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Biomedical subjects

R Q Hintzen

Publications and source records attributed to R Q Hintzen.

At least 19 recordsLinked to original sources
PubMed1996

Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies.

Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.

Adult↗
PubMed1996

Expression of the activation antigen CD27 in rheumatoid arthritis.

Differentiation of CD4+ T-cells is reflected by the change from the CD45RA+CD27+ phenotype via CD45RO+CD27+ to the CD45RO+CD27- phenotype. To provide insight into the migration and activation of T-cells at the site of inflammation in rheumatoid arthritis (RA), CD27 expression by T-cells in peripheral blood (PB), synovial fluid (SF), and synovial tissue (ST) as well as the levels of the soluble form of CD27 (sCD27) in plasma and SF were studied in patients with RA. Since CD4+CD27+ T-cells are involved in providing helper activity for B-cells, we also investigated the levels of rheumatoid factors in serum and SF in relation to CD27 expression. The mean level of sCD27, which is produced by CD27+ cells, and the mean percentage of CD27 T-cells within the CD4+CD45RA- subset were higher in SF than in PB. SF sCD27 levels were higher in the patients with RA than in the patients with osteoarthritis, who served as controls. In ST infiltration by CD4+CD45RO+CD27+ T-cells, could be demonstrated in the rheumatoid perivascular lymphocytic aggregates with a relative increase in the percentage of CD27- T-cells in the diffuse lymphocytic infiltrate. The sCD27 levels and the percentages of CD4+CD27+ cells in SF correlated positively with the levels of rheumatoid factors in serum and SF. The findings presented in this study suggest a continuous influx of preactivated CD4+CD45RO+CD27+ cells from the PB into the rheumatoid ST and further activation and differentiation to CD4+CD45RO+CD27- cells in situ, followed by migration to the SF. These activated T-cells are likely to play a role in synovial inflammation.

Adult↗
PubMed1996

Recombinant interferon-beta blocks proliferation but enhances interleukin-10 secretion by activated human T-cells.

Results from recent clinical trials have indicated that recombinant interferon-beta (rIFN-beta) is a promising drug for the treatment of Multiple Sclerosis (MS), a disease of supposed autoimmune etiology. To gain insight into the immunoregulatory properties of this cytokine, we analyzed effects of interferon-beta (IFN-beta) on T-cell functions in vitro. Interferon-beta inhibited T-cell proliferation, as well as T-cell-dependent immunoglobulin secretion, in a dose-dependent manner. IFN-beta did not inhibit upregulations of CD40L on activated T-cells, but blocked induction of CD25 on stimulated T- and B-lymphocytes. Secretion of interferon-gamma (IFN-gamma), tumour necrosis alpha (TNF-alpha) and IL-13 was inhibited by the addition of IFN-beta, whereas IL-4 secretion was unaffected. Interestingly, IFN-beta enhanced secretion of IL-2 about two-fold and secretion of IL-10 nearly four-fold. In summary, these findings suggest that IFN-beta may exert direct effects on T- and beta-cell function in vivo. In addition, enhanced secretion of IL-10 by activated T-cells may interfere with newly initiated and ongoing inflammatory immune reactions.

B-Lymphocytes↗
PubMed1995

Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation.

Molecules of the TNF-R family have been shown to be essential in the regulation of lymphocyte growth and differentiation. The TNF-R family member CD27 binds to a type II transmembrane molecule belonging to the TNF gene family (CD27L) that is identical to the lymphocyte activation Ag CD70. Using transfected mouse fibroblasts expressing human CD70, we demonstrate here that interaction of CD27 with its ligand provides a potent second signal for cytokine production, induction of activation Ags, and proliferation of unprimed CD45RA+, and to a lesser extent, of primed CD45R0+ peripheral blood T cells. In contrast to costimulatory signals delivered via the CD28-ligand B7-1 (CD80), CD70 was found to induce relatively low IL-2, IL-4, and IL-10 but comparable TNF-alpha secretion. Proliferation of CD45RA+, but not of CD45R0+ T cells, was found to be largely resistant to blocking of IL-2/IL-2R interaction. Finally, the finding that CD70 and CD80 cooperate in the induction of T cell proliferation indicates that cooperation of both molecules may be essential for optimal T cell stimulation. The interaction between CD27 and its ligand CD70 might be of particular importance for the recruitment of T cells from the unprimed T cell pool. Moreover, as CD70 expression in vivo is confined to activated B and T lymphocytes, only a limited set of APC are able to generate this specific second signal for T cell expansion.

Antibodies, Monoclonal↗
PubMed1995

Serum levels of soluble forms of T cell activation antigens CD27 and CD25 in systemic lupus erythematosus in relation with lymphocytes count and disease course.

Systemic lupus erythematosus (SLE) patients are characterized by a low lymphocyte count, which is considered a specific disease marker and is related to disease activity. The membrane bound molecules CD25 and CD27 are expressed and released in a soluble CD25 (sCD25) and soluble CD27 (sCD27) form by activation of predominantly T cells. In previous studies it was claimed that sCD25 as well sCD27 might be used as parameters for activation of the immune system; a correlation between the sCD25 profile with the disease course in SLE patients was also shown. To assess the relationship between lymphocyte count and these T cell activation markers, we performed a cross-sectional and a longitudinal study. In the longitudinal study three SLE patients who were known for a long time at our outpatient clinic were studied. Both T cell markers strongly correlated with each other and formed a reflection of the disease course. In all 7 periods of exacerbation, which we observed in the 3 investigated patients, both levels increased preceding this period; however, no correlation was found with the lymphocyte count. In the cross sectional study of 69 patients with SLE, sCD25 and sCD27 levels were correlated with defined disease manifestations; sCD25 was elevated in all periods of increased disease activity. The same holds true for sCD27, with the exception of patients with nephritis in which the highest levels were observed. Both profiles of sCD25 and sCD27 were strongly correlated during the whole disease course. Our data prove that in the pathogenesis of SLE an active recruitement of unprimed and primed T cells takes place.

Adult↗
PubMed1995

Analysis of CD27 surface expression on T cell subsets in MS patients and control individuals.

Within the peripheral blood, CD4+CD27- T cells only reside within the CD45RA- (memory or primed) T cell subset. Cells with this phenotype have characteristics of specialized effector T cells according to their cytokine secretion profiles and the expression of tissue-specific adhesion molecules. This subset was previously found to be increased in certain diseases that are associated with immune activation. Therefore we analyzed CD27 expression of peripheral blood and CSF T cells in MS patients. Within the CD4+ T cell subset no differences were seen between MS patients and controls in proportions of CD45RA-CD27- cells. However, when the CD3+ T cell compartment was analyzed, CD27- cells were also found within the CD45RA+ subset. These cells, most likely CD8+, are significantly reduced in PBL and CSF of MS patients as compared with OND patients. In MS and OND groups the level of CD27- cells in peripheral blood correlated significantly with that in CSF, indicating a balanced migration of CD27- cells between the two compartments. In OIND patients, however, this equilibrium was lost. The correlation of the level of CD27+ cells with the amount of intrathecally produced IgG in MS patients may suggest that CD27+ cells are responsible for B cell help in this disease.

Adult↗
PubMed1995

CD27-CD70 interaction: unravelling its implication in normal and neoplastic B-cell growth.

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.

Antigens, CD↗
PubMed1994

Characterization of the human CD27 ligand, a novel member of the TNF gene family.

CD27 is a lymphocyte-specific member of the TNF/NGF-R family that is highly induced on T cells after TCR stimulation, primarily on lymphocytes belonging to the unprimed CD45RA+ subset. However, after prolonged activation both in vivo and in vitro, CD27 expression is gradually switched off. In search of physiologic signals that influence CD27 expression, we found that B cell lines can mediate down-regulation of CD27 surface expression on activated T cells via direct cell-to-cell contact and that preincubation of activated T cells with CD27 mAbs prevented this modulation. Based on these observations, we hypothesized that a ligand for CD27L is expressed on B cell lines and that ligand interaction would result in down-modulation of the molecule from the T cell surface. To identify this putative CD27L, mAbs were raised against the Burkitt cell line Ramos and screened for their ability to block down-modulation of CD27 on activated T cells. Using this approach, we isolated a mAb, designated 2F2, that inhibits CD27 down-regulation in a dose-dependent manner. We demonstrate that this mAb recognizes CD27L as it 1) reacted to mouse fibroblasts expressing the recently cloned CD27L, a novel surface-expressed member of the TNF gene family, and 2) prevented binding of a soluble CD27-Fc construct to a CD27L expressing cell line. Down-regulation of CD27 from the T cell surface by recombinant CD27L was shown to be at least partially caused by release of soluble CD27. The 2F2 mAb enabled us to begin to analyze the biochemical properties, tissue distribution, and function of the CD27L on human cells. From cell lysates of 125I surface-labeled Burkitt cells a complex immunoprecipitation pattern with dominant bands of 29, 55, and 122 to 127 kDa was obtained using the 2F2 mAb. Phenotypical analyses showed that freshly isolated lymphocytes lacked CD27L expression, but that expression of the molecule could be induced after in vitro stimulation of T and B cells. No expression was found on cells of the myeloid lineage or on endothelial cells. Finally, blocking of naturally expressed CD27L by the 2F2 mAb exerted a potent inhibitory effect on the proliferation of T cells in response to allogeneic B cells and PHA. The data presented in this paper identify CD27 and its ligand as potentially important structures involved in cellular interactions between T and B lymphocytes.

Animals↗
PubMed1994

Functional defects in peripheral blood T cells of multiple sclerosis patients. Diminished in vitro responsiveness in accessory cell dependent activation systems.

Function and phenotype of peripheral blood (PB) T cells in multiple sclerosis (MS) patients were analyzed. In whole blood cultures, T cell proliferation of multiple sclerosis (MS) patients, using soluble CD3 mAb and CD2 mAb as stimulants, was reduced in comparison to healthy controls. A similar difference was seen when isolated PBMC were tested after stimulation with soluble CD3 mAb. However, in accessory cell-independent activation systems, i.e. after stimulation of PBMC with immobilized CD3 mAb or after co-stimulation with CD28 mAb, both patients and controls responded equally well. Phenotypical analysis of the circulating T cell population showed that there were no differences in the percentage of CD26+, 'memory' (CD45R0+) or 'effector' (CD4+CD45R0+CD27-) cells between MS patients and healthy controls. Finally, although MS patients did show an enhanced proportion of 'naive' (CD4+CD45RA+) T cells, this did not correlate with the observed functional defects.

Adult↗
PubMed1994

CD27: marker and mediator of T-cell activation?

CD27 is a lymphocyte-specific member of the tumour necrosis factor receptor (TNF-R) family, expression of which is tightly regulated during T-cell ontogeny. Recently, the ligand for CD27 was identified and was shown to be identical to CD70, a novel member of the TNF family. Functional experiments show that the interaction between CD27 and its ligand generates a co-stimulatory signal for T-cell activation. Here, Rogier Hintzen and colleagues integrate the phenotypic and functional data available on CD27 and its ligand, and propose a role for CD27 in the amplification of T-cell responses.

Animals↗
PubMed1994

CD70 represents the human ligand for CD27.

The recently identified CD27 ligand (L) is a type II transmembrane molecule with significant structural homology to tumor necrosis factor (TNF)-alpha, TNF-beta, lymphotoxin beta, CD40L, and CD30L. Using a CD27L specific mAb we examined the tissue distribution of the molecule, and found its expression to be restricted to B cells in occasional germinal centers, stromal cells in the thymic medulla, and scattered T cells in tonsils, skin and gut. As the limited expression of CD27L closely resembled the reported distribution of the activation antigen CD70, we tested whether CD70 represents the human CD27L. CD70 mAb were found to react with CD27L-expressing transfected mouse fibroblasts. Moreover a number of CD70 mAb could specifically interfere with the cellular binding of CD27L mAb. Thus, CD70 is identical to the human CD27L.

Antigens, CD↗
PubMed1993

Expression and release of CD27 in human B-cell malignancies.

CD27, a transmembrane disulfide-linked 55-kD homodimer, belongs to the nerve growth factor-receptor family, a group of homologous molecules involved in lymphocyte differentiation and selection. It is expressed on mature thymocytes, peripheral blood T cells, and a subpopulation of B cells. We investigated the expression of CD27 on malignant B cells representative for a broad range of stages in physiologic antigen-independent and -dependent B-cell development. In normal lymphoid tissue CD27+ B cells were only found in the peripheral blood (29.8% +/- 10.8%, n = 13) and in germinal centers. With the exception of pro-B and the majority of pre-pre-B acute lymphocytic leukemias and of myelomas, CD27 expression of variable intensity was detected on almost all immature and mature malignant B cells tested. Moreover, using a sandwich enzyme-linked immunosorbent assay we could show the presence of sometimes very high (up to 6,000 U/mL; normal values < 190 U/mL) amounts of the soluble 28- to 32-kD form of CD27 (sCD27) in the sera of patients with B-cell malignancies. The highest levels of sCD27 were observed in patients with chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. Most importantly, both in transversal and longitudinal studies, we found a strong correlation between sCD27 levels in the serum and tumor load, indicating that sCD27 can be used as a disease-marker in patients with acute and chronic B-cell malignancies.

B-Lymphocytes↗
PubMed1993

Regulation of CD27 expression on subsets of mature T-lymphocytes.

CD27, a lymphocyte-specific member of the TNF/NGF-R family, is expressed on the majority of peripheral blood T cells. Activation of T cells via TCR/CD3 induces high CD27 surface expression and the release of a soluble extracellular part of the molecule. After prolonged activation in vitro, CD27 becomes gradually switched off. There is evidence that also in vivo, CD4+ cells that have persistently been stimulated by Ag, accumulate within the CD45RA-CD27- subset. In addition, an increase of CD27- T cells has been observed under certain immunopathologic conditions and during aging. This study was undertaken to analyze the regulation of CD27 on different T-cell subsets and to determine whether the loss of CD27 expression is an irreversible event and may thereby mark T-cell differentiation. In agreement with earlier findings, all CD4+CD45RA+CD45RO- T cells were found to express CD27, whereas a small fraction of the CD4+CD45RA-CD45RO+ subset lacks the molecule. In contrast, within the CD8+ compartment CD27- subsets were found both in the CD45RA+ and CD45RA- subpopulations. After stimulation with CD3 mAb, both CD27 membrane expression and release was equally up-regulated in CD4+ and CD8+ subpopulations. This stimulus, however, provoked a strikingly predominant up-regulation of membrane CD27 on CD45RO- cells as compared with CD45RA- cells. On CD4+CD45RA-CD27- T cells and long-term grown CD45RA-CD27- TLC, CD27 expression could not be reinduced after stimulation of the TCR/CD3 complex, neither at the protein nor at the mRNA level. Comparison of CD27 expression with its structural homologue FAS/APO-1 showed that down-regulation after prolonged activation is not a general feature of TNF/NGF-R family members. The CD27 ligand was recently identified and was shown to give a co-stimulatory signal to PHA-activated T cells. The restricted up-regulation of CD27 on CD45RA+ cells after T-cell stimulation may point at a discrete role of CD27-CD27 ligand interaction during transition of CD45RO- to CD45RA- T cells. In addition, the CD27 negative phenotype seems a stable reflection of differentiation rather than of activation.

Antigens, CD↗
PubMed1993

Elevated levels of T cell activation antigen CD27 and increased interleukin-4 production in human lymphatic filariasis.

To assess the immunological changes occurring during filarial infection with or without elephantiasis, 145 patients in different clinical groups from an endemic area in Indonesia were compared with respect to plasma levels of both soluble CD25 (sCD25) and sCD27; interleukin-4 (IL-4) and interferon-gamma release by peripheral blood mononuclear cells was also measured in a smaller subset of individuals. Levels of sCD27 were significantly elevated in elephantiasis and microfilaremic patients compared with endemic normals (p < 0.002), whereas sCD25 levels remained low in microfilaremics and was only slightly elevated in elephantiasis patients compared with endemic normals (p < 0.02). As activated T cell populations release both sCD27 and sCD25, these findings imply that there is filarial-driven activation of a T cell subset that releases sCD27 rather than sCD25. The expansion of a particular T cell population by filarial parasites is further suggested by the enhancement in both IL-4-producing and CD4+CD27-T cells in PBMC from elephantiasis and microfilaremic patients compared with endemic normals. More detailed characterization and comparison of CD27-lymphocytes from these individuals may identify mechanisms involved in the pathogenesis of lymphatic filariasis.

CD4-Positive T-Lymphocytes↗
PubMed1993

Soluble and cellular markers of T cell activation in patients with pulmonary sarcoidosis.

We have characterized the activation state of T cells in the bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) from patients with sarcoidosis, to obtain more information about their mechanisms of activation. We analyzed the expression of activation markers (CD25, HLA-DR, Leu-8, and two recently defined markers, CD69 and CD27) on T cells by two-color flow cytometry. We also measured the levels of soluble CD27 and soluble CD25 in nonconcentrated BALF and in serum by ELISA. We found that most T cells in BALF from patients, but not in the peripheral blood, expressed CD69, whereas they did not express CD27. The phenotype (CD69+CD27-) of most BALF T cells and the coexpression of CD69 with HLA-DR and/or VLA-1 indicates that they are in a state of recent and persistent activation. We confirmed previous findings of expression of CD25, HLA-DR, and Leu-8 by T lymphocytes in BALF from patients. We also confirmed increased levels of soluble CD25 in the serum from these patients. The levels of sCD27 and sCD25 in the epithelial lining fluid (ELF) were calculated on the basis of urea in BALF and serum. They were increased in the patients compared with control subjects. In both patients and control subjects, levels in ELF were higher than in the peripheral blood. This indicates shedding of sCD27 (and sCD25) in the lung compartment, which likely contributes to levels in the serum. It is known that in vitro CD27+ cells become CD27- after repeated stimulation and that CD27- cells, after restimulation, do not shed sCD27.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The CD27 membrane receptor, a lymphocyte-specific member of the nerve growth factor receptor family, gives rise to a soluble form by protein processing that does not involve receptor endocytosis.

CD27 is a transmembrane glycoprotein found exclusively on human T and B lymphocytes. It belongs to a recently identified receptor family, whose members are involved in cell differentiation and survival. This family includes the nerve growth factor receptor, two different types of tumor necrosis factor, receptors the Fas antigen, and the B cell-specific protein CD40. T cell activation via the antigen receptor strongly enhances CD27 membrane expression, suggesting a role for CD27 during T cell differentiation. A soluble form of CD27 (sCD27) is released into the supernatant of activated T cells, and detected in serum and urine of healthy individuals and patients. We have investigated the mechanism underlying the generation of sCD27. One mRNA encodes both the transmembrane receptor and sCD27, as shown by cDNA transfection. In line with this, only one CD27 precursor protein is found, that is processed to the mature receptor by extensive O-linked glycosylation. All newly synthesized protein is rapidly transported to the plasma membrane; no internal pool of mature protein is detectable. The transmembrane form gives rise to sCD27 after arrival at the cell surface, most likely via a proteolytic event, that does not involve receptor internalization.

Antigens, CD↗