused STAT1 phosphorylation, formation of the gamma-activated factor capable of binding to a gamma-activated sequence DNA probe, and STAT1 nuclear translocation, even in the presence of CF170S. These results suggest that C protein has the STAT1-binding-independent anti-IFN-γ mechanism, which targets processes after the STAT1 nuclear translocation event. [Copyright &y& Elsevier]

Background: Imiquimod is a local immune response modifier that has demonstrated potent antiviral and antitumor activity. It enhances innate and acquired immune responses via endogenous cytokine production and has proven efficacious in clearing superficial basal cell carcinoma (sBCC). Objective: To evaluate the mechanisms by which topical imiquimod treatment leads to sBCC clearance in vivo. Design: A pilot, open-label, nonrandomized study. Setting: Zurich, Switzerland. Patients: Six persons 18 years or older who had nonrecurrent primary tumors that had not undergone previous biopsy or treatment but were suitable for treatment by surgical excision. The tumors were located on the scalp, extremities, or trunk; had a minimum diameter of 1 cm and a maximum diameter of 2 cm; and were clinically and histologically consistent with sBCC. Interventions: Daily application of 5% imiquimod cream 5 times per week for a maximum of 6 weeks. When the tumor began to show signs of erosion, it was surgically excised. Outcome Measures: Parameters reflecting tumor apoptotic status (Bcl-2), expression of death receptors (Fas and Fas ligand [FasL]), intercellular adhesion molecule (ICAM) 1, immunosuppressive microenvironment (interleukin 10), and antigen presentation machinery (transporter associated with antigen presentation [TAP] 1) before and after imiquimod treatment were evaluated. The changes in the interferon γ messenger RNA (mRNA) levels relative to CD4 and CD8 mRNA were assessed using quantitative polymerase chain reaction. Results: Tumor cells became more susceptible to apoptosis through decreased Bcl-2 expression after treatment with 5% imiquimod cream. Inflammatory infiltrate developed rapidly (within 3 to 5 days after treatment initiation) and was associated with the enhanced expression of ICAM-1. This early response tended to be a mixed cellular response of macrophages and lymphocytes. Interferon γ was produced by CD4 and CD8 T cells. Imiquimod treatment induced a massive increase in macrophage peritumoral and intratumoral infiltration. Interleukin 10 was produced by infiltrating cells but was not produced by tumor cells. Tumor expression of TAP-1 and Fas/FasL appeared to be unaffected in the first 5 days of treatment. [ABSTRACT FROM AUTHOR]

Background/Aims: Pancreatitis goes along with changes in exocrine enzyme synthesis and secretion in pancreatic acini. The multi-KH domain protein vigilin is supposed to play an important role in t-RNA trafficking especially in cells with high protein synthesis rates and may reflect the degree of stimulation of translational machinery during pathological processes. In relation to these phenomena we explored in this connection the impact of two different inflammation mediators in a system of isolated rat pancreatic acini. Methods: Acini were prepared from male Sprague-Dawley rats by collagenase digestion and incubated with mellitin or gamma interferon. Secretion and cytosolic cell content of pancreatic trypsin and amylase as well as the expression of vigilin were determined. Results: The phospholipase A2 activator mellitin caused morphological alterations and increased release of trypsin and amylase, while vigilin expression and the intracellular content of these enzymes decreased. Gammainterferon, a cytokine which is involved at different steps in inflammation processes, selectively inhibits the release of trypsin(ogen) while not affecting amylase secretion and vigilin expression. Conclusion: Mellitin as well as gamma interferon causes alterations in pancreatic enzyme secretion. Additionally, mellitin seems to influence the expressed gene pattern of pancreatic acini while interferon-γ has no effect on protein synthesis but enzyme secretion. [ABSTRACT FROM AUTHOR]

As shown in previous in vivo experiment, the amount of polymeric immunoglobulin receptor (pIgR), which mediates the transcytosis of pIgA across epithelial cells, is regulated by lactogenic hormones (PRL and cortisol) during the development of the mammary gland. In the present in vitro study, it appeared that these hormones were insufficient to induce the strong expression of the gene that we observed in vivo. Several papers have shown that IFN-γ is a strong stimulator of pIgR gene expression in different models. In contrast, nothing is known of the effects of IFN-γ on pIgR gene expression in the mammary gland. We report here that IFN-γ strongly increased pIgR mRNA levels through a direct effect on mammary epithelial cells. We show that IFN-γ activated not only Stat1 but also Stat5 and that expression of the pIgR and IRF-1 genes was strongly correlated following IFN-γ stimulation in mammary epithelial cells. In conclusion, these experiments enabled the analysis of different types of regulation of pIgR gene expression in the mammary gland and suggest possible co-operation between circulating hormones and locally produced cytokines, leading to pIgR gene expression in the mammary gland. [Copyright &y& Elsevier]

Abstract Background and aims: It has been proposed that the expression of Fas ligand (Fas L) in tumors may play an important role in immune escape. This study was undertaken to test a ‘counterattack’ theory as a mechanism of immune escape in gastric carcinoma. Methods: Expression of Fas and Fas L was examined in the human gastric cancer cell lines using reverse transcription–polymerase chain reaction. Cytotoxicity was determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. Apoptosis of target Jurkat cells was examined after coculture with the effector gastric cancer cells in vitro . Immunohistochemical staining was performed for the detection of Fas and FasL in tumor-infiltrating lymphocytes (TIL) and gastric cancer cells in vivo. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method in vitro and in vivo . Results: Fas and FasL mRNA were found to be differentially expressed in gastric cancer cell lines. The coculture experiment showed that apoptosis of Jurkat was induced by a FasL-overexpressing effector gastric cell SNU-484. In a Fas-expressing gastric cell SNU-638, Fas expression was upregulated by the treatment of gamma-interferon in a time- and concentration-dependent manner. SNU-638 treated with gamma-interferon was more sensitive to anti-Fas antibody-mediated cytotoxicity than was the control cell line, suggesting an increase of functional Fas in gastric cancer cells. The expression of FasL in gastric cancer cells and of Fas in apoptotic TIL was also detected in vivo . Conclusion: The data indicate that the FasL expression of gastric cancer cells supports a ‘counterattack theory’ in gastric cancer cells and that the upregulation of Fas by IFN-γ in SNU-638 may accelerate the apoptosis pathway through the Fas and FasL interaction between gastric cancer cells and immune cells. This result is supported by the expression of... [ABSTRACT FROM AUTHOR]

Abstract: Background: Acute hepatitis A virus (HAV) infection can cause severe hepatitis especially in patients with underlying chronic liver disease. In patients with pre-existing chronic hepatitis B (HBV) acute HAV infection can suppress HBV replication. The exact mechanism of HBV suppression during acute HAV infection is still a subject of debate. One mechanism may be the production of HAV infection-induced cytokines leading to suppression of HBV replication and viral clearance. Aim: To evaluate cytokine production and HBV-specific lympho-proliferative responses (LPR) during acute HAV infection in a patient with chronic HBV infection-clearing markers of active HBV replication. Design: Early detection of a case of acute HAV infection in an HBeAg-positive, HBV DNA-positive chronic HBV patient treated with lamivudine. Results: At the time of HAV infection a sharp peak in the gamma-interferon (IFN-γ) level occurred just before the rise in serum transaminase activity. This was subsequently followed by a decrease in HBV DNA and HBeAg below the limit of detection of the assay. However the HBV-specific T-cell response was not modified. After resolution of the acute HAV infection and withdrawal of antiviral therapy HBV replication relapsed. Conclusion: The sharp rise in IFN-γ production mediated by the acute HAV infection may be pivotal in the suppression of HBV replication in chronic hepatitis B. [ABSTRACT FROM AUTHOR]

A study to determine and compare the sensitivities and specificities of the comparative cervical tuberculin (CCT) and gamma-interferon (IFN-γ) tests for the diagnosis of bovine tuberculosis was conducted on 30 zebu oxen. The results of the tests were compared with the presence of acid-fast bacilli found by bacteriological culturing and histopathological examinations. The sensitivity and specificity of CCT test were found to be 90.9% and 100%, respectively. Those of the commercial IFN-γ test were determined to be 95.5% and 87.7%, respectively. No significant differences were found between the sensitivities (Yates' corrected χ2 = 0.32; p = 0.57) or the specificities (Yates' corrected χ2 = 2.54; p = 0.11) of the two tests. Furthermore, a positive correlation ( r = 0.76) was recorded between the increase in skin thickness following injection of bovine purified protein derivative (PPD) and the optical density in the gamma-interferon assay with bovine PPD. On the other hand, the correlation ( r = 0.47) between the change in skin thickness following injection of avian PPD and the optical density in the gamma-interferon assay with avian PPD was relatively weak. On the basis of this preliminary investigation, it was concluded that the choice between the two tests depends on their cost and simplicity and on livestock management and time factors rather than on their respective diagnostic value. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that a proportion of human T cell clones (TCC) derived from tonsil or peripheral blood (PB) of non-allergic donors, upon triggering with phytohaemagglutinin (PHA) or anti-CD3 monoclonal antibody (MoAb), were able to provide help for IgE synthesis in B cells from both allergic and non-allergic individuals. In this study we show that, upon PHA stimulation, culture supernatants from 10 selected TCC active on IgE synthesis also provided helper activity for IgE, whereas supernatants from unstimulated cultures of the same TCC were ineffective. In contrast, culture supernatants derived from five PHA-stimulated TCC, unable to provide helper function for IgE synthesis, consistently failed to elicit production of IgE. While the induction of IgE synthesis by TCC occurred in B cells from virtually all allergic and non-allergic donors, their soluble factor(s) were found to be able to provide substantial help for IgE production only in B cells from a proportion of donors tested. In addition B cells from non-atopic donors usually appeared to be less responsive than atopic B cells to the activity of such factor(s). In contrast, synthesis of both IgG and IgM was induced in every B cell donor by both TCC and their supernatants. Partial characterization of the factor(s) providing helper function for IgE synthesis in B cells showed that it apparently had a mol. wt between 10 and 50 kD and did not bind to immobilized IgE. Such an activity appeared to be associated with the presence of interleukin 4 (IL-4) in supernatants and it was inhibited by adding both gamma-interferon and anti-human IL-4 antibody in culture. [ABSTRACT FROM AUTHOR]

An assay for gamma-interferon (IFNγ) in human lymphocyte culture supernatants, based on reverse passive haemagglutination (RPH) of red cells bearing a monoclonal anti-IFNγ antibody, was developed and compared with a conventional virus inhibition assay. Test samples comprised supernatants of lymphocytes from patients with Schistosoma mansoni infections, cultured with or without a soluble worm antigen preparation. The two assays gave comparable results, the correlations for individual samples being good. The RPH assay was both specific and sensitive, allowing the detection of IFNγ at 13 u/ml (1 ng/ml) or less. The advantages of the RPH assay were that it was quick, relatively inexpensive and suitable for testing large numbers of samples. In particular, between-experiment variation was very low, allowing the assay of different samples on different occasions. [ABSTRACT FROM AUTHOR]

The question of whether the state of T cell activation is responsible for gamma-interferon production in response to alpha-interferon was determined. When peripheral blood mononuclear cells were pre-incubated with phytohemagglutinin for 3 days, their gamma-interferon production was found to be augmented by alpha-interferon, accompanied by an increased proportion of DR-positive T cells. This did not occur with fresh cells. The effect was dose-dependent and inhibited by anti-alpha-interferon antibody. Therefore, alpha-interferon was considered to enhance the production of gamma-interferon of pre-activated peripheral blood mononuclear cells but not of resting ones. In conclusion, alpha-interferon augmented the production of gamma-interferon of peripheral blood mononuclear cells only when they had already been activated, suggesting a role of alpha-interferon as a modulator of the cellular immune response. [ABSTRACT FROM AUTHOR]

We investigated the activity of alpha-interferon (α-IFN), gamma-interferon (γ-IFN) and tumor necrosis factor-alpha (TNF-α) in a panel of ten human bladder tumor cell lines. All cytokines were tested at concentrations of 100-10000 U/ml in a clonogenic assay system. We found that α-IFN was active against five of the ten lines while γ-IFN was only active against one line. TNF was active against five of the ten lines. Maximum synergisms were obtained between the α-IFN and TNF, occurring in nine of the ten cell lines. We conclude that α-IFN and TNF are active as single agents and synergistic when used together in vitro in human bladder tumor cell lines. [ABSTRACT FROM AUTHOR]

HLA class II antigens play an important role in the immunological response. In this study, we report on HLA class II antigen expression in vitro by human nasal cartilage cells as detected with an immunoperoxidase staining and immunofluorescence flow cytometric analysis using monoclonal antibodies. Their expression was induced during a 7-day incubation period with gamma-interferon. These findings suggest that a possible mode of action of the preservation methods of cartilage allografts for inducing a prolonged acceptance time is based on the prevention of HLA class II antigen expression by the cartilage cells. [ABSTRACT FROM AUTHOR]

Human renal tissue was disaggregated by passage through a stainless-steel mesh and the resultant material was separated on the basis of particle size. The tubular fraction recovered from a 45 μm mesh was cultured and after a period of between 5 and 7 days outgrowing adherent epithelial cells were identified. All of these cells contained cytokeratin and after culture for at least 14 days fewer than 5% showed surface HLA-DR antigens. Cultured renal epithelial cells were rapidly lysed by lymphokine activated killer (LAK) cells which were produced from peripheral blood lymphocytes of normal subjects by incubation for 5 days in the presence of either recombinant interleukin-2 (IL-2) or mixed lymphocyte reaction (MLR) supernatant. Stimulation of the cultured epithelial cells for 5 days with either gamma-interferon or MLR supernatant resulted in 67%±9% (mean±SD; =8) of the cells showing an upregulation of HLA-DR expression. These treated cells were markedly less sensitive to lysis by LAK cells than the untreated cells. Thus, if renal cell damaging LAK cells are generated from lymphocytes in vivo by the action of IL-2 produced during rejection, then gamma-interferon, which is also produced during rejection, may partially protect the renal cells from such LAK cell mediated damage. [ABSTRACT FROM PUBLISHER]

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Peripheral blood (PB) and synovial fluid (SF) were compared in parallel samples in rheumatoid arthritis (RA). The kinetics of in vitro T-cell activation was assessed in phytohemaglutinin (PHA) stimulated PB or SF mononuclear cell cultures on days 0, 1, 3 and 5. The early lymphocyte activation as assessed by interleukin-2 receptor expression was faster in SF than in PB cell cultures. In particular, IFN-γ secretion was higher in SF than in PB cell cultures (p<0.01). Accordingly, lymphocyte major histocompatibility complex (MHC) locus II antigen expression was higher in SF than in PB cell cultures (53± 7% vs. 21 ± 5%; p<0.01). Our results suggest that lymphocytes, which are particularly effective producers of IFN-γ when stimulated in vitro are sequestered in the diseased joints in RA. [ABSTRACT FROM AUTHOR]

Included in this study were 43 cases of mucocutaneous lymph node syndrome (MCLS or Kawasaki disease) treated solely with aspirin. Of these, 19 developed coronary aneurysm. Mononuclear cells (MNC) of these MCLS patients were collected weekly and stimulated either with phytohaemagglutinin (PHA) or PHA plus phorbol myristic acetate. The production of interleukin-2 (IL-2), tumour necrotic factor (TNF) and gamma-interferon (IFN-r) was determined. In addition, IL-2, TNF, IFN-r from serial collections of serum samples of these patients were also measured. The results show that serum IL-2 and TNF were detected in the 1st week, reached maximal plateau in the 2nd and 3rd week and decreased 1 month later. The production of IL-2, TNF and IFN-r from MCLS patients' MNC increased from the 1st to the 3rd week, persisted at a high level for 1 month and then decreased. During the 2nd and 3rd weeks, there were significantly higher serum IL-2 levels and IL-2 production in patients with than in patients without coronary lesions. These observations suggest that the serum IL-2 level and IL-2 production during the 2nd week may serve as a predictive parameter for coronary aneurysm formation. It also suggests that the production of TNF, IL-2 and IFN-r from MNC may contribute to the development of vascular injury in acute MCLS. [ABSTRACT FROM AUTHOR]

We report the effect of exposure of human keratinocyte cultures to human recombinant gamma-interferon (g-IFN) on the expression of glycoproteins. Concanavalia ensiformis agglutinin (Con-A), and Arachis hypogaea agglutinin (PNA) were used to investigate expression of glycoproteins. NP-40 extracts from cultures grown with or without 100 U/ml g-IFN were analyzed by incubation of SDS-polyacrylamide gels with I-labeled lectins. Comparison of Con-A binding glycoprotein profiles showed both qualitative and quantitative changes related to the effect of g-IFN. Differences were also apparent after labeling of the gels with PNA. A limited number of components were labeled, with most of the reactivity falling within a couple of diffuse bands with high molecular weight (300 to 360 kDa). These components were strongly labeled in extracts from cells grown in the presence of g-IFN, but weakly reactive in control cultures. Neuraminidase treatment unmasked a 205 kDa PNA binding molecule only when cells were cultured in the absence of g-IFN. These changes are interpreted in terms of increased keratinocyte differentiation induced by g-IFN and demonstrate that glycoproteins bearing carbohydrate residues available to lectins Con-A and PNA have to be taken into account to better understand the complex action of this lymphokine. In inflammatory lesions, such changes in the glycoproteins of keratinocytes expressing HLA-DR antigens remain to be explored. [ABSTRACT FROM AUTHOR]