PubMed Health⌕ Search

Biomedical subjects

P Vandenberghe

Publications and source records attributed to P Vandenberghe.

At least 55 records · Page 3Linked to original sources
PubMed1998

CD57+/CD28- T cells in untreated hemato-oncological patients are expanded and display a Th1-type cytokine secretion profile, ex vivo cytolytic activity and enhanced tendency to apoptosis.

Three-color flow cytometry immunophenotyping revealed significant increases of CD57+ and CD28- cells among both circulating CD4+ and CD8+ T lymphocytes of untreated hemato-oncological patients (n = 54) as compared to healthy donors (n = 55), with CD57 and CD28 expression on the patients' T cells being largely reciprocal. Marked expansion of CD57+ cells among circulating CD4+ T lymphocytes was frequently detected in patients with chronic leukemia of B cell origin (B-CLL, hairy cell leukemia) but not in patients with chronic myeloid leukemia, suggesting a causal relation with the tumor's major histocompatibility complex class II expression. Using immunomagnetic separation techniques, we further demonstrate that the patients' CD57+/CD28- T cells display a typical Th1-type cytokine secretion profile upon anti-CD3 stimulation, with a markedly higher secretion of the Th1-type cytokines IL-2, IFN-gamma, and TNF-alpha than their CD57-/CD28+ counterparts. Cytotoxic activity of circulating CD8+ T lymphocytes, measured ex vivo in an anti-CD3-redirected assay, was almost exclusively exerted by the CD57+/CD28- subset. Moreover, a marked cytotoxic activity was detected within CD4+CD57+ T cells from some B-CLL patients. Finally, the patients' CD57+/CD28- T cells displayed an increased tendency to apoptosis in culture. Collectively, our results indicate that the expanded CD57+/CD28- T cells in hemato-oncological patients represent differentiated effector cells, similar to their (quantitatively minor) counterpart in healthy donors. The reason for their expansion and their pathophysiologic significance, however, remains unclear.

Adult↗
PubMed1998

Patients with high-risk myelodysplastic syndrome can have polyclonal or clonal haemopoiesis in complete haematological remission.

The clonality of mature peripheral blood-derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia (MDS) (five refractory anaemia, RA; one RA with ringed sideroblasts, RARS; three chronic myelomonocytic leukaemia, CMML; four RA with excess of blasts, RAEB; five RAEB in transformation, RAEB-t) was studied by X-chromosome inactivation analysis. Using the human androgen-receptor (HUMARA) assay, we analysed the clonal patterns of highly purified immature CD34+ 38- and committed CD34+ 38+ marrow-derived progenitors, and CD16+ 14- granulocytes, CD14+ monocytes, CD3+ T and CD19+ B lymphocytes from peripheral blood. In high-risk patients (RAEB, RAEB-t), clonality analysis was performed before and after intensive remission-induction treatment. All patients, except one with RA, had predominance of a single clone in their granulocytes and monocytes. The same clonal pattern was found in CD34+ progenitor cells. In contrast, CD3+ T lymphocytes were polyclonal or oligoclonal in 14/18 patients. X-chromosome inactivation patterns of CD19+ B cells were highly concordant with CD3+ T cells except for two patients (one RA, one CMML) with monoclonal B and polyclonal T lymphocytes, therefore suggesting a clonal mutation in a progenitor common to the myeloid and B-lymphoid lineages or the coexistence of MDS and a B-cell disorder in these particular patients. After high-dose non-myeloablative chemotherapy, polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission. Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis.

Adult↗
PubMed1998

Human CTLA-4 is expressed in situ on T lymphocytes in germinal centers, in cutaneous graft-versus-host disease, and in Hodgkin's disease.

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) is a molecule expressed on in vitro activated T cells. CTLA-4 shares important sequence homology with CD28 and binds to the same ligands, CD80 (B7-1) and CD86 (B7-2). CTLA-4 probably functions as a negative regulator of T lymphocyte activation in the mouse, although this remains to be proven for human T lymphocytes. We have developed new monoclonal antibodies against human CTLA-4 and have investigated the in situ expression of CTLA-4 in a wide variety of normal and pathological human tissues expressing CD80 and CD86. As revealed in this study, CTLA-4 is expressed on thymocytes in thymic medulla, on a subset of CD4+ T lymphocytes in germinal centers of follicular hyperplasia, on T cells, mainly CD8+, infiltrating skin affected by graft-versus-host disease, and on T cells, mainly CD4+, infiltrating Hodgkin's disease lesions. In immunoelectron microscopy, CTLA-4 was found on the plasma membrane as well as in the hyaloplasm and cytoplasmic vesicles, in agreement with its pattern of expression on in vitro activated T cells. Interestingly, no or at most scarce expression of CTLA-4 was found in granulomatous lymph nodes, T-cell-mediated inflammatory diseases, or non-Hodgkin's lymphomas, regardless of their expression of CD80 or CD86. Thus, expression of CTLA-4 appears to be induced in selective pathological conditions in vivo. The pathways leading to selective induction of CTLA-4 and its role in the pathophysiology of these conditions need to be further investigated.

Abatacept↗
PubMed1997

Multivariate reconstruction of lymphocyte profiles in a two-dimensional graphical model as a tool for the investigation of lymphocyte subset distribution in health and disease.

Advanced multivariate data-analytical techniques are proposed to concisely represent and evaluate complex lymphocyte profiles (i.e., compound lymphocyte subset distributions) of individual subjects in easily interpretable, two-dimensional, graphical correlation biplots. The lymphocyte profile of each subject is represented by its location in the model, and the score of a subject for a particular lymphocyte subset is inferred from the perpendicular projection on a rotated axis that coincides with this lymphocyte subset. Simultaneously, the model yields information about the correlation between the lymphocyte subsets. Furthermore, individuals with aberrant lymphocyte profiles can be easily identified. In case studies of 80 healthy donors and of 40 patients with multiple myeloma, 10 patients with monoclonal gammopathy of undetermined significance, and 50 age- and sex-matched healthy donors, reconstruction of the two-dimensional lymphocyte profiles from 27 flow-cytometric characterized lymphocyte subsets succeeded in representing 43% and 51% of the total information (variability) contained within the 80 x 27 (= 2,160) and 100 x 27 (= 2,700) flow cytometry measurements, respectively. It is concluded from the present studies that the correlation biplot represents a unique and powerful tool to concisely describe, represent, and analyze complex lymphocyte profiles of individual subjects and the heterogeneity in lymphocyte profiles among these subjects.

Adult↗
PubMed1997

CD40 triggering of chronic lymphocytic leukemia B cells results in efficient alloantigen presentation and cytotoxic T lymphocyte induction by up-regulation of CD80 and CD86 costimulatory molecules.

Freshly collected chronic lymphocytic leukemia B cells (B-CLL cells) are known to be inefficient at stimulating allogeneic T cells, and to lack significant expression of B7 (CD80 and CD86) costimulatory molecules. We investigated the potential of CD40 triggering to up-regulate the expression of adhesion and costimulatory molecules on B-CLL cells, and to enhance their immunogenicity towards allogeneic T cells. B-CLL cells cocultured with human CD40 ligand-expressing mouse fibroblasts rapidly up-regulated CD54 and CD58 adhesion molecules and B7-1 (CD80) and B7-2 (CD86) costimulatory molecules, and acquired a strong stimulatory capacity towards CD4+ as well as isolated CD8+ allogeneic T cells. Costimulation by both CD80 and CD86 proved critical for allogeneic T cell proliferation and CD25 and HLA-DR expression, since these were strongly inhibited by anti-CD80 or anti-CD86 monoclonal antibodies, and completely abrogated by CTLA4-Ig fusion protein, which blocks both CD80 and CD86. B7 costimulation also proved critical for restimulation of primed B-CLL-reactive T cells. Most importantly, priming of purified CD8+ T cells with CD40-triggered allogeneic B-CLL cells resulted in cytotoxic activity against the unstimulated B-CLL cells. These findings raise the possibility that CD40 triggering of B-CLL cells might be exploited in immunotherapeutic protocols.

B-Lymphocytes↗
PubMed1997

Expression of B7-2 (CD86) molecules by Reed-Sternberg cells of Hodgkin's disease.

Ligation of CD28 on T cells with its natural ligands B7-1 (CD80) or B7-2 (CD86) provides a major costimulatory signal for T cells and is of potential importance for tumor rejection. We previously reported a strong expression of B7-1 on Reed-Sternberg cells and anaplastic large cell lymphoma cells. We report here our findings on B7-2 expression by malignant lymphomas (n = 70). B7-2 was present on the neoplastic cells of anaplastic large cell lymphoma in two of three cases studied, and on a subpopulation of the malignant cells in one out of four cases of follicular lymphoma. B7-2 was not expressed by the neoplastic cells of the other non-Hodgkin's lymphomas (n = 32), including T cell-rich B cell lymphoma. In contrast, Reed-Sternberg cells in lymph nodes affected by Hodgkin's disease are strongly positive for B7-2 (n = 31). Evidence for a functional correlate of this expression was obtained by our findings that the combination of anti-B7-1 and anti-B7-2 monoclonal antibodies was more effective than each separately in blocking allogeneic T cell activation (proliferation and cytokine secretion) by Hodgkin's disease-derived cell lines as stimulators. The possible role of B7-1 and B7-2 expression for the course and symptomatology of Hodgkin's disease is discussed.

Antigens, CD↗
PubMed1997

A single course of remission reinduction chemotherapy for acute myelogenous leukemia relapsing after allogeneic bone marrow transplantation is complicated by graft-versus-host disease and followed by sustained complete remission.

Graft-versus-host disease (GVHD) remains a major immunological complication after allogeneic bone marrow transplantation (allo-BMT), but also favors development of the beneficial graft-versus-leukemia (GVL) effect. A patient with AML-M4 (inv (16)) is described, who was given non-myeloablative remission reinduction therapy for leukemic relapse (inv (16), trisomy 8) diagnosed on day 184 after HLA-compatible sibling BMT. On day 236, ie about 6 weeks after completion of this course, a clinical syndrome suggestive of acute GVHD grade 3 had developed. Skin biopsy confirmed the clinical diagnosis of GVHD, with a compatible liver biopsy. Transfusion-associated GVHD was ruled out by analysis of short tandem repeat (STR) alleles in the skin biopsy, revealing alleles from donor and recipient but not from third party origin. Cyclosporin A (CsA) therapy, which had been tapered between days 150 and 175, was resumed, resulting in a favorable response and gradual transition to limited chronic GVHD. The patient has since remained in complete remission with an excellent performance status for more than 40 months, without further chemotherapy. Thus this biopsy proven case of GVHD was induced by marrow donor lymphocytes more than 200 days after transplantation and apparently triggered by remission reinduction chemotherapy. The case indicates that intensive non-myeloablative chemotherapy can cure AML relapsing after allo-BMT. The therapeutic effect in this case probably involved a direct pharmacological suppression of the leukemic clone followed by a GVL effect initiated by donor-derived alloreactive T lymphocytes.

Acute Disease↗
PubMed1997

Autologous peripheral blood progenitor cell transplantation in patients with high-risk myelodysplastic syndromes.

Most patients with myelodysplastic syndromes (MDSs) who achieve a complete remission under aggressive chemotherapy develop a recurrence within 18 to 24 months. Autologous stem cell transplantation has therefore been suggested as a potential means of increasing treatment efficacy. As compared with bone marrow stem cell autografts, peripheral stem cell autografts have a higher harvesting yield and a shorter duration of aplasia after reinjection. Also, the results reported herein suggest that polyclonal stem cells harvested after chemotherapy-induced aplasia and growth factor therapy are capable of ensuring normal hematopoiesis and may provide prolonged remissions in some patients.

Adult↗
PubMed1996

Successful control of refractory and life-threatening autoimmune hemolytic anemia with intravenous immunoglobulins in a man with the primary antiphospholipid syndrome.

A 58-year old man with a history of hypothyroidism and primary antiphospholipid syndrome (with recurrent thromboembolic disease and therapy-refractory autoimmune thrombocytopenic purpura) presented with a life-threatening crisis of warm autoimmune hemolytic anemia (AIHA) while under chronic low-dose steroid therapy. The exacerbation was eventually controlled with a 5-day course of intravenous immunoglobulin (IVIG, Sandoglobulin) (400 mg/kg per day) but hemolysis rapidly recurred, despite therapy with steroids, azathioprine, and cyclosporin, necessitating a second course of IVIG. Control of packed cell transfusion needs for about 7 months was achieved by weekly administration of IVIG (800 mg/kg), although there is no direct evidence that IVIG therapy reduced the production of anticardiolipin or RBC antibodies. Three months after discontinuation of IVIG and change to maintenance with intermediate-dose corticosteroids plus cyclosporin A, the patient succumbed to duodenal perforation with peritonitis and invasive pulmonary aspergillosis. The case illustrates that IVIG therapy may be helpful in selected life-threatening and refractory cases of AIHA. It also sadly illustrates the long-term toxicity of standardly used therapeutics in refractory AIHA.

Anemia, Hemolytic, Autoimmune↗
PubMed1996

Feasibility of peripheral blood progenitor cell harvest and transplantation in patients with poor-risk myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of clonal haematological disorders with a highly unfavourable prognosis. Allogeneic bone marrow transplantation offers the sole possibility for cure and prolonged survival, but is only available for a minority of patients. Therefore, we investigated the feasibility of PBPC collection and transplantation in 11 patients with high-risk myelodysplasia who were not eligible for allogeneic bone marrow transplantation. In six patients, PBPC were harvested after mobilization with G-CSF alone. Five patients were harvested during the recovery phase of intensive chemotherapy combined with G-CSF. This resulted in seven patients in an adequate CD34 progenitor yield > 1 x 10(6)/kg. Six patients obtained a CFU-GM content of the PBPC harvest > 10 x 10(4)/kg. Five patients were subsequently transplanted following a standard BuCy4 regimen. The median to ANC (absolute neutrophil count) > or = 0.5 and 1.0 x 10(9)/l was respectively 14 d (range 10-18) and 16 d (range 11-25). Platelets were self-supporting > or = 20 x 10(9)/l after a median of 41 d (ranges 8-144). One patient had a persistent lack of platelet engraftment unresponsive to infusion of back-up bone marrow. These data demonstrate that in selected patients with high-risk MDS, adequate PBPC collection appears feasible, enabling the harvest of sufficient cell numbers required for rapid and stable engraftment after reinfusion. Improvement in mobilization efficiency may enable the collection of higher CD34+ progenitor cell numbers required for more rapid platelet engraftment. PBPC transplantation may be an alternative treatment option for patients who lack an allogeneic marrow donor. Follow-up is, however, still too limited to draw any conclusion regarding the long-term cure rate.

Adult↗
PubMed1996

Imaging red blood cells with the atomic force microscope.

A novel technique for the reproduction of ultramorphological images and details of the surface of normal and pathological red blood cells (RBC) was investigated. The atomic force microscope (AFM) provided high-resolution images of cell surfaces. The RBC dimensions obtained by this technique revealed differences between native red cells in smears and glutaraldehyde-fixed red cells. It was shown that fixed red blood cells were best suited for the ultramorphological imaging of the cell surface.

Erythrocytes↗
PubMed1996

CD80, CD86 and CD40 provide accessory signals in a multiple-step T-cell activation model.

In this review, a sequential multiple-step model for T-cell activation is proposed. In a series of in vitro studies, highly purified freshly isolated human peripheral blood T lymphocytes were stimulated through the CD28 receptor, with mAb or with natural ligands B7-1 or B7-2, along with TCR stimulation, in the absence of other costimulatory interactions. Ligation of the CD28 receptor, along with stimulation of the TCR, was found to up-regulate pleiotropic in vitro activities, including the secretion of both Th1 and Th2-type cytokines, B-cell help, and the development of cytotoxic activity. This costimulatory action involves CD4+ and CD8+ as well as naive and memory T-cell subsets. The expression of B7-1 and B7-2 on professional APC in situ in both normal and pathological tissues, and its up-regulation on monocytes by GM-CSF and IFN-gamma is consistent with this role. Additional studies have addressed the contribution of interactions between CD28 and B7-1 and B7-2 in T-cell activation initiated by normal un-engineered APC, such as stimulation with recall antigens and primary MLR. Blockade of the interaction between CD28 and B7-1/B7-2 under these conditions failed to completely inhibit T-cell responses or to induce anergy. Complete inhibition and anergy were, however, induced with a combination of CsA, targeting downstream TCR-triggered signalling, as well as anti-B7-1- and anti-B7-2-directed reagents. Interestingly, and in contrast to anti-LFA-1 mAb, the addition of anti-B7-1 or anti-B7-2 reagents could be delayed until at least 48 h after the initiation of T-cell stimulation, indicating a requirement for a late interaction between CD28 and its counter-receptors. Interactions between CD40L on activated T cells and CD40 on APC may serve to sustain, enhance or prolong the presentation of B7-1 or B7-2 on the APC, and thus to prevent anergy induction, or ineffective or abortive T-cell stimulation. Based on these data a sequential multiple-step T-cell activation model is proposed, and novel strategies for immuno-intervention can be designed.

Antigens, CD↗
PubMed1996

Treatment of patients with myelodysplastic syndromes with allogeneic bone marrow transplantation from genotypically HLA-identical sibling and alternative donors.

Between December 1981 and March 1994, 24 patients with a myelodysplastic syndrome (MDS) underwent allogeneic bone marrow transplantation (BMT) for RA with trilineage dysplasia (n = 4), CMML (n = 1), RAEB (n = 4), RAEBt (n = 9) and AML following MDS (n = 6). Fifteen patients (two RAEB, seven RAEBt and six sAML) received chemotherapy before BMT resulting in complete remission in 10 patients (six RAEBt and four sAML) at the time of BMT. Sixteen marrow donors were genotypically HLA-identical siblings. Remaining donors were other family members (five) or unrelated donors (three). The status of the underlying disease at the time of conditioning was the major factor determining long-term survival. The disease-freed survival of RA patients and patients presenting with RAEB, RAEBt and AML but transplanted in complete remission, was respectively 50 and 60%. On the contrary, none of the nine high-risk MDS patients transplanted with persistent disease, survived. Outcome after transplantation with alternative donors was inferior with one long-term survivor, mainly related to the high incidence of severe acute GVHD and its accompanying infectious complications. Six patients relapsed resulting in an actuarial probability of relapse of 28%. Twelve patients died of transplant-related complications leading to a non-relapse mortality at 5 years of 50%. At present eight patients are alive and disease-free 20 to 132 months post-transplantation resulting in an actuarial 5-year disease-free survival of 40.7%. Our results suggest that allogeneic bone marrow transplantation is a feasible treatment option for patients with MDS. However, improvement in GVHD prophylaxis and supportive care to reduce transplant-treated mortality and improved relapse prevention are imperative.

Adolescent↗
PubMed1995

Polyclonal primitive hematopoietic progenitors can be detected in mobilized peripheral blood from patients with high-risk myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) form a heterogeneous group of clonal hematopoietic disorders with unfavourable prognosis. Allogeneic bone marrow transplantation is the only potentially curative treatment, but remains limited to a small subgroup of younger patients with HLA-compatible donors. As autologous stem cell transplantation is currently being explored as an alternative treatment strategy for MDS, more information needs to be acquired regarding the clonal nature of the progenitor cells in these autografts. Therefore, we have analyzed the clonal patterns of highly purified hematopoietic progenitors and their mature daughter cells in mobilized peripheral blood collections produced from five female patients with high-risk MDS in complete hematologic remission. X-chromosome activation patterns of flow-sorted immature (CD34 + 38low, CD34 + 33low) and committed (CD34 + 38high, CD34 + 33high) progenitors were studied with the polymerase chain reaction-based HUMARA assay. In four patients, a polyclonal remission was shown in all stem cell subpopulations and their mature daughter cells whereas one patient was found to remain skewed in all fractions, except T lymphocytes. This study provides strong evidence that polyclonal immature hematopoietic progenitors can be mobilized and harvested in patients high-risk MDS after treatment with high-dose chemotherapy.

Adult↗
PubMed1995

Therapy-related acute myeloid leukemia with t(8;16)(p11;p13) following anthracycline-based therapy for nonmetastatic osteosarcoma.

A case of therapy-related AML with t(8;16)(p11;p13) 14 months following the end of anthracycline-containing chemotherapy for a nonmetastatic osteosarcoma of the left tibia is presented. The patient was successfully treated with intensive remission-induction chemotherapy. Subsequently, he underwent an uncomplicated allogeneic bone marrow transplantation from his HLA-identical brother and is at present alive and disease-free 10 months after diagnosis of the secondary AML.

Acute Disease↗
PubMed1995

Distinct signal transduction in mouse CD4+ and CD8+ splenic T cells after CD28 receptor ligation.

Current evidence suggests that recognition of Ag/MHC by the TCR alone is insufficient to lead to T cell proliferation or effector function. For a Th cell to produce sufficient IL-2 to allow autocrine-driven clonal expansion, there is a requirement for so-called "costimulatory" or "accessory" signals in addition to TCR ligation by Ag/MHC. Although the first signal delivered by TCR ligation has been well characterized, information regarding the biochemical nature of second signals is limited. In the present report, using a newly generated mAb specific for CD28, signal transduction by the CD28 receptor has been studied in mouse splenic T cells. When freshly isolated splenic T cells were assessed, cross-linking of CD28 by mAb did not induce increases in intracellular calcium concentration were assessed, cross-linking of CD28 by mAb did not induce increases in intracellular calcium concentration whereas TCR cross-linking was able to induce calcium mobilization. In contrast, when T cells were activated by phorbol ester treatment or by in vitro culture, CD28 ligation was able to induce calcium mobilization in 60 to 70% of splenic T cells. Unexpectedly, the CD28-induced calcium response was mainly limited to T cells of the CD4+ subset, whereas both CD4+ and CD8+ T cell subsets showed increases in [Ca2+]i of similar magnitude after CD3 epsilon ligation. The temporal nature of the CD28-induced signal was also different from TCR-induced calcium mobilization. CD28-induced signals were delayed in onset and sustained in duration in contrast to TCR signals that had short latency and brief duration. Differential expression of CD28 on the surface of activated CD4+ or CD8+ T cells did not appear to account for the differences in signal transduction between the two T cell subsets. The preferential responsiveness of the CD4+ T cell population to CD28-induced signaling was also observed in downstream events such as the induction of IL-2R, CD69 expression, and in cellular proliferation. These results indicate that the costimulatory signal delivered by CD28 may have fundamentally different biochemical properties in CD4 and CD8 T cell subsets, and therefore the functional role of CD28 may differ in these T cell subsets.

Animals↗
PubMed1995

An update on peripheral blood progenitor cell transplantation.

High-dose therapy with stem cell rescue is increasingly being used as a salvage or consolidation therapy for patients with poor-risk malignant disease. The availability of peripheral blood progenitor cells (PBPC) has opened new therapeutic perspectives to alleviate the severe toxicity related to prolonged myelo-suppression. The preferred method of collection is still a matter of much debate. PBPC can be collected in steady state and after chemotherapeutic conditioning, growth factor priming, or both. Usually a heterogeneous population containing both committed progenitors and pluripotent stem cells can be harvested. Studies comparing engraftment after mobilized PBPC with recovery after autologous bone marrow transplantation confirm the beneficial effect on neutrophil and platelet engraftment. The accelerated hematological recovery can be associated with a number of clinical benefits including a reduction of platelet transfusions and shorter hospital stay. Only a few randomized studies are currently available on the long-term outcome after PBPC transplantation. Recent findings on tumor cell mobilization stimulated the development of techniques for tumor cell reduction, based on negative selection ("purging") of tumor cells or positive selection of CD34-positive progenitor cells. Positive CD34 selection is also imperative for successful ex vivo expansion of progenitor cells and gene transfer experiments. The value of PBPC in the field of allogeneic transplantation is currently being examined.

Blood Specimen Collection↗