The SAGE Handbook of Research in International Education
The study of teacher–student relationships is crucial to the improvement of all education, whethe... more The study of teacher–student relationships is crucial to the improvement of all education, whether international or national. Such a focus can have an immediate positive impact on classroom instruction and student learning, as well as on teacher education and research. This chapter presents a model for understanding such relationships in terms of the perceptions that students (and occasionally teachers) have of teachers' interpersonal behaviour. It focuses on corresponding research on teachers' interactions with students in ...
Tubular cells are important targets during acute renal allograft rejection and induction of apopt... more Tubular cells are important targets during acute renal allograft rejection and induction of apoptosis might be a mechanism of tubular cell destruction. Susceptibility to induction of apoptosis is regulated by the homologous Bcl-2 and Bax proteins. Expression of Bcl-2 and Bax is regulated by p53, which down-regulates expression of Bcl-2, while simultaneously up-regulating expression of Bax. We studied apoptotic tubular cell death in 10 renal allograft biopsies from transplant recipients with acute rejection by in situ end-labelling and the DNA-binding fluorochrome propidium iodide. Tubular expression of p53, Bcl-2 and Bax was studies by immunohistochemistry. Five renal allograft biopsies from transplant recipients with uncomplicated clinical course and histologically normal renal tissue present in nephrectomy specimens from 4 patients with renal adenocarcinoma served as control specimens. Apoptotic cells and apoptotic bodies were detected in tubular epithelia and tubular lumina in 9 out of 10 acute rejection biopsies. In control renal tissue, apoptotic cells were detected in 1 biopsy only. Compared to control renal tissue, acute renal allograft rejection was, furthermore, associated with a shift in the ratio of Bcl-2 to Bax in favour of Bax in tubular epithelia and increased expression of p53 in tubular nuclei. These observations demonstrate that apoptosis contributes in part to tubular cell destruction during acute renal allograft rejection. In accordance, the shift in the ratio of Bcl-2 to Bax in favour of Bax indicates increased susceptibility of tubular epithelia to induction of apoptosis. The expression of p53 in tubular nuclei during acute renal allograft rejection indicates the presence of damaged DNA, which can be important in initiation of part of the observed apoptosis. These findings elucidate part of the mechanisms controlling apoptotic tubular cell death during acute renal allograft rejection.
HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumula... more HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumulation of an ''anergic'' CD56 À CD16 1 NK subset, which is characterised by low natural cytotoxicity receptor expression and low cytokine producing capacity. In contrast to humans, chimpanzee NK cells do not display a distinguishable CD56 bright and CD56 dim subset but, as shown here, could be subdivided into functionally different CD8 1 and CD8 À subsets. The CD8 1 NK cells expressed significantly higher levels of triggering receptors including NKp46 and, upon in vitro activation, produced more IFN-c, TNF-a and CD107 than their CD8 À counterparts. In addition, chimpanzee CD8 À NK cells had relatively high levels of HLA-DR expression, suggestive of an activated state. Killing inhibitory receptors were expressed only at low levels; however, upon in vitro stimulation, they were upregulated in CD8 1 but not in CD8 À NK cells and were functionally capable of inhibiting NKp30-triggered killing. In contrast to HIV-1-infected humans, infected chimpanzees maintained their dominant CD8 1 NK cell population, with high expression of natural cytotoxicity receptors.
Virchows Archiv B Cell Pathology Including Molecular Pathology, 1985
The aim of the present study was to compare the effects of LPS on the cellular composition of the... more The aim of the present study was to compare the effects of LPS on the cellular composition of the splenic white pulp in responder C3H/He and non-responder C3H/HeJ mice. The present results show that an intravenous injection of LPS in C3H/He mice results in a number of prominent changes in the histology of the spleen, but none of these histological changes could be demonstrated in the unresponsive C3H/ HeJ mice. However, the present study shows that LPS administration resulted in the disappearance of previously trapped immune complexes from the follicles in both responder C3H/He and non-responder C3H/ HeJ mice. The significance of this phenomenon is discussed.
Members of the Tumour Necrosis Factor-Receptor (TNFR) family play an essential role in the contro... more Members of the Tumour Necrosis Factor-Receptor (TNFR) family play an essential role in the control of lymphoid cell growth and differentiation. The ligand of one of its lymphoid-specific members, CD27, was recently characterized as CD70, a type II transmembrane molecule with homology to TNF that is expressed on activated T and B cells. Ligation of CD27 by its natural ligand generates a potent costimulatory signal for cytokine production and proliferation of activated T cells. In contrast to normal B cells, where CD27 expression is confined to germinal centre cells and to a small subset of circulating B lymphocytes, CD27 expression is found on a large array of distinct B-cell neoplasia. Here, we review recent data on the expression and function of TNFR family members on normal and malignant lymphocytes and propose a role for CD27-CD70 interaction in B-cell development.
The effects of several preparations of Iscador, a commercially obtainable extract of mistletoe, V... more The effects of several preparations of Iscador, a commercially obtainable extract of mistletoe, Viscum album L., on cell proliferation and cell viability was studied. Iscador Quercus was shown to inhibit cell proliferation of: human fibroblast cell lines, mouse tumour cell lines, human carcinoma tumour cell lines and a human lymphoblastic tumour cell line. Iscador Quercus, Iscador Ulnus and Iscador Malus were about equally cytostatic to mouse 3T3 fibroblasts. Iscador Pinus was somewhat less cytostatic. Iscador Quercus had a very direct cytotoxic effect on MOLT 4 tumour cells as assessed by trypan blue dye exclusion. The cytostatic and cytotoxic properties of Iscador could be annulled by heating Iscador for 30 min. at 90~ Iscador reduced the cloning efficiency of ASG and CHO cells in a dose-and time-dependent manner. From the cloning efficiency experiments it can be concluded that a small percentage of CHO cells is insensitive to high concentrations of Iscador at short incubation times.
Recent advances in human immunodeficiency virus (HIV) vaccine design have resulted in induction o... more Recent advances in human immunodeficiency virus (HIV) vaccine design have resulted in induction of strong CD4 T-cell proliferative and polyfunctional cytokine responses, which are also characteristic for long-term non-progressing (LTNP) HIV-infected individuals. However, limited information is available on the persistence of these responses after infection. Results from studies in non-human primates indicate that vaccine-induced immune responses are partially maintained upon viral infection and differ from the responses seen in non-vaccinated animals that typically progress to disease. However, it is unclear how these partially preserved responses compare to immune responses that are acquired naturally by LTNP animals. In this study, immune-response profiles were compared between vaccinated animals that, upon SHIV 89.6p challenge, became infected but were able to control virus replication, and a group of animals having spontaneous control of this viral infection. Both groups were found to develop very similar immune responses with regard to induction of CD4 and CD8 T-cell polyfunctional cytokine responses, proliferative capacity and cytotoxic capacity, as measured by a standard 51 Cr release assay and more direct ex vivo and in vivo CTL assays. Hence, vaccinated animals that become infected, but control infection, appear to establish immune responses that are similar to those elicited by long-term non-progressors.
Current data suggest that prophylactic human immunodeficiency virus type 1 (HIV) vaccines will be... more Current data suggest that prophylactic human immunodeficiency virus type 1 (HIV) vaccines will be most efficacious if they elicit a combination of adaptive humoral and T-cell responses. Here, we explored the use of different vaccine strategies in heterologous prime-boost regimes and evaluated the breadth and nature of immune responses in rhesus monkeys induced by epidermally delivered plasmid DNA or recombinant HIV proteins formulated in the AS02A adjuvant system. These immunogens were administered alone or as either prime or boost in mixed-modality regimes. DNA immunization alone induced cell-mediated immune (CMI) responses, with a strong bias towards Th1-type cytokines, and no detectable antibodies to the vaccine antigens. Whenever adjuvanted protein was used as a vaccine, either alone or in a regime combined with DNA, high-titre antibody responses to all vaccine antigens were detected in addition to strong Th1-and Th2-type CMI responses. As the vaccine antigens included HIV-1 Env, Nef and Tat, as well as simian immunodeficiency virus (SIV) mac239 Nef, the animals were subsequently exposed to a heterologous, pathogenic simian-human immunodeficiency virus (SHIV) 89.6p challenge. Protection against sustained high virus load was observed to some degree in all vaccinated groups. Suppression of virus replication to levels below detection was observed most frequently in the group immunized with protein followed by DNA immunization, and similarly in the group immunized with DNA alone. Interestingly, control of virus replication was associated with increased SIV Nef-and Gag-specific gamma interferon responses observed immediately following challenge.
Influenza virus infection of non-human primates is a well-established animal model for studying p... more Influenza virus infection of non-human primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection and there is no information on relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce in humans and largely confined to evaluation of attenuated virus strains. Here we have compared the effect of a commonly used dose (4 x 10(6) TCID50) versus a hundred fold higher dose, given by intra-bronchial installation, in two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of IFNγ in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high dose group it was present at higher levels and for a longer duration. The virus specific antibody response was not significantly different between the groups. However, antibody ELISA, virus neutralization and hemaglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between level of virus production upon infection and induction of functional antibody responses against the virus. There is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or non-human primates. We showed only a marginal and variable effect of virus dose on virus production in the trachea, but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer and antibody dependent cell mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates.
In the germinal center (GC), B cells are either selected to become memory cells or are eliminated... more In the germinal center (GC), B cells are either selected to become memory cells or are eliminated through the process of programmed cell death. FDC which are intimately associated with the GC B cells are thought to be important in this selection process. Previously, we have shown that the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and VLA-4 (CD49d)-VCAM-1 (CD106) adhesion pathways are involved in FDC-B cell interaction. In the present study, we have explored whether these adhesive interactions contribute to the process of B cell selection by studying the effects on apoptosis of GC B cells. Using FDC and B cells derived from human tonsils, we found that only B cells adherent to FDC remain viable: disruption of FDC-B-cell clusters with mAb against LFA-1 alpha (CD11a), VLA-4 (CD49d), ICAM-1 (CD54), or VCAM-1 (CD106) results in apoptosis of the B cells. Furthermore, we found that GC B cells, upon adhesion to plastic-coated purified ICAM-1 (CD54) or VCAM-1 (CD106), show diminished apoptosis. Impor...
The close immunological and physiological resemblance with humans makes non-human primates a valu... more The close immunological and physiological resemblance with humans makes non-human primates a valuable model for studying influenza virus pathogenesis and immunity and vaccine efficacy against infection. Although both cynomolgus and rhesus macaques are frequently used in influenza virus research, a direct comparison of susceptibility to infection and disease has not yet been performed. In the current study a head-to-head comparison was made between these species, by using a recently described swine-origin pandemic H1N1 strain, A/Mexico/InDRE4487/2009. In comparison to rhesus macaques, cynomolgus macaques developed significantly higher levels of virus replication in the upper airways and in the lungs, involving both peak level and duration of virus production, as well as higher increases in body temperature. In contrast, clinical symptoms, including respiratory distress, were more easily observed in rhesus macaques. Expression of sialyl-α-2,6-Gal saccharides, the main receptor for hum...
Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that medi... more Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that mediates lymphocyte migration to the intestinal mucosa by binding to MAdCAM-1, a vascular recognition molecule (addressin) selectively expressed on mucosal endothelium. In the present study, we have assessed the expression of alpha 4 beta 7 on B- and T-cell non-Hodgkin's lymphomas of different primary localization and on related normal lymphocytes. Among B-lineage lymphomas, expression of alpha 4 beta 7 was present in the majority of cases of malignant lymphomatous polyposis of the intestine and low-grade lymphoma of the mucosa-associated lymphoid tissue/monocytoid B-cell lymphoma and in some cases of precursor B-cell lymphoma. CLL/small lymphocytic lymphoma, (nodal) mantle cell lymphoma, follicular center cell lymphoma, Burkitt's lymphoma, and diffuse large B-cell lymphoma were virtually always alpha 4 beta 7 negative, as was the case when localized in the mucosa-associated lymphoid...
Tubular cells are important targets during acute renal allograft rejection and induction of apopt... more Tubular cells are important targets during acute renal allograft rejection and induction of apoptosis might be a mechanism of tubular cell destruction. Susceptibility to induction of apoptosis is regulated by the homologous Bcl-2 and Bax proteins. Expression of Bcl-2 and Bax is regulated by p53, which down-regulates expression of Bcl-2, while simultaneously up-regulating expression of Bax. We studied apoptotic tubular cell death in 10 renal allograft biopsies from transplant recipients with acute rejection by in situ end-labelling and the DNA-binding fluorochrome propidium iodide. Tubular expression of p53, Bcl-2 and Bax was studies by immunohistochemistry. Five renal allograft biopsies from transplant recipients with uncomplicated clinical course and histologically normal renal tissue present in nephrectomy specimens from 4 patients with renal adenocarcinoma served as control specimens. Apoptotic cells and apoptotic bodies were detected in tubular epithelia and tubular lumina in 9 ...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1994
In the germinal center (GC), B cells are either selected to become memory cells or are eliminated... more In the germinal center (GC), B cells are either selected to become memory cells or are eliminated through the process of programmed cell death. FDC which are intimately associated with the GC B cells are thought to be important in this selection process. Previously, we have shown that the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and VLA-4 (CD49d)-VCAM-1 (CD106) adhesion pathways are involved in FDC-B cell interaction. In the present study, we have explored whether these adhesive interactions contribute to the process of B cell selection by studying the effects on apoptosis of GC B cells. Using FDC and B cells derived from human tonsils, we found that only B cells adherent to FDC remain viable: disruption of FDC-B-cell clusters with mAb against LFA-1 alpha (CD11a), VLA-4 (CD49d), ICAM-1 (CD54), or VCAM-1 (CD106) results in apoptosis of the B cells. Furthermore, we found that GC B cells, upon adhesion to plastic-coated purified ICAM-1 (CD54) or VCAM-1 (CD106), show diminished apoptosis. Impor...
A recently described splice variant of CD44 has been shown to confer metastatic potential to non-... more A recently described splice variant of CD44 has been shown to confer metastatic potential to non-metastasizing rat pancreatic carcinoma and sarcoma cell lines. Using antibodies raised against a bacterial fusion protein encoded by variant CD44 sequences, we have explored the expression of variant CD44 glycoproteins in human lymphoid cells and tissues, in non-Hodgkin's lymphomas, and in colorectal neoplasia. Normal lymphohematopoietic cells express barely detectable low levels of variant CD44 glycoproteins, while T lymphocytes, upon activation by mitogen or antigen, transiently upregulate expression of specific CD44 variant glycoproteins. The reaction pattern of various antibodies indicates that these CD44 variants contain the domain encoded by exon v6, which is part of the variant that in the rat confers metastatic capability. Interestingly, overexpression of v6 was also found in several aggressive, but not in low-grade, non-Hodgkin's lymphomas (NHL). In human colorectal neop...
The K88ab adhesin operon of Escherichia coli encodes for a fimbrial protein (the K88ab adhesin) w... more The K88ab adhesin operon of Escherichia coli encodes for a fimbrial protein (the K88ab adhesin) which is involved in colonization of the porcine intestine. We characterized a structural gene (gene A) which is part of the K88ab adhesin operon and codes for an as yet unidentified polypeptide (pA). A mutation in gene A resulted in accumulation of K88ab adhesin subunits inside the cell. The nucleotide sequence of gene A was determined, and the deduced amino acid sequence suggested that pA is synthesized as a precursor containing a typical N-terminal signal peptide. The molecular weight of pA was calculated to be ca. 17,600. Gene A is preceded by a sequence showing homology with the consensus promoter. Fimbrial subunits from a number of E. coli strains have significant homology at their N- and C-termini. pA also contained some of these conserved sequences and showed a number of other similarities with fimbrial subunits. Therefore, it seems likely that the K88ab adhesin operon codes for a...
Virchows Archiv. B, Cell pathology including molecular pathology, 1985
The aim of the present study was to compare the effects of LPS on the cellular composition of the... more The aim of the present study was to compare the effects of LPS on the cellular composition of the splenic white pulp in responder C3H/He and non-responder C3H/HeJ mice. The present results show that an intravenous injection of LPS in C3H/He mice results in a number of prominent changes in the histology of the spleen, but none of these histological changes could be demonstrated in the unresponsive C3H/HeJ mice. However, the present study shows that LPS administration resulted in the disappearance of previously trapped immune complexes from the follicles in both responder C3H/He and non-responder C3H/HeJ mice. The significance of this phenomenon is discussed. The localization of intravenously injected LPS in both mouse strains was compared using an immunoperoxidase technique. Most of the injected LPS was taken up by marginal zone macrophages at 2 h after administration. No major differences could be detected in the localization pattern of LPS between C3H/He and C3H/HeJ mice. The prese...
The Thai trial (RV144) indicates that a prime/boost vaccine combination that induces both T-cell ... more The Thai trial (RV144) indicates that a prime/boost vaccine combination that induces both T-cell and antibody responses may be desirable for an effective HIV vaccine. We have previously shown that immunisation with synthetic long peptides (SLP), covering the conserved parts of SIV, induced strong CD4 T-cell and antibody responses, but only modest CD8 T-cell responses. To generate a more balanced CD4/CD8 T-cell and antibody response, this study evaluated a pox-vector prime/SLP boost strategy in rhesus macaques. Priming with a replication competent NYVAC, encoding HIV-1 clade C gag, pol, nef, induced modest IFNγ T-cell immune responses, predominantly directed against HIV-1 gag. Booster immunization with SLP, covering the conserved parts of HIV-1 gag, pol, env, resulted in a more than 10 fold increase in IFNγ ELISpot responses in 4 of 6 animals, which were predominantly HIV-1 Pol-specific. The animals showed a balanced polyfunctional CD4 and CD8 T-cell response and high Ab titers.
The SAGE Handbook of Research in International Education
The study of teacher–student relationships is crucial to the improvement of all education, whethe... more The study of teacher–student relationships is crucial to the improvement of all education, whether international or national. Such a focus can have an immediate positive impact on classroom instruction and student learning, as well as on teacher education and research. This chapter presents a model for understanding such relationships in terms of the perceptions that students (and occasionally teachers) have of teachers' interpersonal behaviour. It focuses on corresponding research on teachers' interactions with students in ...
Tubular cells are important targets during acute renal allograft rejection and induction of apopt... more Tubular cells are important targets during acute renal allograft rejection and induction of apoptosis might be a mechanism of tubular cell destruction. Susceptibility to induction of apoptosis is regulated by the homologous Bcl-2 and Bax proteins. Expression of Bcl-2 and Bax is regulated by p53, which down-regulates expression of Bcl-2, while simultaneously up-regulating expression of Bax. We studied apoptotic tubular cell death in 10 renal allograft biopsies from transplant recipients with acute rejection by in situ end-labelling and the DNA-binding fluorochrome propidium iodide. Tubular expression of p53, Bcl-2 and Bax was studies by immunohistochemistry. Five renal allograft biopsies from transplant recipients with uncomplicated clinical course and histologically normal renal tissue present in nephrectomy specimens from 4 patients with renal adenocarcinoma served as control specimens. Apoptotic cells and apoptotic bodies were detected in tubular epithelia and tubular lumina in 9 out of 10 acute rejection biopsies. In control renal tissue, apoptotic cells were detected in 1 biopsy only. Compared to control renal tissue, acute renal allograft rejection was, furthermore, associated with a shift in the ratio of Bcl-2 to Bax in favour of Bax in tubular epithelia and increased expression of p53 in tubular nuclei. These observations demonstrate that apoptosis contributes in part to tubular cell destruction during acute renal allograft rejection. In accordance, the shift in the ratio of Bcl-2 to Bax in favour of Bax indicates increased susceptibility of tubular epithelia to induction of apoptosis. The expression of p53 in tubular nuclei during acute renal allograft rejection indicates the presence of damaged DNA, which can be important in initiation of part of the observed apoptosis. These findings elucidate part of the mechanisms controlling apoptotic tubular cell death during acute renal allograft rejection.
HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumula... more HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumulation of an ''anergic'' CD56 À CD16 1 NK subset, which is characterised by low natural cytotoxicity receptor expression and low cytokine producing capacity. In contrast to humans, chimpanzee NK cells do not display a distinguishable CD56 bright and CD56 dim subset but, as shown here, could be subdivided into functionally different CD8 1 and CD8 À subsets. The CD8 1 NK cells expressed significantly higher levels of triggering receptors including NKp46 and, upon in vitro activation, produced more IFN-c, TNF-a and CD107 than their CD8 À counterparts. In addition, chimpanzee CD8 À NK cells had relatively high levels of HLA-DR expression, suggestive of an activated state. Killing inhibitory receptors were expressed only at low levels; however, upon in vitro stimulation, they were upregulated in CD8 1 but not in CD8 À NK cells and were functionally capable of inhibiting NKp30-triggered killing. In contrast to HIV-1-infected humans, infected chimpanzees maintained their dominant CD8 1 NK cell population, with high expression of natural cytotoxicity receptors.
Virchows Archiv B Cell Pathology Including Molecular Pathology, 1985
The aim of the present study was to compare the effects of LPS on the cellular composition of the... more The aim of the present study was to compare the effects of LPS on the cellular composition of the splenic white pulp in responder C3H/He and non-responder C3H/HeJ mice. The present results show that an intravenous injection of LPS in C3H/He mice results in a number of prominent changes in the histology of the spleen, but none of these histological changes could be demonstrated in the unresponsive C3H/ HeJ mice. However, the present study shows that LPS administration resulted in the disappearance of previously trapped immune complexes from the follicles in both responder C3H/He and non-responder C3H/ HeJ mice. The significance of this phenomenon is discussed.
Members of the Tumour Necrosis Factor-Receptor (TNFR) family play an essential role in the contro... more Members of the Tumour Necrosis Factor-Receptor (TNFR) family play an essential role in the control of lymphoid cell growth and differentiation. The ligand of one of its lymphoid-specific members, CD27, was recently characterized as CD70, a type II transmembrane molecule with homology to TNF that is expressed on activated T and B cells. Ligation of CD27 by its natural ligand generates a potent costimulatory signal for cytokine production and proliferation of activated T cells. In contrast to normal B cells, where CD27 expression is confined to germinal centre cells and to a small subset of circulating B lymphocytes, CD27 expression is found on a large array of distinct B-cell neoplasia. Here, we review recent data on the expression and function of TNFR family members on normal and malignant lymphocytes and propose a role for CD27-CD70 interaction in B-cell development.
The effects of several preparations of Iscador, a commercially obtainable extract of mistletoe, V... more The effects of several preparations of Iscador, a commercially obtainable extract of mistletoe, Viscum album L., on cell proliferation and cell viability was studied. Iscador Quercus was shown to inhibit cell proliferation of: human fibroblast cell lines, mouse tumour cell lines, human carcinoma tumour cell lines and a human lymphoblastic tumour cell line. Iscador Quercus, Iscador Ulnus and Iscador Malus were about equally cytostatic to mouse 3T3 fibroblasts. Iscador Pinus was somewhat less cytostatic. Iscador Quercus had a very direct cytotoxic effect on MOLT 4 tumour cells as assessed by trypan blue dye exclusion. The cytostatic and cytotoxic properties of Iscador could be annulled by heating Iscador for 30 min. at 90~ Iscador reduced the cloning efficiency of ASG and CHO cells in a dose-and time-dependent manner. From the cloning efficiency experiments it can be concluded that a small percentage of CHO cells is insensitive to high concentrations of Iscador at short incubation times.
Recent advances in human immunodeficiency virus (HIV) vaccine design have resulted in induction o... more Recent advances in human immunodeficiency virus (HIV) vaccine design have resulted in induction of strong CD4 T-cell proliferative and polyfunctional cytokine responses, which are also characteristic for long-term non-progressing (LTNP) HIV-infected individuals. However, limited information is available on the persistence of these responses after infection. Results from studies in non-human primates indicate that vaccine-induced immune responses are partially maintained upon viral infection and differ from the responses seen in non-vaccinated animals that typically progress to disease. However, it is unclear how these partially preserved responses compare to immune responses that are acquired naturally by LTNP animals. In this study, immune-response profiles were compared between vaccinated animals that, upon SHIV 89.6p challenge, became infected but were able to control virus replication, and a group of animals having spontaneous control of this viral infection. Both groups were found to develop very similar immune responses with regard to induction of CD4 and CD8 T-cell polyfunctional cytokine responses, proliferative capacity and cytotoxic capacity, as measured by a standard 51 Cr release assay and more direct ex vivo and in vivo CTL assays. Hence, vaccinated animals that become infected, but control infection, appear to establish immune responses that are similar to those elicited by long-term non-progressors.
Current data suggest that prophylactic human immunodeficiency virus type 1 (HIV) vaccines will be... more Current data suggest that prophylactic human immunodeficiency virus type 1 (HIV) vaccines will be most efficacious if they elicit a combination of adaptive humoral and T-cell responses. Here, we explored the use of different vaccine strategies in heterologous prime-boost regimes and evaluated the breadth and nature of immune responses in rhesus monkeys induced by epidermally delivered plasmid DNA or recombinant HIV proteins formulated in the AS02A adjuvant system. These immunogens were administered alone or as either prime or boost in mixed-modality regimes. DNA immunization alone induced cell-mediated immune (CMI) responses, with a strong bias towards Th1-type cytokines, and no detectable antibodies to the vaccine antigens. Whenever adjuvanted protein was used as a vaccine, either alone or in a regime combined with DNA, high-titre antibody responses to all vaccine antigens were detected in addition to strong Th1-and Th2-type CMI responses. As the vaccine antigens included HIV-1 Env, Nef and Tat, as well as simian immunodeficiency virus (SIV) mac239 Nef, the animals were subsequently exposed to a heterologous, pathogenic simian-human immunodeficiency virus (SHIV) 89.6p challenge. Protection against sustained high virus load was observed to some degree in all vaccinated groups. Suppression of virus replication to levels below detection was observed most frequently in the group immunized with protein followed by DNA immunization, and similarly in the group immunized with DNA alone. Interestingly, control of virus replication was associated with increased SIV Nef-and Gag-specific gamma interferon responses observed immediately following challenge.
Influenza virus infection of non-human primates is a well-established animal model for studying p... more Influenza virus infection of non-human primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection and there is no information on relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce in humans and largely confined to evaluation of attenuated virus strains. Here we have compared the effect of a commonly used dose (4 x 10(6) TCID50) versus a hundred fold higher dose, given by intra-bronchial installation, in two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of IFNγ in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high dose group it was present at higher levels and for a longer duration. The virus specific antibody response was not significantly different between the groups. However, antibody ELISA, virus neutralization and hemaglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between level of virus production upon infection and induction of functional antibody responses against the virus. There is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or non-human primates. We showed only a marginal and variable effect of virus dose on virus production in the trachea, but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer and antibody dependent cell mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates.
In the germinal center (GC), B cells are either selected to become memory cells or are eliminated... more In the germinal center (GC), B cells are either selected to become memory cells or are eliminated through the process of programmed cell death. FDC which are intimately associated with the GC B cells are thought to be important in this selection process. Previously, we have shown that the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and VLA-4 (CD49d)-VCAM-1 (CD106) adhesion pathways are involved in FDC-B cell interaction. In the present study, we have explored whether these adhesive interactions contribute to the process of B cell selection by studying the effects on apoptosis of GC B cells. Using FDC and B cells derived from human tonsils, we found that only B cells adherent to FDC remain viable: disruption of FDC-B-cell clusters with mAb against LFA-1 alpha (CD11a), VLA-4 (CD49d), ICAM-1 (CD54), or VCAM-1 (CD106) results in apoptosis of the B cells. Furthermore, we found that GC B cells, upon adhesion to plastic-coated purified ICAM-1 (CD54) or VCAM-1 (CD106), show diminished apoptosis. Impor...
The close immunological and physiological resemblance with humans makes non-human primates a valu... more The close immunological and physiological resemblance with humans makes non-human primates a valuable model for studying influenza virus pathogenesis and immunity and vaccine efficacy against infection. Although both cynomolgus and rhesus macaques are frequently used in influenza virus research, a direct comparison of susceptibility to infection and disease has not yet been performed. In the current study a head-to-head comparison was made between these species, by using a recently described swine-origin pandemic H1N1 strain, A/Mexico/InDRE4487/2009. In comparison to rhesus macaques, cynomolgus macaques developed significantly higher levels of virus replication in the upper airways and in the lungs, involving both peak level and duration of virus production, as well as higher increases in body temperature. In contrast, clinical symptoms, including respiratory distress, were more easily observed in rhesus macaques. Expression of sialyl-α-2,6-Gal saccharides, the main receptor for hum...
Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that medi... more Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that mediates lymphocyte migration to the intestinal mucosa by binding to MAdCAM-1, a vascular recognition molecule (addressin) selectively expressed on mucosal endothelium. In the present study, we have assessed the expression of alpha 4 beta 7 on B- and T-cell non-Hodgkin's lymphomas of different primary localization and on related normal lymphocytes. Among B-lineage lymphomas, expression of alpha 4 beta 7 was present in the majority of cases of malignant lymphomatous polyposis of the intestine and low-grade lymphoma of the mucosa-associated lymphoid tissue/monocytoid B-cell lymphoma and in some cases of precursor B-cell lymphoma. CLL/small lymphocytic lymphoma, (nodal) mantle cell lymphoma, follicular center cell lymphoma, Burkitt's lymphoma, and diffuse large B-cell lymphoma were virtually always alpha 4 beta 7 negative, as was the case when localized in the mucosa-associated lymphoid...
Tubular cells are important targets during acute renal allograft rejection and induction of apopt... more Tubular cells are important targets during acute renal allograft rejection and induction of apoptosis might be a mechanism of tubular cell destruction. Susceptibility to induction of apoptosis is regulated by the homologous Bcl-2 and Bax proteins. Expression of Bcl-2 and Bax is regulated by p53, which down-regulates expression of Bcl-2, while simultaneously up-regulating expression of Bax. We studied apoptotic tubular cell death in 10 renal allograft biopsies from transplant recipients with acute rejection by in situ end-labelling and the DNA-binding fluorochrome propidium iodide. Tubular expression of p53, Bcl-2 and Bax was studies by immunohistochemistry. Five renal allograft biopsies from transplant recipients with uncomplicated clinical course and histologically normal renal tissue present in nephrectomy specimens from 4 patients with renal adenocarcinoma served as control specimens. Apoptotic cells and apoptotic bodies were detected in tubular epithelia and tubular lumina in 9 ...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1994
In the germinal center (GC), B cells are either selected to become memory cells or are eliminated... more In the germinal center (GC), B cells are either selected to become memory cells or are eliminated through the process of programmed cell death. FDC which are intimately associated with the GC B cells are thought to be important in this selection process. Previously, we have shown that the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and VLA-4 (CD49d)-VCAM-1 (CD106) adhesion pathways are involved in FDC-B cell interaction. In the present study, we have explored whether these adhesive interactions contribute to the process of B cell selection by studying the effects on apoptosis of GC B cells. Using FDC and B cells derived from human tonsils, we found that only B cells adherent to FDC remain viable: disruption of FDC-B-cell clusters with mAb against LFA-1 alpha (CD11a), VLA-4 (CD49d), ICAM-1 (CD54), or VCAM-1 (CD106) results in apoptosis of the B cells. Furthermore, we found that GC B cells, upon adhesion to plastic-coated purified ICAM-1 (CD54) or VCAM-1 (CD106), show diminished apoptosis. Impor...
A recently described splice variant of CD44 has been shown to confer metastatic potential to non-... more A recently described splice variant of CD44 has been shown to confer metastatic potential to non-metastasizing rat pancreatic carcinoma and sarcoma cell lines. Using antibodies raised against a bacterial fusion protein encoded by variant CD44 sequences, we have explored the expression of variant CD44 glycoproteins in human lymphoid cells and tissues, in non-Hodgkin's lymphomas, and in colorectal neoplasia. Normal lymphohematopoietic cells express barely detectable low levels of variant CD44 glycoproteins, while T lymphocytes, upon activation by mitogen or antigen, transiently upregulate expression of specific CD44 variant glycoproteins. The reaction pattern of various antibodies indicates that these CD44 variants contain the domain encoded by exon v6, which is part of the variant that in the rat confers metastatic capability. Interestingly, overexpression of v6 was also found in several aggressive, but not in low-grade, non-Hodgkin's lymphomas (NHL). In human colorectal neop...
The K88ab adhesin operon of Escherichia coli encodes for a fimbrial protein (the K88ab adhesin) w... more The K88ab adhesin operon of Escherichia coli encodes for a fimbrial protein (the K88ab adhesin) which is involved in colonization of the porcine intestine. We characterized a structural gene (gene A) which is part of the K88ab adhesin operon and codes for an as yet unidentified polypeptide (pA). A mutation in gene A resulted in accumulation of K88ab adhesin subunits inside the cell. The nucleotide sequence of gene A was determined, and the deduced amino acid sequence suggested that pA is synthesized as a precursor containing a typical N-terminal signal peptide. The molecular weight of pA was calculated to be ca. 17,600. Gene A is preceded by a sequence showing homology with the consensus promoter. Fimbrial subunits from a number of E. coli strains have significant homology at their N- and C-termini. pA also contained some of these conserved sequences and showed a number of other similarities with fimbrial subunits. Therefore, it seems likely that the K88ab adhesin operon codes for a...
Virchows Archiv. B, Cell pathology including molecular pathology, 1985
The aim of the present study was to compare the effects of LPS on the cellular composition of the... more The aim of the present study was to compare the effects of LPS on the cellular composition of the splenic white pulp in responder C3H/He and non-responder C3H/HeJ mice. The present results show that an intravenous injection of LPS in C3H/He mice results in a number of prominent changes in the histology of the spleen, but none of these histological changes could be demonstrated in the unresponsive C3H/HeJ mice. However, the present study shows that LPS administration resulted in the disappearance of previously trapped immune complexes from the follicles in both responder C3H/He and non-responder C3H/HeJ mice. The significance of this phenomenon is discussed. The localization of intravenously injected LPS in both mouse strains was compared using an immunoperoxidase technique. Most of the injected LPS was taken up by marginal zone macrophages at 2 h after administration. No major differences could be detected in the localization pattern of LPS between C3H/He and C3H/HeJ mice. The prese...
The Thai trial (RV144) indicates that a prime/boost vaccine combination that induces both T-cell ... more The Thai trial (RV144) indicates that a prime/boost vaccine combination that induces both T-cell and antibody responses may be desirable for an effective HIV vaccine. We have previously shown that immunisation with synthetic long peptides (SLP), covering the conserved parts of SIV, induced strong CD4 T-cell and antibody responses, but only modest CD8 T-cell responses. To generate a more balanced CD4/CD8 T-cell and antibody response, this study evaluated a pox-vector prime/SLP boost strategy in rhesus macaques. Priming with a replication competent NYVAC, encoding HIV-1 clade C gag, pol, nef, induced modest IFNγ T-cell immune responses, predominantly directed against HIV-1 gag. Booster immunization with SLP, covering the conserved parts of HIV-1 gag, pol, env, resulted in a more than 10 fold increase in IFNγ ELISpot responses in 4 of 6 animals, which were predominantly HIV-1 Pol-specific. The animals showed a balanced polyfunctional CD4 and CD8 T-cell response and high Ab titers.
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Papers by Gerrit Koopman