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PubMed2005

A novel glyco-conjugate vaccine against fungal pathogens.

To generate a vaccine to protect against a variety of human pathogenic fungi, we conjugated laminarin (Lam), a well-characterized but poorly immunogenic beta-glucan preparation from the brown alga Laminaria digitata, with the diphtheria toxoid CRM197, a carrier protein used in some glyco-conjugate bacterial vaccines. This Lam-CRM conjugate proved to be immunogenic and protective as immunoprophylactic vaccine against both systemic and mucosal (vaginal) infections by Candida albicans. Protection probably was mediated by anti-beta-glucan antibodies as demonstrated by passive transfer of protection to naive mice by the whole immune serum, the immune vaginal fluid, and the affinity-purified anti-beta-glucan IgG fractions, as well as by administration of a beta-glucan-directed IgG2b mAb. Passive protection was prevented by adsorption of antibodies on Candida cells or beta-glucan particles before transfer. Anti-beta-glucan antibodies bound to C. albicans hyphae and inhibited their growth in vitro in the absence of immune-effector cells. Remarkably, Lam-CRM-vaccinated mice also were protected from a lethal challenge with conidia of Aspergillus fumigatus, and their serum also bound to and markedly inhibited the growth of A. fumigatus hyphae. Thus, this novel conjugate vaccine can efficiently immunize and protect against two major fungal pathogens by mechanisms that may include direct antifungal properties of anti-beta-glucan antibodies.

Analysis of Variance↗

PubMed1987

Perspectives in mucosal immunity: a ruminant model.

All mammalian species have developed specialized defence mechanisms at the interface between mucosal surfaces and the environment and this system operates independently of the systemic immune system. Attachment of organisms to the mucosal epithelium is a primary prerequisite for infection and is an important virulence determinant for pathogens of these sites. The mucosal immune defences are thus characterized by production of IgA antibodies, the principal mode of action of which is to inhibit the adherence of pathogens to the mucosal epithelium. This introduction to the symposium on mucosal immunity will attempt to underline the role of local immunity in the intestine in providing local defence at that site, in addition to providing cellular molecular effectors for other mucosal sites.

Animals↗

PubMed2005

CD4+CD25+ regulatory T cells control the progression from periinsulitis to destructive insulitis in murine autoimmune diabetes.

Non-obese diabetic (NOD) mice develop spontaneous T-cell responses against pancreatic beta-cells, leading to islet cell destruction and diabetes. Despite high genetic similarity, non-obese resistant (NOR) mice do not develop diabetes. We show here that spleen cells of both NOD and NOR mice respond to the islet cell antigen glutamic acid decarboxylase-65 in IFN-gamma-ELISPOT assays. Moreover, NOR-T cells induce periinsulitis in NOD SCID recipient mice. Thus, a potentially pathogenic islet cell-specific T-cell response arises in NOR and NOD mice alike; the mechanism that prevents the autoimmune progression of self-reactive T cells in NOR mice presumably acts at the level of effector function. Consistent with this hypothesis, CD4+CD25+ cell-depleted spleen cells from NOR mice mediated islet cell destruction and overt diabetes in NOD SCID mice. Therefore, islet cell-specific effector cells in NOR mice appear to be under the control of CD4+CD25+ regulatory T cells, confirming the importance of regulatory cells in the control of autoimmune diabetes.

Adoptive Transfer↗

PubMed2002

High affinity binding of long-chain polysialic acid to antibody, and modulation by divalent cations and polyamines.

Long-chain polysialic acid (PSA) is expressed on the vertebrate neural cell adhesion molecule (NCAM) during neuronal plasticity. Its structural similarity to the capsular PSAs of some pathogenic bacteria has hampered the development of polysaccharide vaccines against meningitis. The antibodies formed during immunization require a long epitope for binding, and cross-react with host tissue PSA. The nature of the epitope and possible external effectors involved are still unclear. We have evaluated the interaction of PSA with its antibody mAb735 by surface plasmon resonance. The influences of PSA chain length, pH, temperature, ionic environment, and polyamines were also determined. The antibody binding affinity was found to dramatically increase with PSA chain length. A sub-nanomolar dissociation constant (K(D)=8.5 x 10(-10)M) was obtained for the binding of very long chain native MenB polysaccharides (approximately 200 Neu5Ac-residues). Colominic acid from Escherichia coli K1 (approximately 100 residues) and shorter polymers exhibited progressively weaker affinities. The antibody also bound tightly (K(D) approximately 5 x 10(-9)M) to polysialylated glycopeptides from human embryonal brain. The effects of pH and ionic strength suggested that the interaction is largely electrostatic. Ca2+ and Mn2+ ions promoted the observed surface plasmon resonance response in a concentration dependent fashion. Spermine increased the response in a similar way. Our results suggest that divalent cations and polyamines may play significant role in the regulation of the PSA epitope presentation in vivo.

Animals↗

PubMed2004

Gene transfer approaches in cancer immunotherapy.

The idea of enhancing or establishing effective immune response against endogenously developed tumor cells is not novel. More than a hundred years ago, bacterial components were used to develop antitumor immune response. Later, when a number of immune system-effecting cytokines had been discovered, they were used for systemic treatment of cancer patients. However, systemic treatment often resulted in even negative outcome. Recent developments of genetic approaches of cell modifications allowed developing of modern techniques of targeted tumor cell elimination. In the present paper, we review modern trends of the antitumor response enhancement based on immunoregulatory gene transfer into different cell types both in vivo and in vitro. Almost all these approaches are based on the activation of the adaptive arm of the immune system in response to tumor cells. However, recent studies indicate that the innate arm of the immune system, as well as adaptive arm, is involved in tumor suppression. The innate immune system uses nonrearranging germline receptors, which could trigger cellular effector responses that are conditional (or instructive) to the subsequent adaptive immune response. Last years' viewpoints on 'self' and 'non-self' recognition and primary induction of the immune response have changed. The key role of lymphocytes is pathogen recognition and, following immune response induction, switched on the central role of dendritic cells in 'non-self' recognition and induction of both innate and adaptive responses. Moreover, innate response is supposed to be an essential starting point in induction of successful and effective acquired response. Most cancer vaccines do not have 'non-self' marks presentation due to their endogenous origin, thus lacking their effectiveness in the induction of the specific long-lasting immune response. Taking this point into consideration, we can conclude that to make cancer vaccine more effective we have to present tumor antigens, together with the molecules that can potentially activate downstream 'non-self' recognition events not in parallel, but as a consequence of tumor antigen processing and presentation.

Animals↗

PubMed2002

Iron and immunity: a double-edged sword.

Iron is a crucial element for many central metabolic pathways of the body. Lack of iron leads to growth arrest and anaemia while increased accumulation of this metal, as it occurs in highly frequent inherited diseases such as hereditary haemochromatosis and thalassaemia, is associated with toxic radical formation and progressive tissue damage. As shown by several groups, iron also modulates immune effector mechanisms, such as cytokine activities (IFN-gamma effector pathways towards macrophages), nitric oxide (NO) formation or immune cell proliferation, and thus host immune surveillance. Therefore, gaining control over iron homeostasis is one of the central battlefields in deciding the fate of an infection with intracellular pathogens or a malignant disease. Thus, the reticulo-endothelial system has evoked sophisticated strategies to control iron metabolism in general and especially the handling of the metal within immune cells.

Cytokines↗

PubMed2003

Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses.

The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus.

Animals↗

PubMed2003

Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response.

Infection with the human microbial pathogen Helicobacter pylori is assumed to lead to invasive gastric cancer. We find that H. pylori activates the hepatocyte growth factor/scatter factor receptor c-Met, which is involved in invasive growth of tumor cells. The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response. CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2. The H. pylori-induced motogenic response is suppressed and blocked by the inhibition of PLCgamma and of MAPK, respectively. Thus, upon translocation, CagA modulates cellular functions by deregulating c-Met receptor signaling. The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Cytomegalovirus (CMV)-specific CD8+ T cells in individuals with HIV infection: correlation with protection from CMV disease.

CD8+ cytotoxic T cells play a key role in immunological protection from clinical cytomegalovirus (CMV) disease. Numbers of CMV-specific CD8+ T cells are increased in untreated and antiretroviral-treated HIV patients compared with healthy controls. Accumulation of CMV-specific CD8+ T cells during HIV infection may reflect persistent reactivation of CMV owing to suboptimal immune control and/or oligoclonal expansion of the limited populations of CMV-specific CD8+ T cells present before antiretroviral therapy (ART). CD8+ T cells directed against the CMV immediate early (IE)-1 protein may play an important role in preventing CMV replication to pathogenic levels. However, immunological protection from CMV disease in HIV-infected individuals on ART does not appear to depend on total numbers of CMV-specific CD8+ T cells but rather on the presence of both effector-memory and effector CMV-specific CD8+ T cells that produce interferon-gamma and/or perforin in response to CMV antigens.

CD8-Positive T-Lymphocytes↗

PubMed2004

Analysis of Ehrlichia ruminantium-specific T1/T2 responses during vaccination with a protective killed vaccine and challenge of goats.

Ehrlichia ruminantium is an obligate intracellular bacterium that causes heartwater in ruminants and for which T-cell-mediated immunity is believed to play an important role in protection. To better characterize protective cellular immunity, E. ruminantium-specific IFN-gamma and IL-4 recall responses in major T-cell subsets were analysed by flow cytometry during immunization of goats with a killed vaccine and following a virulent challenge. The killed vaccine elicited both CD8+ and CD4+ subsets to produce cytoplasmic IFN-gamma in the absence of IL-4, thus indicating a biased T1 response. The relative capacity of CD8+ T-cells to produce IFN-gamma was significantly higher than CD4+ T-cells but the final contribution of both subsets was comparable. Circulating ER-specific CD4 and CD8 effectors substantially decreased in numbers after the booster injection and could not be detected in most animals during challenge, which warrants further investigation in immune compartments other than blood. Since IFN-gamma inhibits the growth of the pathogen in target cells, the information provided in this study on E. ruminantium-specific T1 responses will be valuable to develop cellular tools for the identification of potential protective antigens.

Animals↗

PubMed2004

Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette-Guérin.

The kinetics of activation and induction of several effector functions of human natural killer (NK) cells in response to Mycobacterium bovis bacille Calmette-Guérin (BCG) were investigated. Owing to the central role of monocytes/macrophages (MM) in the initiation and maintenance of the immune response to pathogens, two different experimental culture conditions were analysed. In the first, monocyte-depleted nylon wool non-adherent (NW) cells from healthy donors were stimulated with autologous MM preinfected with BCG (intracellular BCG). In the second, the NW cells were directly incubated with BCG, which was therefore extracellular. In the presence of MM, CD4+ T lymphocytes were the cell subset mainly expressing the activation marker, CD25, and proliferating with a peak after 7 days of culture. In contrast, in response to extracellular BCG, the peak of the proliferative response was observed after 6 days of stimulation, and CD56+ CD3- cells (NK cells) were the cell subset preferentially involved. Such proliferation of NK cells did not require a prior sensitization to mycobacterial antigens, and appeared to be dependent upon contact between cell populations and bacteria. Following stimulation with extracellular BCG, the majority of interferon-gamma (IFN-gamma)-producing cells were NK cells, with a peak IFN-gamma production at 24-30 hr. Interleukin (IL)-2 and IL-4 were not detectable in NK cells or in CD3+ T lymphocytes at any time tested. IL-12 was not detectable in the culture supernatant of NW cells stimulated with extracellular BCG. Compared to the non-stimulated NW cells, the NW cells incubated for 16-20 hr with BCG induced the highest levels of expression of apoptotic/death marker on the NK-sensitive K562 cell line. BCG also induced expression of the activation marker, CD25, and proliferation, IFN-gamma production and cytotoxic activity, on negatively selected CD56+ CD3- cells. Altogether, the results of this study demonstrate that extracellular mycobacteria activate several NK-cell functions and suggest a possible alternative mechanism of NK-cell activation as the first line of defence against mycobacterial infections.

Adult↗

PubMed2006

Butyrate specifically down-regulates salmonella pathogenicity island 1 gene expression.

Invasion of intestinal epithelial cells by Salmonella enterica is decreased after exposure to butyric acid. To understand the molecular mechanisms of this phenomenon, a comparative transcriptomic analysis of Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium grown in medium supplemented with butyrate was performed. We found that butyrate down-regulated the expression of 19 genes common to both serovars by a factor of twofold or more, and 17 of these genes localized to the Salmonella pathogenicity island 1 (SPI1). These included the SPI1 regulatory genes hilD and invF. Of the remaining two genes, ampH has 91% homology to an Escherichia coli penicillin-binding protein and sopE2 encodes a type III-secreted effector protein associated with invasion but located at a separate site on the chromosome from SPI1.

Animals↗

PubMed1996

Avian gut-associated lymphoid tissues and intestinal immune responses to Eimeria parasites.

Coccidiosis, an intestinal infection caused by intracellular protozoan parasites belonging to several different species of Eimeria, seriously impairs the growth and feed utilization of livestock and poultry. Host immune responses to coccidial infection are complex. Animals infected with Eimeria spp. produce parasite-specific antibodies in both the circulation and mucosal secretions. However, it appears that antibody-mediated responses play a minor role in protection against coccidiosis. Furthermore, there is increasing evidence that cell-mediated immunity plays a major role in resistance to infection. T lymphocytes appear to respond to coccidial infection through both cytokine production and a direct cytotoxic attack on infected cells. The exact mechanisms by which T cells eliminate the parasites, however, remain unclear. Although limited information is available on the intestinal immune system of chickens, gut lymphoid tissues have evolved specialized features that reflect their role as the first line of defense at mucosal surfaces, including both immunoregulatory cells and effector cells. This review summarizes our current understanding of the avian intestinal immune system and mucosal immune responses to Eimeria spp., providing an overview of the complex cellular and molecular events involved in intestinal immune responses to enteric pathogens.

Animals↗

PubMed2005

Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis.

A type III secretion system (TTSS) is encoded on a virulence plasmid that is common to three pathogenic Yersinia species: Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis. Pathogenic Yersinia species require this TTSS to survive and replicate within lymphoid tissues of their animal or human hosts. A set of pathogenicity factors, including those known as Yersinia outer proteins (Yops), is exported by this system upon bacterial infection of host cells. Two translocator Yops (YopB and YopD) insert into the host plasma membrane and function to transport six effector Yops (YopO, YopH, YopM, YopT, YopJ, and YopE) into the cytosol of the host cell. Effector Yops function to counteract multiple signaling responses in the infected host cell. The signaling responses counteracted by Yops are initiated by phagocytic receptors, Toll-like receptors, translocator Yops, and additional mechanisms. Innate and adaptive immune responses are thwarted as a consequence of Yop activities. A biochemical function for each effector Yop has been established, and the importance of these proteins for the pathogenesis process is being elucidated. This review focuses on the biochemical functions of Yops, the signaling pathways they modulate, and the role of these proteins in Yersinia virulence.

Animals↗

PubMed2004

CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion.

It is well established that CD4(+)CD25(+) regulatory T cells (Tregs) inhibit autoimmune pathology. However, precisely how the behavior of disease-inducing T cells is altered by Tregs remains unclear. In this study we use a TCR transgenic model of diabetes to pinpoint how pathogenic CD4 T cells are modified by Tregs in vivo. We show that although Tregs only modestly inhibit CD4 cell expansion, they potently suppress tissue infiltration. This is associated with a failure of CD4 cells to differentiate into effector cells and to up-regulate the IFN-gamma-dependent chemokine receptor CXCR-3, which confers the ability to respond to pancreatic islet-derived CXCL10. Our data support a model in which Tregs permit T cell activation, yet prohibit T cell differentiation and migration into Ag-bearing tissues.

Animals↗

PubMed1994

Vitalethine modulates erythropoiesis and neoplasia.

Novel compounds based upon the thiol N-(carboxy)-beta-alanyl-cysteamine (vitaletheine) have strikingly potent and seemingly diverse biological activities. Concentrations of vitaletheine modulators from 1 femtograms/ml to 100 picograms/ml medium regulate RBC production from progenitors initially deprived of erythropoietin. Similarly, as little as attograms/ml concentrations of the disulfide vitalethine stimulate immunological responses of murine splenocytes toward sheep RBC in a hemolytic plaque assay. Because dosages of vitalethine as low as femtograms/kg substantially diminish tumor size and incidence and increase survival to 80% in mice inoculated with a uniformly fatal melanoma (Cloudman S-91), activities of these compounds have in vivo significance. A preliminary probe of the benzyl derivative of vitalethine in a myeloma model (NS-1) suggests efficacy (100% survival) as well. The high potencies of the vitaletheine modulators, both in cell culture and in vivo, indicate that these or similar regulatory components, if constitutively present, probably occur endogenously at vanishingly small concentrations and may be prone to deficiency resulting from metabolic imbalances, irradiation, aging, diet, pathogenic or parasitic infections, or exposure to environmental pollutants. Pathways for the biosynthesis of vitaletheine are proposed and chemical syntheses of the vitaletheine modulators are described. Possible molecular mechanisms of action, including interactions with peptidyl hormones, other endogenous effectors, and xenobiotic and pharmaceutical compounds, are explored. Indications for the treatment of other diseases are identified.

Animals↗

PubMed1979

Presence of natural killer cells in specific-pathogen-free chickens.

Spleen cells of normal specific-pathogen-free N, P, and 15 X 7 chickens were cytotoxic in vitro for target cells of Marek's disease lymphoma line MSB-1. The natural killer (NK) cell activity, best expressed in chickens over 7 weeks old, varied among several genetic lines of chickens tested. The NK cells were thermolabile, and incubation of the cells at 37 degrees C for 30--60 minutes resulted in substantial loss of cytotoxicity. The specificity of NK effector cells was directed against common antigen(s) on tumor cell lines of diverse origin but not on normal adult or embryonic cells.

Animals↗

PubMed2005

The interaction of pemphigus autoimmunoglobulins with epidermal cells: activation of the fas apoptotic pathway and the use of caspase activity for pathogenicity tests of pemphigus patients.

Pemphigus is a fatal autoimmune disease in which autoimmunoglobulins PV-IgG (binding to desmoglein 3) and PF-IgG (binding to desmoglein 1) in pemphigus vulgaris and pemphigus foliaceus, respectively, cause intraepidermal blisters, cell-cell separation (acantholysis), and cell death. The mechanism of acantholytic lesion formation has not yet been elucidated. Recently, we have reported that an apoptotic mechanism might be operative in PV-IgG-induced acantholysis: (1) in patients' lesional and some perilesional skin portions, the FasR pathway is activated as its components were enriched; (2) in cultured keratinocytes, PV-IgG upregulates effectors of the FasR pathway (including the mitochondrial loop), as found by immunodetermination (cytochemistry, Western blot of pathway effectors) and determination of caspases 1, 3, and 8 activity/activation; (3) in organ cultures of skin incubated with PV-IgG, activated caspase 8 was found also in perilesional cells and coaggregated with bound PV-IgG; (4) caspase 8 activation in DISCs precedes caspase 3 activation in keratinocytes in cultures upon incubation with PV-IgG. Because caspase activation was shown to accompany lesion formation in cell and organ cultures incubated with PV-IgG, we used caspase activity to monitor the pathogenicity of PV-IgG in relation to PV-IgG binding to epithelia. A rough correlation was found between sera titers, determined by IIF and by immunoblot binding to desmoglein 3, and activation of caspase 3.

Acantholysis↗