There is an increasing demand for non-antibiotics solutions to control infectious disease in intensive pig production. Here, one such alternative, namely pig antibodies purified from slaughterhouse ...blood was investigated in order to elucidate its potential usability to control post-weaning diarrhoea (PWD), which is one of the top indications for antibiotics usage in the pig production. A very cost-efficient and rapid one-step expanded bed adsorption (EBA) chromatography procedure was used to purify pig immunoglobulin G from slaughterhouse pig plasma (more than 100 litres), resulting in >85% pure pig IgG (ppIgG). The ppIgG thus comprised natural pig immunoglobulins and was subsequently shown to contain activity towards four pig-relevant bacterial strains (three different types of Escherichia coli and one type of Salmonella enterica) but not towards a fish pathogen (Yersinia ruckeri), and was demonstrated to inhibit the binding of the four pig relevant bacteria to a pig intestinal cell line (IPEC-J2). Finally it was demonstrated in an in vivo weaning piglet model for intestinal colonization with an E. coli F4+ challenge strain that ppIgG given in the feed significantly reduced shedding of the challenge strain, reduced the proportion of the bacterial family Enterobacteriaceae, increased the proportion of families Enterococcoceae and Streptococcaceae and generally increased ileal microbiota diversity. Conclusively, our data support the idea that natural IgG directly purified from pig plasma and given as a feed supplement can be used in modern swine production as an efficient and cost-effective means for reducing both occurrence of PWD and antibiotics usage and with a potential for the prevention and treatment of other intestinal infectious diseases even if the causative agent might not be known.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Innate defense mechanisms are aimed at quickly containing and removing infectious microorganisms and involve local stromal and immune cell activation, neutrophil recruitment and activation and the ...induction of host defense peptides (defensins and cathelicidins), acute phase proteins and complement activation. As an alternative to antibiotics, innate immune mechanisms are highly relevant as they offer rapid general ways to, at least partially, protect against infections and enable the build-up of a sufficient adaptive immune response. This review describes two classes of promising alternatives to antibiotics based on components of the innate host defense. First we describe immunoglobulins applied to mimic the way in which they work in the newborn as locally acting broadly active defense molecules enforcing innate immunity barriers. Secondly, the potential of host defense peptides with different modes of action, used directly, induced in situ or used as vaccine adjuvants is described.
Summary
Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on ...mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex‐matched and age‐matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose‐dependent release of interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α) and interleukin‐10 (IL‐10) by patient‐derived MNCs. The patients’ cells produced higher amounts of IFN‐γ and TNF‐α, and lower amounts of IL‐10, than cells from healthy controls (P < 0·03 to P < 0·04). Five patients with MS and no controls, displayed MBP‐induced CD4+ T‐cell proliferation. These high‐responders exhibited enhanced production of IL‐17, IFN‐γ, IL‐5 and IL‐4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0·002 to P < 0·01). A strong correlation was found between the MBP‐induced CD4+ T‐cell proliferation and production of IL‐17, IFN‐γ, IL‐5 and IL‐4 (P < 0·0001 to P < 0·01) within the patient group, and the production of IL‐17 and IL‐5 correlated with the number of active plaques on magnetic resonance images (P = 0·04 and P = 0·007). These data suggest that autoantigen‐driven CD4+ T‐cell proliferation and release of IL‐17 and IL‐5 may be associated with disease activity. Larger studies are needed to confirm this.
Immunisation by administration of antibodies (immunoglobulins) has been known for more than one hundred years as a very efficient means of obtaining immediate, short-lived protection against ...infection and/or against the disease-causing effects of toxins from microbial pathogens and from other sources. Thus, due to its rapid action, passive immunisation is often used to treat disease caused by infection and/or toxin exposure. However immunoglobulins may also be administered prior to exposure to infection and/or toxin, although they will not provide long-lasting protection as is seen with active immunisation (vaccination) in which an immunological memory is established by controlled exposure of the host to the pathogen in question. With multi-factorial infectious diseases in production animals, especially those that have proven hard to control by vaccination, the potential of passive immunisation remains big. This review highlights a number of examples on the use of passive immunisation for the control of infectious disease in the modern production of a range of animals, including pigs, cattle, sheep, goat, poultry and fish. Special emphasis is given on the enablement of passive immunisation strategies in these production systems through low cost and ease of use as well as on the sources, composition and purity of immunoglobulin preparations used and their benefits as compared to current measures, including vaccination (also comprising maternal vaccination), antibiotics and feed additives such as spray-dried plasma. It is concluded that provided highly efficient, relatively low-price immunoglobulin products are available, passive immunisation has a clear role in the modern animal production sector as a means of controlling infectious diseases, importantly with a very low risk of causing development of bacterial resistance, thus constituting a real and widely applicable alternative to antibiotics.
Enteric infectious disease in weaner piglets, including postweaning diarrhoea (PWD), are usually treated and/or prevented with antibiotics and/or zinc oxide in the piglet feed. However extensive use ...of antibiotics and zinc oxide in intensive animal production is unwanted as it may promote microbial antibiotic resistance and pose environmental problems. Recently, in an experimental model of PWD, we observed that oral administration of purified porcine immunoglobulin G (ppIgG) from pooled natural pig plasma could reduce enteric infection. In the present study we were able to reproduce these results as it was observed that oral ppIgG accelerated clearance of faecal haemolytic bacteria in pigs challenged with E. coli in comparison with pigs not receiving ppIgG. This effect was observed upon feeding ppIgG for seven days postweaning suggesting that ppIgG does not have to be used prophylactically for several days preweaning. Furthermore, the effect of oral administration of ppIgG for seven days postweaning was equal to or better than that of dietary zinc oxide in reducing diarrhoea symptoms and in clearing faecal haemolytic bacteria for 14days postweaning. These observations warrant future trials of dietary ppIgG in intensive swine production units to establish its performance as an alternative to dietary antibiotics and zinc oxide for preventing PWD.
The epidermal growth factor receptor (EGFR) is over-expressed, as well as mutated, in many types of cancers. In particular, the EGFR variant type III mutant (EGFRvIII) has attracted much attention as ...it is frequently and exclusively found on many tumor cells, and hence both EGFR and EGFRvIII have been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies.
Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous ...and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Treatment with interferon-beta (IFN-beta) increases B-cell activating factor of the TNF family (BAFF) expression in multiple sclerosis (MS), raising the concern that treatment of MS ...patients with IFN-beta may activate autoimmune B cells and stimulate the production of MS-associated autoantibodies.
Objective: To investigate whether BAFF levels are associated with disease severity/activity in untreated MS patients, and to assess the effect of IFN-beta therapy on circulating BAFF and anti-myelin basic protein (MBP) autoantibody levels.
Results: Twenty-three patients with relapsing–remitting MS (RRMS) were followed longitudinally from initiation of IFN-beta therapy. Their blood levels of BAFF correlated positively at baseline with the expanded disability status scale (p < 0.009) and MS severity score (p < 0.05), but not with disease activity as determined by the number of gadolinium-enhanced lesions. The patients were followed for up to 26 months, during which the BAFF levels remained elevated without association to increased disease activity. IFN-beta therapy caused an increase in plasma BAFF levels after both 3 and 6 months of therapy (p < 0.002). However, an 11% decrease in IgM and a 33% decrease in IgG anti-MBP autoantibodies (p < 0.09 and p < 0.009, respectively) was observed after 6 months.
Conclusion: Pre-treatment BAFF levels correlate with high disability scores in MS, suggesting that high BAFF expression is a negative prognostic marker. Despite its known beneficial effects, IFN-beta therapy causes a sustained increase in plasma BAFF levels, which does not translate into increased levels of anti-MBP autoantibodies.
Anti-myelin basic protein (-MBP) autoantibodies have generally been considered to be absent from sera from healthy individuals, but to be detectable in sera from some patients with multiple sclerosis ...(MS). However, their pathogenic role is uncertain. We demonstrate the presence of MBP-reactive autoantibodies in sera from 17 healthy individuals and 17 MS patients. The addition of MBP to the sera caused a dose-dependent deposition of MBP and co-deposition of immunoglobulin M (IgM) and fragments of complement component 3 (C3) on allogeneic monocytes. Calcium chelation abrogated the immunoglobulin deposition, indicating that formation of complement-activating immune complexes played a role in the binding process. Furthermore, MBP elicited tumour necrosis factor (TNF)-α and interleukin (IL)-10 production by normal mononuclear cells in the presence of serum from both patients and controls. Mononuclear cells from MS patients responded to MBP with the production of interferon (IFN)-γ, IL-4 and IL-5, in addition to TNF-α and IL-10. The production of IFN-γ and IL-5 was increased when MS serum was added rather than normal serum. Denaturation of MBP strongly inhibited MBP deposition and the MBP-induced IgM deposition and cytokine production, indicating that these events were facilitated by autoantibodies recognizing conformational epitopes on MBP. We infer that MBP-elicited TNF-α and IL-10 responses are promoted to equal extents by naturally occurring MBP autoantibodies and autoantibodies contained in MS sera. However, the latter seem to be more efficient in facilitating the production of IFN-γ and IL-5.
Objective The purpose of the research was to investigate how leakage of stomal effluent and peristomal skin complications (PSC) affects the quality of life (QoL) of people living with a stoma.
Method ...Data were collected from an online questionnaire sent out to approximately 20,000 people living with a stoma. The validated Ostomy-Q scale was used to measure changes in QoL.
Results More than 4,200 people from 13 countries completed the study between 30 August and 3 October 2016. Leakage had a statistically significant impact on the QoL for participants who experienced leakage four times (or more) out of ten baseplates changes. All four domains in the Ostomy-Q scale - confidence in stoma appliance, comfort, discretion and socialising - were affected. Also, people with PSC had a significantly lower QoL than those who had not experienced PSC in the 6 months before the survey. PSC impacted the confidence and comfort domains significantly. The discretion and socialising domains were also significantly affected by PSC but were below the pre-defined limit for a minimal important difference.
Conclusion The data support that leakage and PSC have a significant physical and psychological impact on people living with a stoma.