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J Hammer

Publications and source records attributed to J Hammer.

At least 73 records · Page 4Linked to original sources
PubMed1999

A peptide binding motif for I-Eg7, the MHC class II molecule that protects E alpha-transgenic nonobese diabetic mice from autoimmune diabetes.

The nonobese diabetic (NOD) mouse, a model of spontaneous insulin-dependent diabetes mellitus (IDDM), fails to express surface MHC class II I-Eg7 molecules due to a deletion in the E alpha gene promoter. E alpha-transgenic NOD mice express the E alpha E beta g7 dimer and fail to develop either insulitis or IDDM. A number of hypotheses have been proposed to explain the mechanisms of protection, most of which require peptide binding to I-Eg7. To define the requirements for peptide binding to I-Eg7, we first identified an I-Eg7-restricted T cell epitope corresponding to the sequence 4-13 of Mycobacterium tuberculosis 65-kDa heat shock protein (hsp). Single amino acid substitutions at individual positions revealed a motif for peptide binding to I-Eg7 characterized by two primary anchors at relative position (p) 1 and 4, and two secondary anchors at p6 and p9. This motif is present in eight of nine hsp peptides that bind to I-Eg7 with high affinity. The I-Eg7 binding motif displays a unique p4 anchor compared with the other known I-E motifs, and major differences are found between I-Eg7 and I-Ag7 binding motifs. Analysis of peptide binding to I-Eg7 and I-Ag7 molecules as well as proliferative responses of draining lymph node cells from hsp-primed NOD and E alpha-transgenic NOD mice to overlapping hsp peptides revealed that the two MHC molecules bind different peptides. Of 80 hsp peptides tested, none bind with high affinity to both MHC molecules, arguing against some of the mechanisms hypothesized to explain protection from IDDM in E alpha-transgenic NOD mice.

Amino Acid Sequence↗
PubMed1999

Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with histocompatibility leukocyte antigen DR11.

In this study we used TEPITOPE, a new epitope prediction software, to identify sequence segments on the MAGE-3 protein with promiscuous binding to histocompatibility leukocyte antigen (HLA)-DR molecules. Synthetic peptides corresponding to the identified sequences were synthesized and used to propagate CD4(+) T cells from the blood of a healthy donor. CD4(+) T cells strongly recognized MAGE-3281-295 and, to a lesser extent, MAGE-3141-155 and MAGE-3146-160. Moreover, CD4(+) T cells proliferated in the presence of recombinant MAGE-3 after processing and presentation by autologous antigen presenting cells, demonstrating that the MAGE-3 epitopes recognized are naturally processed. CD4(+) T cells, mostly of the T helper 1 type, showed specific lytic activity against HLA-DR11/MAGE-3-positive melanoma cells. Cold target inhibition experiments demonstrated indeed that the CD4(+) T cells recognized MAGE-3281-295 in association with HLA-DR11 on melanoma cells. This is the first evidence that a tumor-specific shared antigen forms CD4(+) T cell epitopes. Furthermore, we validated the use of algorithms for the prediction of promiscuous CD4(+) T cell epitopes, thus opening the possibility of wide application to other tumor-associated antigens. These results have direct implications for cancer immunotherapy in the design of peptide-based vaccines with tumor-specific CD4(+) T cell epitopes.

Amino Acid Sequence↗
PubMed1999

Identification of destabilizing residues in HLA class II-selected bacteriophage display libraries edited by HLA-DM.

HLA-DM (DM) functions as a peptide editor by catalyzing the release of class II-associated invariant chain peptides (CLIP) and other unstable peptides, thus supporting the formation of stable class II-peptide complexes for presentation. To investigate the general features that determine the DM susceptibility of HLA-DR1/peptide complexes, we generated a large DM-sensitive peptide repertoire from an M13 bacteriophage display library using a novel double selection protocol: we selected bacteriophage capable of binding to DR1 molecules and, subsequently, we enriched DR1-bound bacteriophage susceptible to elution by purified DM molecules. Sequence and mutational analyses of the DR1/DM double-selected peptides revealed that the amino acids Gly and Pro play a destabilizing role in the dissociation kinetics of DR1 ligands. This observation was confirmed also in natural peptide sequences such as CLIP 89-101, HA 307-319 and bovine collagen II (CII) 261-273. Our results demonstrate that DM susceptibility does not only depend on the number and nature of anchor residues, or the peptide length. Instead, less obvious sequence characteristics play a major role in the DM editing process and ultimately in the composition of peptide repertoires presented to T cells.

Amino Acid Sequence↗
PubMed1999

Breast boost--why, how, when...?

BACKGROUND: Breast conservation management including tumorectomy or quadrantectomy and external beam radiotherapy with a dose of 45 to 50 Gy in the treatment of small breast carcinomas is generally accepted. The use of a radiation boost--in particular for specific subgroups--has not been clarified. With regard to the boost technique there is some controversy between groups emphasizing the value of electron boost treatment and groups pointing out the value of interstitial boost treatment. This controversy has become even more complicated as there is an increasing number of institutions reporting the use of HDR interstitial brachytherapy for boost treatment. The most critical issue with regard to interstitial HDR brachytherapy is the assumed serious long-term morbidity after a high single radiation dose as used in HDR-treatments. METHODS AND RESULTS: This article gives a perspective and recommendations on some aspects of this issue (indication, timing, target volume, dose and dose rate). CONCLUSION: More information about the indication for a boost is to be expected from the EORTC trial 22881/10882. Careful selection of treatment procedures for specific subgroups of patients and refinement in surgical procedures and radiotherapy techniques may be useful in improving the clinical and cosmetic results in breast conservation therapy. Prospective trials comparing on the one hand different boost techniques and on the other hand particular morphologic criteria in treatments with boost and without boost are needed to give more detailed recommendations for boost indications and for boost techniques.

Brachytherapy↗
PubMed1999

Effect of inhaled nitric oxide on respiratory mechanics in ventilated infants with RSV bronchiolitis.

OBJECTIVE: To evaluate the bronchodilator effect of inhaled nitric oxide (NO) in infants with respiratory failure caused by respiratory syncytial virus (RSV) bronchiolitis and to compare the effect with the one obtained by salbutamol. DESIGN: Prospective study. SETTING: Pediatric intensive care unit of a university children's hospital. PATIENTS: Twelve acutely ill, intubated infants (mean age 4.5 months, mean weight 4.9 kg) with respiratory failure due to documented RSV bronchiolitis. INTERVENTIONS: Total respiratory system resistance (Rrs) was measured by single breath occlusion at the baseline and after inhaling NO at 20, 40 and 60 ppm for 1 h, and after inhalation of a standard beta2-agonist, salbutamol. Arterial blood gas analysis was performed at each study level on 6 of the 12 patients. RESULTS: The baseline mean Rrs (SE) was 0.29 (0.04) cm H2O/ml per s. At each dose of NO, the mean Rrs (SE) was 0.28 (0.04) cm H2O/ml per s. With salbutamol, the mean Rrs (SE) was 0.21 (0.03) cm H20/ml per s. These values were not significantly different from each other (by ANOVA). Inhaled NO produced a significant decrease in Rrs of greater than 4 times the coefficient of variation of the baseline measurement in 3 of 12 patients. Seven of 12 patients had no significant change while two patients had a significant increase in Rrs. Inhaled salbutamol produced a significant decrease in Rrs in 5 of 11 patients, while 6 showed no change in Rrs. CONCLUSION: Inhaled NO has no apparent bronchodilator effect in the majority of acutely ill infants with RSV bronchiolitis and does not appear to provide any additional benefit over the use of salbutamol. The clinical benefit of inhaled NO as a bronchodilator is questionable under these conditions.

Administration, Inhalation↗
PubMed1999

Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices.

Most pockets in the human leukocyte antigen-group DR (HLA-DR) groove are shaped by clusters of polymorphic residues and, thus, have distinct chemical and size characteristics in different HLA-DR alleles. Each HLA-DR pocket can be characterized by "pocket profiles," a quantitative representation of the interaction of all natural amino acid residues with a given pocket. In this report we demonstrate that pocket profiles are nearly independent of the remaining HLA-DR cleft. A small database of profiles was sufficient to generate a large number of HLA-DR matrices, representing the majority of human HLA-DR peptide-binding specificity. These virtual matrices were incorporated in software (TEPITOPE) capable of predicting promiscuous HLA class II ligands. This software, in combination with DNA microarray technology, has provided a new tool for the generation of comprehensive databases of candidate promiscuous T-cell epitopes in human disease tissues. First, DNA microarrays are used to reveal genes that are specifically expressed or upregulated in disease tissues. Second, the prediction software enables the scanning of these genes for promiscuous HLA-DR binding sites. In an example, we demonstrate that starting from nearly 20,000 genes, a database of candidate colon cancer-specific and promiscuous T-cell epitopes could be fully populated within a matter of days. Our approach has implications for the development of epitope-based vaccines.

Alleles↗
PubMed1999

Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules.

We have identified a heptapeptide with high affinity to rheumatoid arthritis-associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

Amino Acid Sequence↗
PubMed1999

Nonulcer dyspepsia.

Nonulcer dyspepsia, characterized by unexplained persistent or recurrent epigastric pain or discomfort, affects approximately 20% of the general population. Symptom-based diagnostic criteria, first developed by an international group of experts, have been refined in the past year in an effort to increase the applicability of the criteria (Rome II criteria). New disease-specific questionnaires that were developed to measure quality of life in patients with dyspepsia are now available and are expected to be widely used in clinical research studies. Studies on the pathophysiology and management of nonulcer dyspepsia were other major topics in the past year, including three large, well-conducted randomized controlled trials of Helicobacter pylori eradication and symptom resolution.

Journal Article↗
PubMed1999

Fibreoptic bronchoscopy in sedated infants facilitated by an airway endoscopy mask.

Fibreoptic bronchoscopy (FB) is frequently associated with a decline in PaO2, whose degree and duration can be substantial especially in infants. The effect of a face mask, which allows the administration of 100% oxygen and continuous positive airway pressure during FB, on the incidence and severity of hypoxaemia was studied in thirty-one consecutive infants. Sedation was provided by intravenous propofol titrated to allow patient comfort. A transient fall in SpO2 <95% was recorded in 6/31 patients during endoscopy of the upper airway (lasting 1.6+/-1.1 min) and in 11/31 patients during endoscopy of the lower airways (lasting 1.4+/-1.1 min). Capillary blood gas analysis before and after endoscopy of the lower airways demonstrated an increase in the PCO2 6.4+/-1.3 to 7.3+/-1.4 kPa (49+/-10 to 56+/-11 mmHg). The risk of hypoxaemia in sedated infants breathing spontaneously is low when 100% oxygen and continuous positive airway pressure are administered during FB

Blood Pressure↗
PubMed1999

A neural network model approach to the study of human TAP transporter.

We used an artificial neural network (ANN) computer model to study peptide binding to the human transporter associated with antigen processing (TAP). After validation, an ANN model of TAP-peptide binding was used to mine a database of HLA-binding peptides to elucidate patterns of TAP binding. The affinity of HLA-binding peptides for TAP was found to differ according to the HLA supertype concerned: HLA-B27, -A3 or -A24 binding peptides had high, whereas HLA-A2, -B7 or -B8 binding peptides had low affinity for TAP. These results support the idea that TAP and particular HLA molecules may have co-evolved for efficient peptide processing and presentation. The strong similarity between the sets of peptides bound by TAP or HLA-B27 suggests functional co-evolution whereas the lack of a relationship between the sets of peptides bound by TAP or HLA-A2 is against these particular molecules having co-evolved. In support of these conclusions, the affinities of HLA-A2 and HLA-B7 binding peptides for TAP show similar distributions to that of randomly generated peptides. On the basis of these results we propose that HLA alleles constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3 and -A24) and those that are TAP-inefficient (HLA-A2, -B7 and -B8). Computer modelling can be used to complement laboratory experiments and thereby speed up knowledge discovery in biology. In particular, we provide evidence that large-scale experiments can be avoided by combining initial experimental data with limited laboratory experiments sufficient to develop and validate appropriate computer models. These models can then be used to perform large-scale simulated experiments the results of which can then be validated by further small-scale laboratory experiments.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

[Respiratory syncytial virus infection in childhood].

Respiratory syncytial virus is the most frequent cause of respiratory tract infections in infants and is responsible for annual winter epidemics of acute bronchiolitis. Over the last decades medical therapy has remained unchanged and controversial, despite intensive research. Inhaled bronchodilators are often not effective and should be discontinued if no beneficial response can be documented. Steroids and ribavirin are not indicated in previously healthy infants with acute RSV bronchiolitis. There is some evidence, however, that certain risk groups may benefit from their use. With good supportive care the mortality from RSV infection is now low. Postinfectious alterations in lung function are usually transient and reversible. High-risk infants can be protected from severe RSV infections by monthly infusions of RSV immune globulins. This treatment modality has, however, not gained wide acceptance because of the benign nature of the disease and the high costs and side effects of regular immune globulin infusions. An international consensus statement on the treatment of RSV bronchiolitis may help to reduce the wide differences in clinical practice.

Bronchiolitis↗
PubMed1998

Relationship between peptide selectivities of human transporters associated with antigen processing and HLA class I molecules.

Efficiency of presentation of a peptide epitope by a MHC class I molecule depends on two parameters: its binding to the MHC molecule and its generation by intracellular Ag processing. In contrast to the former parameter, the mechanisms underlying peptide selection in Ag processing are poorly understood. Peptide translocation by the TAP transporter is required for presentation of most epitopes and may modulate peptide supply to MHC class I molecules. To study the role of human TAP for peptide presentation by individual HLA class I molecules, we generated artificial neural networks capable of predicting the affinity of TAP for random sequence 9-mer peptides. Using neural network-based predictions of TAP affinity, we found that peptides eluted from three different HLA class I molecules had higher TAP affinities than control peptides with equal binding affinities for the same HLA class I molecules, suggesting that human TAP may contribute to epitope selection. In simulated TAP binding experiments with 408 HLA class I binding peptides, HLA class I molecules differed significantly with respect to TAP affinities of their ligands. As a result, some class I molecules, especially HLA-B27, may be particularly efficient in presentation of cytosolic peptides with low concentrations, while most class I molecules may predominantly present abundant cytosolic peptides.

ATP-Binding Cassette Transporters↗
PubMed1998

Chronic gastrointestinal symptoms in hemodialysis patients.

INTRODUCTION: Gastrointestinal disorders occur frequently in dialysis patients. Few data are available on the prevalence of symptoms originating from the gastrointestinal tract in this group of patients. Our aim was to obtain data on the prevalence of chronic gastrointestinal symptoms in patients undergoing hemodialysis. METHODS: All 109 patients of our dialysis unit were given a questionnaire to complete which was previously validated and designed to measure the occurrence of gastrointestinal, and some general symptoms during the preceding year. 105 subjects responded (96% response rate). RESULTS: 79% of dialysis patients had at least one of the following chronic gastrointestinal symptoms: Esophageal symptoms were reported in 21% abdominal pain in 28% and dyspeptic symptoms in 48%. The irritable bowel syndrome was diagnosed in 12 patients (11%), 40% had chronic constipation and 24% had chronic diarrhoea. Colonic pain was described in 20% of patients. Frequent general symptoms (such as weakness, headaches, insomnia and fatigue) were described in up to 51%, and patients were severely bothered by symptoms in up to 33% of cases. CONCLUSION: Although patients on hemodialysis generally report a good quality of life, the prevalence of gastrointestinal symptoms and of general symptoms is high and many dialysis patients consider these symptoms to cause major impairment of daily life.

Adult↗