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Biomedical subjects

M De Boer

Publications and source records attributed to M De Boer.

At least 19 recordsLinked to original sources
PubMed2004

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys.

Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3-4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8(+) lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.

Adenoviridae↗
PubMed2004

Blocking B7 and CD40 co-stimulatory molecules decreases antiviral T cell activity.

Inhibition of co-stimulatory signals for T cells by interrupting CD80/CD86-CD28 and CD40-CD154 interactions is a promising approach to prevent transplant rejection and to induce graft tolerance. However, this tolerizing treatment might affect T cell reactivity towards all the antigens to which the immune system is exposed during treatment. We addressed the question whether such inhibition of co-stimulatory ligands on human antigen presenting cells (APC) would affect T cell reactivity against a virus. This was tested in an in vitro system with freshly isolated human monocytes transduced with adenovirus (ad) containing either murine interferon-gamma (mIFN-gamma) or green fluorescent protein (GFP) as marker transgene. T cells co-cultured with transduced monocytes proliferated and produced cytokines. These 'primed' T cells had strong antiviral activity as they subsequently killed ad/GFP-transduced monocytes and reduced mIFN-gamma accumulation in coculture with ad/mIFN-transduced monocytes. However, if priming had occurred in the presence of blocking anti-CD40/CD80/CD86 MoAbs, generation of this antiviral activity was completely prevented. Moreover, T cells primed in the absence of co-stimulatory cells failed to proliferate upon restimulation with adenovirus-transduced monocytes. The results confirm that co-stimulatory signals from APC are required for efficient induction of antiviral T cell activity and point to a potential infectious risk of blocking co-stimulatory signals.

Adenoviridae↗
PubMed2001

Measuring information needs among cancer patients.

A scale for assessing information needs of cancer patients was constructed and validated. Two studies were conducted. Study 1 was designed to test the factor structure of the measurement instrument. A total of 498 patients with breast cancer and Hodgkin disease were interviewed. In study 2, 133 patients with head and neck cancer were measured just before treatment as well as 6, 13 and 52 weeks after treatment. Study 2 aimed to confirm the factor structure established in study 1, and to test for construct validity in a new population, the psychometric properties of the information needs scales, and the scales' sensitivity to change. In study 1 a two-factor structure (an action and a disease-oriented scale) including 17 items was revealed. The second study confirmed the factor structure from study 1. As hypothesized, greater information needs related to higher levels of state-anxiety, more depression, and more psychological complaints. Although, correlations over time per information need scale indicate some stability of scores, findings suggested that the need for information about disease and treatment is less stable over time than need for information about access to help and solutions. Further validation of the instrument is required.

Adult↗
PubMed2000

Point mutations in the promoter region of the CYBB gene leading to mild chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a clinical syndrome of recurrent bacterial and fungal infections caused by a rare disorder of phagocytic cells. In CGD, the phagocytes are unable to generate oxygen radicals after stimulation of these cells, due to a defect in the NADPH oxidase system. This NADPH oxidase is a multicomponent enzyme of at least four subunits, of which the beta-subunit of cytochrome b558, gp91-phox, is encoded by an X-linked gene (called CYBB). We report here five patients from two families; in each family we found a different mutation in the promoter region of CYBB. Both mutations prevented the expression of gp91-phox in the patients' neutrophils and thus caused inability of these cells to generate oxygen radicals. However, the mutations left the gp91-phox expression and the function of the NADPH oxidase in the patients' eosinophils intact. The relatively mild course of the CGD in these patients can probably be attributed to the fact that the eosinophils have retained their oxidative capacity. Furthermore, our results indicate that neutrophils and eosinophils differ in their regulation of gp91-phox expression.

Adolescent↗
PubMed1999

A scale to assess activities of daily living in persons affected by leprosy.

The aim of this study was to develop a scale for identifying disability among people in the rural areas of developing countries. The studies were carried out in the Green Pastures Hospital and the leprosy field programme of the Western Region of Nepal. With the help of staff experienced in working with people with disability, a 68-question questionnaire was made, based on the International Classification of Impairments, Activities and Participation (ICIDH-2). A survey was carried out of 269 people affected by leprosy who had impairments, as well as a sample of those who were unimpaired. The survey results were used to develop the questionnaire into a scale, using standard scale development methods. This included checking of criterion validity, discrimination and reliability and stability using weighted kappa statistics. Of the 68 questions, 38 were included in the second draft of the instrument. Eight questions were added to identify difficulty in relationships, about the use of aids and about occupation and employment. The sum score of the scale against the expert score gave a Spearman correlation coefficient of 0.72. Intra- and inter-interviewer reliability coefficients were 0.77 (95% CI 0.73-0.81) and 0.61 (95% CI 0.56-0.67), respectively. The stability test gave an overall kappa of 0.76 (95% CI 0.70-0.82). Four questions with particularly poor results were omitted from the final draft of the instrument. An interview-based instrument was developed for identifying limitations in activities of daily living (disability) in people living in a rural setting in a developing country--the Green Pastures Activity Scale (GPAS). The scale performed well during validity and reliability testing. It consists of 34 activity questions, five relationship questions, and three questions on the use of aids, occupation and employment.

Activities of Daily Living↗
PubMed1998

T cell apoptosis in human heart allografts: association with lack of co-stimulation?

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation.

Antigens, CD↗
PubMed1998

Requirement of CD28-CD86 costimulation for allergen-specific T cell proliferation and cytokine expression.

BACKGROUND: Allergen-specific T lymphocytes biased to the production of type 2 cytokines play an important role in the pathophysiology of atopic disease. It is not known whether optimal activation of these T cells requires costimulation via interaction of B7 (CD86/CD80) with CD28. METHODS: Peripheral blood mononuclear cells (PBMC), isolated from 10 house dust mite Dermatophagoides pteronyssinus (Der p)-allergic asthma patients and 10 non-allergic control individuals, were stimulated with house dust mite (Der p) and the control antigens Candida albicans (CA) and tetanus toxoid (TT). The role of costimulation in activation for proliferation and cytokine mRNA production of peripheral blood T cells was studied by blocking CD28, CTLA-4, and their ligands CD80 (B7-1) and CD86 (B7-2). RESULTS: The proliferation and the production of type 1 and 2 cytokine mRNA by T cells in response to Der p as well as the control antigens TT and CA was inhibited by simultaneously masking CD80 and CD86 using CTLA4-Ig, a soluble form of CTLA-4. Notably, Der p-specific proliferation of T cells from Der p-allergic asthma patients and non-allergic controls were inhibited equally well. Additional experiments with MoAbs revealed that activation of these T cells was optimally inhibited by blocking the interaction of CD28 with CD86. CONCLUSION: In vitro responses of allergen- and antigen-specific T cells of allergic patients and non-allergic control persons are equally dependent on costimulation via the CD28-CD86 pathway, suggesting that inhibition of this pathway may prevent complete activation of allergen-specific T cells in allergic individuals in vivo.

Allergens↗
PubMed1998

Regulation of expression of the amino acid transporter gene BAP3 in Saccharomyces cerevisiae.

The BAP3 gene of Saccharomyces cerevisiae encodes a protein with a high similarity to the BAP2 gene product, a high-affinity permease for branched-chain amino acids. In this paper, we show that, like BAP2, the expression of the BAP3 gene in S. cerevisiae is induced by the addition of branched-chain amino acids to the medium. Unexpectedly, most other naturally occurring L-amino acids found in proteins (with the exception of proline, lysine, arginine and histidine) have the same effect on the expression of BAP3. The induction of BAP3 expression appears to be dependent on Stp1p, a nuclear protein, previously shown to be involved in pre-tRNA maturation and also required for the expression of BAP2, as induction is no longer observed in an stp1 - mutant. The transcriptional regulator Leu3p is not involved in the induction of BAP3 expression, but may act as a repressor of BAP3 expression in the absence of leucine, as can be inferred from a transcriptional analysis in a Deltaleu3 mutant. By extensive deletion analysis of the BAP3 promoter fused to a GUS reporter, as well as by fusions of different parts of the BAP3 promoter to a LacZ reporter, we have found that a portion of the BAP3 promoter from - 418 to - 392 relative to the ATG start codon is both necessary and sufficient for the Stp1p-dependent induction of BAP3 expression by (most) amino acids. We have therefore named this sequence UASaa (amino acid-dependent upstream activator sequence). Neither Stp1p nor Leu3p appear to bind to the UASaa, at least in vitro, as judged from gel retardation assays. Sequences similar to the UASaa can be found in the promoters of BAP2, PTR2 and TAT1; genes that, like BAP3, encode permeases inducible by amino acids, suggesting that amino acid induction of all these genes is exerted via a common mechanism.

Amino Acid Transport Systems↗
PubMed1998

CD40 in clinical inflammation: from multiple sclerosis to atherosclerosis.

The interactions of CD40 and CD40L have been known for some time to critically regulate B-cell responses with respect to proliferation, isotype switching, antibody production, and memory formation. More recent findings demonstrated that CD40 can be expressed on several other antigen-presenting cell (APC) types such as macrophages, dendritic cells, and fibroblasts. This expression of CD40 regulates T-cell-APC interaction and is centrally involved in a wide array of inflammatory events. Here, currently available data are reviewed demonstrating that CD40-CD40L interactions are operational in two chronic inflammatory clinical conditions, namely, multiple sclerosis and atherosclerosis. The functional correlates of these interactions are discussed in the light of recent other findings, shedding light on the multiple effects of CD40-CD40L interactions.

Animals↗
PubMed1996

Alloantigen-specific T-cell anergy induced by human keratinocytes is abrogated upon loss of cell-cell contact.

The activation of primary human T cells largely depends on the expression of both major histocompatibility complex (MHC) class II and B7 molecules on antigen-presenting cells (APC), whereas APC expressing HLA class II but not B7 antigens are expected to induce anergy. According to this concept, interferon-gamma (IFN-gamma)-activated keratinocytes (KC) expressing HLA class II but not B7 costimulatory antigens should be able to induce anergy. However, in terms of anergy versus activation contradicting data have been published on the outcome of interaction between T cells and human KC. In addition, it has been shown that human KC can express a B7-like molecule with unknown function, whereas MHC expression may be functionally impaired. To evaluate this item we transfected the human A431 KC cell line with B7-1 coding sequences and up-regulated HLA-DR by treatment with IFN-gamma, yielding A431DR,B7-1 cells. Irradiated A431DR,B7-1 cells were found to be capable of inducing vigorous proliferative primary T-cell responses in resting allogeneic T cells, whereas A431DR cells could induce proliferation only when interleukin-2 (IL-2) was added. These data indicate that KC can present alloantigens, and that lack of costimulatory molecules on KC is the main reason why these cells cannot induce primary T-cell responses. Surprisingly, however, no evidence could be obtained of stable anergy induction by A431DR cells, as T cells contacted with A431DR cells and then transferred to A431DR,B7-1 cells clearly demonstrated alloresponsiveness. T-cell non-responsiveness was maintained only when T cells remained in contact with A431DR cells. These data indicate that, despite expression of HLA class II in the absence of B7 costimulatory molecules, human KC cannot induce stable anergy but rather induce short-term anergy in primary resting T cells.

B7-1 Antigen↗
PubMed1995

Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8+ T cells from HIV-infected subjects.

The CD28 receptor on CD4+ and CD8+ T cells interacts with B7 molecules on antigen-presenting cells (APC) to generate essential costimulatory signals. The cytolytic potential of CD8+ T cells could be linked to CD28 expression. Since HIV induces dysfunction of both CD4+ and CD8+ T cells, we evaluated CD28 expression and function in both subsets during HIV infection. CD28 expression on CD8+ T cells from HIV+ subjects was strongly reduced in a disease stage-related fashion. CD28- CD8+ T cells preferentially expressed CD57 and CD11b, but lacked CD26 and IL-2R alpha. The CD8+ T cells from the patients showed a significantly reduced proliferative response to co-stimulation with cell-bound anti-CD3 and B7. Nevertheless, when stimulated with plate-fixed anti-CD3, CD8+ T cells from HIV-infected subjects proliferated normally, and normal levels of IL-2R alpha and transferrin-receptor could be induced on CD28- CD8+ T cells from the patients. In addition, stimulation with plate-fixed anti-CD3 induced proliferative responses in highly purified CD28- CD8+ T cells from both HIV- and HIV+ persons. Furthermore, the increased cytotoxic activity of peripheral blood mononuclear cells (PBMC) from HIV+ subjects, measured in an anti-CD3 redirected assay, was predominantly exerted by CD28- CD57+ T cells. CD4+ T cells from the patients showed a slight but significant CD28 down-regulation and were slightly hyporesponsive to B7 co-stimulation. Decrease of CD28 on CD8+ T cells from HIV+ subjects is associated with an impaired response to co-stimulation via B7. CD28- CD8+ T cells from seropositives, however, are not completely inert, since they contain in vivo activated CTL and they can be additionally activated through a B7-independent stimulation.

Adult↗
PubMed1995

Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden.

To estimate the prevalence of chronic granulomatous disease (CGD) in Sweden, an inquiry asking for known and possible CGD cases was mailed to paediatric, internal medicine and infectious disease departments all over Sweden. The detected patients were characterized as to genetics and the clinical presentation. Twenty-one patients (belonging to 16 different families) were found, corresponding to a prevalence of approximately 1/450,000 individuals. The patients with X-linked disease, lacking a functional gp91phox protein (n = 12), comprised 57% and 43% of the patients had an autosomal recessive (AR) disease lacking p47phox (n = 7) or p67phox (n = 1), respectively. All unrelated patients with X-linked disease displayed different gene abnormalities such as point mutations predicting nonsense (n = 3), missense (n = 1) or splice site mutations (n = 2), but also a total deletion and a unique 40 base pair duplicature insertion. The patients with p47phox-deficiency showed a GT deletion at a GTGT tandem repeat, and the p67phox-deficient patient displayed a heterozygous in-frame deletion of AAG combined with a large deletion in the other allele. Three patients died during the study period, two from pseudomonas cepacia infections. Patients with X-linked disease had more frequent infections (mean of 1.7 per year), than the patients with AR inheritance (0.5 infections per year). The most common infections were dermal abscesses (n = 111), followed by lymphadenitis (n = 82) and pneumonias (n = 73). Inflammatory bowel disease-like symptoms, mimicking Crohn's disease of the colon, was seen in three CGD patients.

Adolescent↗
PubMed1994

Expression of functional B7 and CTLA4 on rheumatoid synovial T cells.

To assess the role of B7, CTLA4, and CD28 in the pathogenesis of chronic synovitis we analyzed the expression and function of these cell surface molecules in patients with rheumatoid arthritis, osteoarthritis, and psoriatic arthritis, and in normal controls. Immunoperoxidase staining of rheumatoid synovial membranes showed reactivity of 30% of T cells with anti-B7 mAb, in contrast to osteoarthritic and normal synovial membranes, in which no such staining was seen. In addition, rheumatoid synovial fluid T cells were positive by flow cytometric analysis for B7 (mean 20%, range 0 to 96%), as measured by staining with anti-B7 mAb or the CTLA4 Ig fusion protein, whereas no B7 expression was detected on peripheral blood T cells (mean 1%). To analyze the functional importance of B7 expressed on synovial fluid T cells, we used these cells as stimulator cells in primary allogeneic MLC. Purified synovial fluid T cells were far stronger stimulator cells compared with paired peripheral blood T cells and resulted in a fivefold greater increase in allogeneic T cell proliferation. Furthermore, the proliferation induced by purified synovial T cells was markedly inhibited by addition of the CTLA4 Ig fusion protein (77%). Moreover, anti-B7 mAb (37%), anti-CTLA4 mAb (33%), and Fab fragments of anti-CD28 mAb (52%) partially inhibited the primary MLC. The expression of functional B7, together with the increased expression of MHC class II molecules, indicates that synovial T cells may serve as functional APCs and may be capable of autocrine stimulation via the CD28 activation pathway.

Abatacept↗
PubMed1993

CD40 plays an essential role in the activation of human B cells by murine EL4B5 cells.

A mutant subclone of the murine thymoma EL-4, known as EL4B5, can strongly activate human B cells to proliferate and differentiate in a cell-cell contact-dependent manner. We have investigated whether interaction via CD40 plays a role in this helper activity. For this purpose, three newly generated anti-CD40 monoclonal antibodies (mAb) were used. In contrast with other anti-CD40 mAb described in the literature, these mAb did not co-stimulate proliferation of human B cells. On the other hand, these novel mAb could inhibit the co-stimulatory effect of the previously described anti-CD40 mAb S2C6 on anti-IgM-induced human B-cell proliferation. It was found that addition of these non-stimulatory anti-CD40 mAb could completely inhibit EL4B5-induced human B-cell proliferation. Maximal inhibition occurred already at a mAb concentration of 10 ng/ml. Similarly, a fusion protein, consisting of the extracellular portion of CD40 and human IgM constant domains CH2, CH3 and CH4, could completely inhibit EL4B5-induced human B-cell proliferation. Induction of human B-cell proliferation by EL4B5 cells was also inhibited by anti-CD40 mAb S2C6 and G28.5, but less effectively. In contrast, mAb against B-cell surface antigens CD20 or B7 had no inhibitory effects. It is concluded that interaction via CD40 is essential for the induction of human B-cell proliferation by EL4B5 cells.

Animals↗
PubMed1992

Dependence of the adenovirus tripartite leader on the p220 subunit of eukaryotic initiation factor 4F during in vitro translation. Effect of p220 cleavage by foot-and-mouth-disease-virus L-protease on in vitro translation.

The adenovirus tripartite leader (TPT) 5' untranslated region (5'UTR) allows translation in poliovirus-infected cells, in which the p220 subunit of eukaryotic initiation factor 4F is degraded. This p220-independent translation was investigated by measuring in vitro translation in a reticulocyte lysate of a reporter gene, chloramphenicol acetyltransferase, coupled to the TPT 5'UTR. The p220 subunit was degraded by translation of a foot-and-mouth-disease L-protease construct. Surprisingly, the TPT 5'UTR was dependent on intact p220, as are other naturally capped mRNA species. Translation of encephalomyocarditis virus RNA was p220 independent, as expected from its ability to support internal, cap-independent initiation. In vitro protein-synthesis experiments with purified initiation factors confirmed the dependence of TPT mRNA translation on eukaryotic initiation factor 4F. The relationship between adenovirus TPT-5'UTR-directed translation and poliovirus-induced host cell shut-off is discussed.

Adenoviridae↗
PubMed1992

Prenatal diagnosis in a family with X-linked chronic granulomatous disease with the use of the polymerase chain reaction.

In the X-linked form of chronic granulomatous disease (X91 degrees CGD), the genetic defect is linked to the CYBB locus on the X chromosome. We studied a family with a genetic defect in this gene, consisting of a G----A substitution at the fifth base of the 5' donor splice site of intron 3. This mutation leads to skipping of exon 3 after transcription of the gene. The expectant mother was diagnosed as a carrier. Analysis of polymerase chain reaction (PCR)-amplified genomic DNA from a chorionic villus biopsy (CVB) showed the same mutation in the male fetus. After termination of the pregnancy, the diagnosis was confirmed by conventional methods. This is the first time that PCR has been used for prenatal diagnosis of CGD.

Abortion, Eugenic↗
PubMed1992

Fluvoxamine treatment for chronic PTSD: a pilot study.

A group of 24 Dutch World War II Resistance veterans with a documented traumatic war history and a (partially) positive diagnosis of current posttraumatic stress disorder (PTSD) was studied. This special group of war victims is characterised by chronicity, suffering from intractable posttraumatic complaints for decades. They were treated with fluvoxamine (Fevarin), a selective serotonin reuptake inhibitor with antidepressive and anxiolytic properties. The study was designed as an open-ended, outpatient pilot study, with a treatment period of 12 weeks. Results of clinical examination, and questionnaires investigating PTSD, depression, sleeping problems, anxiety, and vital exhaustion indicate that a significant number of the subjects improved with respect to their PTSD symptomatology, and their symptoms of anxiety and vital exhaustion. However, at the end of the study, quantitative improvement was modest. The results indicate that treatment with fluvoxamine may offer alleviation of chronic PTSD symptoms, in particular insomnia, nightmares, anxiety, intrusive recollections, guilt feelings and tiredness.

Aged↗