Human T-cell responses to HLA-A-restricted high binding affinity peptides of human papillomavirus type 18 proteins E6 and E7.

Human Papillomaviruses (HPVs) are sexually transmitted pathogens, which are implicated in the etiology of cervical cancer. The early proteins E6 and E7 of HPV have transforming capacity and interfere with the cell cycle control of infected host cells and are essential for the maintenance of the transformed state. Identification of MHC class I-restricted, immunogenic peptides derived from either the E6 or the E7 protein is essential for the design of vaccines as well as the monitoring of clinical trials and immunotherapeutic approaches for the treatment of HPV-18-induced carcinomas.

Papillomavirus virus-like particles as anticancer vaccines.

Papillomavirus virus-like particles (VLPs) are empty, non-replicative, non-infectious particles that retain conformationally correct epitopes for the generation of antibody responses to the viral capsid proteins. Chimeric human papillomavirus (HPV) virus-like particles incorporating non-structural virus proteins offer an exciting approach for combined prophylactic and therapeutic vaccines against HPV-induced lesions. Both HPV VLPs and chimeric VLPs can induce potent humoral and cellular immune responses when injected into mice, leading to the generation of virus-neutralizing antibodies, priming of CD8+ T-cells and activation of cytotoxic T-cell effector functions.

Cervical cancer vaccines: emerging concepts and developments.

Certain human cancers are linked to infection by oncogenic viruses that are able to cause transformation of the normal host cell into a cancerous cell. Human papillomavirus (HPV) DNA and expression of viral transforming proteins are found in virtually all cervical cancer cells, indicating an important role of this virus in the pathogenesis of the disease. Evidence exists that the immune response to cancer cells can play a major role in determining the outcome of disease.

Molecular characterization of melanoma-derived antigens.

In the last decade, many antigens expressed by tumors and recognized by the immune system have been identified. Melanoma was among the first tumors found to express such tumor-associated antigens, and, therefore, melanoma is currently one of the best and extensively studied tumors for which new techniques have been introduced to optimize the characterization of tumor antigens. In this chapter, we discuss the techniques used for identification of melanoma-expressed antigens recognized by cytotoxic T-lymphocytes (CTLs).

Growth of primary school children: a validation of the 1990 references and their use in growth monitoring.

Aims: To determine whether the British 1990 growth charts are valid for cross sectional and longitudinal use in primary school children.

Methods: A total of 694 children aged 7-10 years from 10 Leeds primary schools were weighed and measured annually over three years by an expert auxologist. SD scores were calculated using both the Tanner-Whitehouse (TW) and the revised British 1990 growth references.

Molecular basis for nonanaphylactogenicity of a monoclonal anti-IgE antibody.

IgE Abs mediate allergic responses by binding to specific high affinity receptors (FcepsilonRI) on mast cells and basophils. Therefore, the IgE/FcepsilonRI interaction is a target for clinical intervention in allergic disease. An anti-IgE mAb, termed BSW17, is nonanaphylactogenic, although recognizing IgE bound to FcepsilonRI, and interferes with binding of IgE to FcepsilonRI.

The macrocyclic peptide antibiotic micrococcin P(1) is secreted by the food-borne bacterium Staphylococcus equorum WS 2733 and inhibits Listeria monocytogenes on soft cheese.

Staphylococcus equorum WS 2733 was found to produce a substance exhibiting a bacteriostatic effect on a variety of gram-positive bacteria. The metabolite was purified to homogeneity by ammonium sulfate precipitation and semipreparative reversed-phase high-performance liquid chromatography. Electrospray mass spectrometry confirmed the high purity of the compound and revealed a molecular mass of 1,143 Da.

Anthropometric indices of failure to thrive.

Aims: To compare five anthropometric methods of classifying failure to thrive in order to ascertain their relative merits in predicting developmental, dietary, and eating problems.

Methods: The five anthropometric methods were compared in 83 children with failure to thrive.

Results: The methods were inconsistent in classification of severity, and no one method was superior in predicting problems.

The reality of drug use in COPD: the European perspective.

COPD guidelines provide advice about the appropriate use of various medications in treating patients with this condition. Comparisons of drug therapy as recommended by these guidelines with what is actually prescribed by both primary care physicians and specialist pulmonologists in a number of European countries can be examined in a variety of ways. Nonadherence to guidelines and differences between countries are caused by a number of factors, including varying degrees of misdiagnosis and different national attitudes to various classes of drugs.

Small bowel intussusception in celiac disease.

Intussusception is not a widely recognized complication of celiac disease and yet it is not rare. The authors report on 3 children with spontaneously resolving small bowel intussusception in association with celiac disease. Small bowel intussusception in a child with suspected celiac disease initially should be managed expectantly rather than by early surgical reduction.

Oral anti-IgE immunization with epitope-displaying phage.

An essential requirement for oral vaccines is the ability to survive the harsh environment of the stomach in an antigenically intact form. As bacteriophages are adapted to this environment we used epitope-displaying M13 bacteriophages as carriers for an experimental oral anti-IgE vaccine. The feasibility of this approach was tested in a simulated gastric fluid using two different mimotopes as well as an anti-idiotypic Fab of the non-anaphylactogenic monoclonal anti-IgE antibody BSW17.

Exploring the scope for advocacy by paediatricians.

Aims: To ascertain the type and extent of problems requiring advocacy in paediatrics. To develop an approach for analysing problems according to their root causes and the level of society at which advocacy is needed.

Methods: Nine paediatricians kept detailed clinical diaries for two weeks to identify problems.

Molecular mimicry of the unidentified antigen of myeloma antibody IgE-ND.

Antigen-specific human IgE is in short supply. Thus, we sought to determine the yet unknown specificity of a widely available human IgE, namely the myeloma cell line U266-derived IgE-ND. For this purpose highly specific peptides able to mimic the putative antigen recognized by IgE-ND were isolated from phage-display random peptide libraries.

Inositol 1,3,4-trisphosphate acts in vivo as a specific regulator of cellular signaling by inositol 3,4,5,6-tetrakisphosphate.

Ca2+-activated Cl- channels are inhibited by inositol 3,4,5, 6-tetrakisphosphate (Ins(3,4,5,6)P4) (Xie, W., Kaetzel, M. A.

A randomised controlled trial of specialist health visitor intervention for failure to thrive.

Aims: To determine whether home intervention by a specialist health visitor affects the outcome of children with failure to thrive.

Methods: Children referred for failure to thrive were randomised to receive conventional care, or conventional care and additional specialist home visiting for 12 months. Outcomes measured were growth, diet, use of health care resources, and Bayley, HAD (hospital anxiety and depression), and behavioural scales.

A search for the evidence supporting community paediatric practice.

Aim: Controversy exists regarding the evidence base of medicine. Estimates range from 20% to 80% in various specialties, but there have been no studies in paediatrics. The aim of this study was to ascertain the evidence base for community paediatrics.

Induction of HPV16 capsid protein-specific human T cell responses by virus-like particles.

It has been postulated that upon binding to a cell surface receptor, papilloma virus-like particles (VLPs) gain entry into the cytosol of infected cells and the capsid proteins L1 and L2 can be processed in the MHC class I presentation pathway. Vaccination of mice with human papilloma virus-like particles consisting of capsid proteins L1 and L2 induced a CD8-mediated and perforin dependent protective immune response against a tumor challenge with human papilloma virus transformed tumor cells, which express only minute amounts of L1 protein. Here we show that HPV16 capsid proteins stimulate a MHC class I restricted CTL response with human peripheral blood lymphocytes (PBL) in vitro.

Antigen interaction and heat inactivation expose new epitopes on human IgE.

It is well established that heat-denatured IgE is no longer capable of binding to FcepsilonRI. We have found an antibody that interacts with heat-denatured IgE. Interestingly, this antibody can also be used to detect some serum IgE, but not IgE synthesized de novo in vitro.

A membrane-permeant, bioactivatable derivative of Ins(1,3,4)P3 and its effect on Cl(-)-secretion from T84 cells.

The synthesis of rac-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate hexakis(acetoxymethyl) ester [Bt3-Ins(1,3,4)P3/AM, 1], a membrane-permeant derivative of myo-inositol 1,3,4-trisphosphate [Ins(1,3,4)P3] is reported. 1 inhibited calcium-mediated chloride secretion of T84 cells, suggesting a regulatory link of Ins(1,3,4)P3 and the biosynthesis of the known inhibitor myo-inositol 3,4,5,6-tetrakisphosphate.

2-Deoxy derivative is a partial agonist of the intracellular messenger inositol 3,4,5,6-tetrakisphosphate in the epithelial cell line T84.

We have synthesized the first deoxy analogues of myo-inositol 3,4,5, 6-tetrakisphosphate (1) [Ins(3,4,5,6)P4], rac-2-deoxy-myo-inositol 3, 4,5,6-tetrakisphosphate (rac-2), 2-deoxy-myo-inositol 1,4,5, 6-tetrakisphosphate (ent-2), and rac-1-deoxy-myo-inositol 3,4,5, 6-tetrakisphosphate (rac-3). In order to evaluate the binding properties of the three derivatives to the yet unidentified intracellular binding sites for Ins(3,4,5,6)P4, the analogues were converted to membrane-permeant derivatives. Starting with common inositol precursors, various forms of Barton-McCombie deoxygenation and classical protection/deprotection procedures yielded the desired precursors rac-1-O-butyryl-2-deoxy-myo-inositol (rac-12), ent-3-O-butyryl-2-deoxy-myo-inositol (ent-12), and rac-2-O-butyryl-1-deoxy-myo-inositol (rac-19), respectively.