MULTIPRED: A computational system for prediction of promiscuous HLA binding peptides

MULTIPRED is a web-based computational system for the prediction of peptide binding to multiple molecules ( proteins) belonging to human leukocyte antigens (HLA) class I A2, A3 and class II DR supertypes. It uses hidden Markov models and artificial neural network methods as predictive engines. A novel data representation method enables MULTIPRED to predict peptides that promiscuously bind multiple HLA alleles within one HLA supertype. Extensive testing was performed for validation of the prediction models. Testing results show that MULTIPRED is both sensitive and specific and it has good predictive ability ( area under the receiver operating characteristic curve A(ROC) > 0.80). MULTIPRED can be used for the mapping of promiscuous T-cell epitopes as well as the regions of high concentration of these targets termed T-cell epitope hotspots. MULTIPRED is available at http:// antigen.i2r.a-star.edu.sg/ multipred/.

Modulation of macrophage immune responses by Echinacea

Echinacea preparations are widely used herbal medicines for the prevention and treatment of colds and minor infections. There is little evidence for the individual components in Echinacea that contribute to immune regulatory activity. Activity of an ethanolic Echinacea extract and several constituents, including cichoric acid, have been examined using three in vitro measures of macrophage immune function - NF-kappa B, TNF-alpha and nitric oxide (NO). In cultured macrophages, all components except the monoene alkylamide (AA1) decreased lipopolysaccharide (LPS) stimulated NF-kappa B levels. 0.2 mu g/ml cichoric acid and 2.0 mu g/mL Echinacea Premium Liquid (EPL) and EPL alkylamide fraction (EPL AA) were found to significantly decrease TNF-alpha production under LPS stimulated conditions in macrophages. In macrophages, only the alkylamide mixture isolated from the ethanolic Echinacea extract decreased LPS stimulated NO production. In this study, the mixture of alkylamides in the Echinacea ethanolic liquid extract did not respond in the same manner in the assays as the individual alkylamides investigated. While cichoric acid has been shown to affect NF-kappa B, TNF-alpha and NO levels, it is unlikely to be relevant in the Echinacea alterations of the immune response in vivo due to its nonbioavailability - i.e. no demonstrated absorption across the intestinal barrier and no detectable levels in plasma. These results demonstrate that Echinacea is an effective modulator of macrophage immune responses in vitro.

The mononuclear phagocyte system

The mononuclear phagocyte system (MPS) has been defined as a family of cells comprising bone marrow progenitors, blood monocytes and tissue macrophages. Macrophages are a major cell population in most of the tissues in the body, and their numbers increase further in inflammation, wounding and malignancy. Their trophic roles for other cell types in development and homeostasis are becoming increasingly evident. The receptor for macrophage colony-stimulating factor (CSF-1R) is expressed in a large proportion of cells considered to be mononuclear phagocytes, including antigen-presenting dendritic cells, which can be considered a specialized adaptive state rather than a separate lineage. The unity of the MPS is challenged by evidence that there is a separate embryonic phagocyte lineage, by the transdifferentiation and fusion of MPS cells with other cell types, and by evidence of local renewal of tissue macrophage populations as opposed to monocyte recruitment. The concept of the MPS may have partly outlived its usefulness.

Metal binding to transferrin and immune reactions in Parkinson's disease

The binding of iron (59Fe) and gallium (67Ga) to the plasma protein transferrin (Tf) was investigated by G75 gel filtration chromatography in control patients and treated and untreated patients with Parkinson's disease (PD). Fe-Tf binding was 100% in all controls and PD patients suggesting that a defect in Fe-Tf binding was not involved in the aetiology of PD. Ga-Tf binding was significantly reduced in both untreated and treated PD patients compared to controls. In addition, treated PD patients had significantly higher Ga-Tf binding than untreated patients. A reduction in metal binding to Tf could result in the increase of a low molecular weight species which may more readily enter the CNS. Alternatively, it could lead to a decrease in the transport of essential metals into the brain via the Tf receptor system. A significant elevation in neopterin was demonstrated within the plasma of untreated PD patients compared to controls suggesting the activation of a cellular immune response. Furthermore, plasma neopterin was lower in treated compared to untreated PD patients, although the difference was not significant. There was no evidence for the activation of the humoral immune response in untreated or treated PD patients as measured by circulating immune complex (CIC) levels within the plasma. An inverse relationship between Ga-Tf binding and neopterin was observed in untreated PD patients. The addition of oxidants in the form of potassium permanganate and activated manganese dioxide reduced Ga-Tf binding in control plasma. However, relatively little response was observed using monocyte preparations. The results suggest that oxidants produced by activation of the cellular immune system could damage the Tf molecule thereby reducing its ability to bind metals.

Influence of microbial antigen formulation and delivery route on the immune response

Recent technological advances have resulted in the production of safe subunit and synthetic small peptide vaccines. Unfortunately, these vaccines are weakly or non-immunogenic in the absence of an immunological adjuvant (agents that can induce strong immunity to antigens). In addition, in order to prevent and/or control infection at the mucosal surface, stimulation of the mucosal immune system is essential. This may be achieved via the common mucosal immune system by exposure to antigen at a mucosal surface remote from the area of infection. Initial studies investigated the potential of multiple emulsions in effecting oral absorption and the subsequent immune responses to a lipopolysaccharide vaccine (LPS) after immunisation. Nasal delivery of LPS was carried out in parallel work using either aqueous solution or gel formulations. Tetanus toxoid vaccine in simple solution was delivered to guinea pigs as free antigen or entrapped in DSPC liposomes. In addition, adsorbed tetanus toxoid vaccine was delivered nasally free or in an aerosil gel formulation. This work was extended to investigate guinea pigs immunised by various mucosal routes with a herpes simplex virus subunit vaccine prepared from virus infected cells and delivered in gels, multiple emulsions and liposomes. Comparable serum antibody responses resulted but failed to produce enhanced protection against vaginal challenge when compared to subcutaneous immunisation with alhydrogel adjuvanted vaccine. Thus, immunisation of the mucosal surface by these methods may have been inadequate. These studies were extended in an attempt to protect against HSV genital challenge by construction of an attenuated Salmonella typhimurium HWSH aroA mutant expressing a cloned glycoprotein D-l gene fused to the Es-cherichia coli lac z promoter. Preliminary work on the colonisation of guinea pigs with S. typhimurium HWSH aroA mutants were carried out, with the aim of using the guinea pig HSV vaginal model to investigate protection.

Proteins accessible to immune surveillance show significant T-cell epitope depletion:implications for vaccine design

T cell activation is the final step in a complex pathway through which pathogen-derived peptide fragments can elicit an immune response. For it to occur, peptides must form stable complexes with Major Histocompatibility Complex (MHC) molecules and be presented on the cell surface. Computational predictors of MHC binding are often used within in silico vaccine design pathways. We have previously shown that, paradoxically, most bacterial proteins known experimentally to elicit an immune response in disease models are depleted in peptides predicted to bind to human MHC alleles. The results presented here, derived using software proven through benchmarking to be the most accurate currently available, show that vaccine antigens contain fewer predicted MHC-binding peptides than control bacterial proteins from almost all subcellular locations with the exception of cell wall and some cytoplasmic proteins. This effect is too large to be explained from the undoubted lack of precision of the software or from the amino acid composition of the antigens. Instead, we propose that pathogens have evolved under the influence of the host immune system so that surface proteins are depleted in potential MHC-binding peptides, and suggest that identification of a protein likely to contain a single immuno-dominant epitope is likely to be a productive strategy for vaccine design.

Immune-inspired adaptive information filtering

Adaptive information filtering is a challenging research problem. It requires the adaptation of a representation of a user’s multiple interests to various changes in them. We investigate the application of an immune-inspired approach to this problem. Nootropia, is a user profiling model that has many properties in common with computational models of the immune system that have been based on Franscisco Varela’s work. In this paper we concentrate on Nootropia’s evaluation. We define an evaluation methodology that uses virtual user’s to simulate various interest changes. The results show that Nootropia exhibits the desirable adaptive behaviour.

The Danger Theory and Its Application to Artificial Immune Systems

Over the last decade, a new idea challenging the classical self-non-self viewpoint has become popular amongst immunologists. It is called the Danger Theory. In this conceptual paper, we look at this theory from the perspective of Artificial Immune System practitioners. An overview of the Danger Theory is presented with particular emphasis on analogies in the Artificial Immune Systems world. A number of potential application areas are then used to provide a framing for a critical assessment of the concept, and its relevance for Artificial Immune Systems.

'On the Effects of Idiotypic Interactions for Recommendation Communities in Artificial Immune Systems'

It has previously been shown that a recommender based on immune system idiotypic principles can outperform one based on correlation alone. This paper reports the results of work in progress, where we undertake some investigations into the nature of this beneficial effect. The initial findings are that the immune system recommender tends to produce different neighbourhoods, and that the superior performance of this recommender is due partly to the different neighbourhoods, and partly to the way that the idiotypic effect is used to weight each neighbour's recommendations.