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Biomedical subjects

J C Bensa

Publications and source records attributed to J C Bensa.

At least 19 recordsLinked to original sources
PubMed1999

Functional expression of CD80 and CD86 allows immunogenicity of malignant B cells from non-Hodgkin's lymphomas.

We analyzed the accessory function of malignant B cells from non-Hodgkin's lymphomas (NHLs). Among the 70 samples of malignant B cells included, four patterns of expression of the costimulatory molecules CD80 and CD86 were distinguished (+/+, +/-, -/+ and -/-). In two-thirds of the cases, CD80, CD86, or both were expressed. To investigate the relevance of these molecules for tumor immunogenicity, mixed lymphocyte reactions (MLR) were performed with allogeneic responding T cells and malignant B cells from nine NHL patients. Regardless of the level of expression of CD80 and CD86, significant proliferation was induced in the responder cells. The addition of monoclonal antibodies directed against CD80 and CD86 at the beginning of MLR almost completely inhibited this proliferation. We show that, during MLR, a high level of expression of CD80 and CD86 was induced in NHL B cells. Thus, cooperation between responding and stimulator cells seems to occur during MLR, allowing induction of optimal accessory function of B cells. We investigated whether malignant B cells cultured with CD40-L-transfected L cells in the presence of IL-4 could augment their antigen-presenting cell (APC) functions. The culture of NHL B cells in this sytem induced strong upregulation of the expression of CD80 and CD86 as well as other molecules involved in accessory cell functions (HLA class I, CD54, and CD58). In half of the cases, this activation resulted in enhanced proliferation of allo-T cells as compared to the proliferation induced by nonactivated malignant B cells. Our results show that NHL B cells are able to express functional CD80 and CD86 and to be fully competent APC. This suggests that the absence of an efficient T cell-mediated antitumor response in vivo is not related to a deficiency in the APC functions of malignant B cells.

Adult↗
PubMed1998

Tumor B cells from non-Hodgkin's lymphoma are resistant to CD95 (Fas/Apo-1)-mediated apoptosis.

Apoptosis mediated by the CD95 (Fas/Apo-1) molecule plays a crucial role in the regulation of the B-cell immune response. In this study, we examined the function of the CD95 antigen in B-cell-derived non-Hodgkin's lymphoma (NHL), a malignant disease of mature B cells. Membrane CD95 molecules were found to be constitutively expressed in a large number of NHL, including mantle cell (MCL, n = 10), lymphocytic (LCL, n = 10), follicular (FL, n = 11), and diffuse large cell lymphoma (DLCL, n = 9) with, however, different levels of intensity. Indeed, the levels of CD95 were low in MCL and LCL as compared with FL and DLCL. However, regardless of the intensity of expression, CD95 triggering with anti-CD95 monoclonal antibody (MoAb) did not induce apoptosis of lymphoma B cells, while these cells underwent apoptosis after irradiation or staurosporine treatment. Further experiments were then performed to address whether apoptosis could be restored by B-cell activation via CD40 cross-linking. We showed that CD40 engagement in the presence of interleukin (IL)-4 was more effective than CD40 engagement alone in upregulating the CD95 antigen and induced CD95-mediated cell death in nontumoral B cells. Concerning malignant B cells, CD40 ligation in the presence of IL-4 strongly increased CD95 expression, but did not markedly increase CD95-induced apoptosis. Furthermore, using cytotoxic T cells, we showed that CD95L was also ineffective in inducing apoptosis in lymphoma B cells, whereas these cells were killed by the perforin pathway. Our findings suggest that the CD95-mediated cell death pathway is altered in malignant cells from the NHL we tested. This could be a mechanism allowing lymphoma B cells to escape from immune regulation.

Antibodies, Monoclonal↗
PubMed1998

Heterogeneity and immunochemical properties of anti-beta2-glycoprotein I autoantibodies.

Most anticardiolipin antibodies (ACA) associated with antiphospholipid syndrome (APS) are directed against epitopes expressed on beta2-glycoprotein I (beta2GPI). Despite a good correlation between standard ACA assays and those using purified human beta2GPI as the sole antigen, some sera from APS patients only react in the latter. This is indicative of heterogeneity in anti-beta2GPI antibodies. To characterize their reactivity profiles, human and bovine beta2GPI were immobilized on gamma-irradiated plates (beta2GPI-ELISA), plain polystyrene precoated with increasing cardiolipin concentrations (CL/beta2GPI-ELISA), and affinity columns. Fluid-phase inhibition experiments were also carried out with both proteins. Of 56 selected sera, restricted recognition of bovine or human beta2GPI occurred respectively in 10/29 IgA-positive and 9/22 IgM-positive samples, and most of the latter (8/9) were missed by the standard ACA assay, as expected from a previous study. Based on species specificity and ACA results, IgG-positive samples (53/56) were categorized into three groups: antibodies reactive to bovine beta2GPI only (group I) or to bovine and human beta2GPI, group II being ACA-negative, and group III being ACA-positive. The most important group, group III (n = 33) was characterized by (i) binding when beta2GPI was immobilized on gamma-irradiated polystyrene or cardiolipin at sufficient concentration (regardless of beta2GPI density, as assessed using 125I-beta2GPI); (ii) and low avidity binding to fluid-phase beta2GPI (Kd in the range 10(-5) M). In contrast, all six group II samples showed (i) ability to bind human and bovine beta2GPI immobilized on non-irradiated plates; (ii) concentration-dependent blockade of binding by cardiolipin, suggesting epitope location in the vicinity of the phospholipid binding site on native beta2GPI; (iii) and relative avidities approximately 100-fold higher than in group III. Group I patients were heterogeneous with respect to CL/beta2GPI-ELISA and ACA results (6/14 scored negative), possibly reflecting antibody differences in terms of avidity and epitope specificity. Affinity fractionation of 23 sera showed the existence, in individual patients, of various combinations of antibody subsets solely reactive to human or bovine beta2GPI, together with cross-species reactive subsets present in all samples with dual reactivity namely groups III and II, although the latter antibodies were poorly purified on either column. Therefore, the mode of presentation of beta2GPI greatly influences its recognition by anti-beta2GPI antibodies with marked inter-individual heterogeneity, in relation to ACA quantitation and, possibly, disease presentation and pathogenesis.

Adolescent↗
PubMed1997

Relationships between susceptibility to LAK cell-mediated lysis, conjugate formation and expression of adhesion molecules in B-cell derived non-Hodgkin's lymphomas.

Adoptive immunotherapy with LAK cells has been investigated for the treatment of B-cell-derived lymphomas, but only a few significant tumor regressions were obtained. In order to explain this refractory state, the sensitivity to normal LAK-mediated lysis of 30 non-Hodgkin's lymphoma (NHL) malignant B-cells was determined using flow cytofluorimetry. A large heterogeneity was found, and we report a close correlation (p < 0.001) between the extent of lysis of malignant B-cells and their ability to form conjugates with LAK cells; which is the first step in LAK-mediated cytolysis. The levels of expression of HLA class I molecules, LFA-1 (CD11a/CD18), CD54 and CD58 were also studied and found to be expressed very heterogeneously. CD54 expression on malignant B-cells plays a major role in the initial conjugate formation with LAK cells (p < 0.001), and this was confirmed by inhibition experiments. Our results suggest that a weak expression of CD54 could constitute one mechanism by which NHL tumor B-cells escape natural immune surveillance and resist LAK cells immunotherapies.

Adult↗
PubMed1996

False-negative results in anti-HLA antibody detection by Sangstat ELISA: complement dependent cytotoxicity is not yet obsolete.

Although ELISA on purified HLA molecules for detecting anti-HLA antibody (P-S ELISA) does detect some antibodies previously missed by the conventional complement dependent cytotoxicity method (C Cytotox), HLA ELISA should not fail to detect antibodies already detected by the conventional reference method to be able to make C Cytotox obsolete and to replace it in routine testing. Among 40 selected sera, 8 false-negative reactions were observed in P-S ELISA. These sera were reanalyzed blind in two laboratories and found to contain non-IgM, warm anti- HLA antibodies. These antibodies were directed in 4 cases against an HLA molecule expressed on a kidney transplant previously rejected by the subject. These antibodies, if missed, would have been potentially harmful in kidney transplantation. Thus P-S ELISA can't yet replace C Cytotox in routine anti-HLA class I detection. The cost/benefit ratio of P-S ELISA as a second-line test remains to be investigated.

Antibodies↗
PubMed1996

HCV-Infection in blood donors: association between anti-HCV core IgM antibodies and serum HCV RNA.

Among 47 blood donors tested positive with HCV EIA 2.0 Abbott, 27 (57.4%) also reacted with four ¿third-generation' EIAs. The presence of anti-HCV antibodies was confirmed with 3 different immunoblot assays in 16 of 27 sera (34.0%) while 10 samples (21.3%) had indeterminate profile with antibodies usually directed against structural core antigen. Anti-HCV core IgM response was found in 12 of 47 sera (25.5%) and HCV viremia detected by the polymerase chain reaction (PCR) procedure was observed in 15 samples (31.9%). A comparative study of the different markers confirmed a good correlation between a strong antibody response in EIAs and immunoblot assays and the presence of HCV RNA in the serum; only 2 immunoblot indeterminate samples were PCR positive. An association was observed between IgM antibodies against "core' epitopes and HCV RNA carriage: all IgM-positive sera were found positive by PCR. However, the direct detection of viral genome remains the best method for identifying HCV carriers in the blood donor population.

Adult↗
PubMed1996

Species specificity of anti-beta 2 glycoprotein I autoantibodies and its relevance to anticardiolipin antibody quantitation.

Some patients suspected of having antiphospholipid antibody syndrome (APS) were found to be positive for anti-beta 2 glycoprotein I (beta 2GPI) antibodies despite negative results for antibodies to cardiolipin (ACA). Since the major source of beta 2GPI in the ACA assay is animal (usually bovine) serum, we studied the influence on ACA quantitation of the species specificity of anti-beta 2GPI antibodies from patients with various autoimmune disorders, mostly systemic lupus erythematosus and primary APS. Ninety-seven sera were selected based on IgG (n = 76) or IgM (n = 64) positivity by ELISA using gamma-irradiated plates coated with human or bovine purified beta 2GPI. A higher proportion of IgM (43.7%) than IgG (7.9%) reacted to human, but not bovine, beta 2GPI. Furthermore, from the samples reactive to both proteins, the ratio of antibody level against bovine to that against human beta 2GPI was 1.08 +/- 0.58 for IgG and 0.58 +/- 0.3 for IgM (p < 10(-5)). IgG and IgM ACA were detected in 78 and 40 sera, respectively; concordance between the two ELISAs for ACA and anti-beta 2GPI antibodies was 94% for IgG and 75% for IgM. Out of 28 IgM showing recognition restricted to human beta 2GPI, 21 were missed by the ACA assay, possibly because of lower concentrations of beta 2GPI in those patients' sera. The antibody reactivity pattern towards human and bovine beta 2GPI of individual sera showed no variation with time and was related to the relative antibody avidity for each protein. A murine anti-human beta 2GPI monoclonal antibody, 9G1, that cross-reacts with bovine beta 2GPI, competed to a large extent with the patients' anti-beta 2GPI antibody binding sites whatever isotype involved or protein recognized. Therefore, anti-beta 2GPI antibodies of IgM isotype display a marked preference for human compared to bovine beta 2GPI responsible for frequent inconsistencies in the ACA assay.

Animals↗
PubMed1995

Beneficial effect of one HLA haplo- or semi-identical transfusion versus three untyped blood units on alloimmunization and acute rejection episodes in first renal allograft recipients.

Acute allograft rejection is the major risk factor of renal function decline and graft loss. Beside histocompatibility matches and pharmacological immunosuppression, blood transfusion is empirically used to detect responder subjects and to induce immune tolerance. Alloimmunization associated with blood transfusions readily detected by anti-HLA antibodies could induce acute vascular rejection episodes during the early period after grafting. Our open prospective study was aimed at analyzing the 1 year follow-up of 105 successive first cadaver renal transplant recipients according to the transfusion protocol as assessed by anti-HLA antibody production, acute rejection episodes, and graft survival. Our conventional transfusion protocol involved 3 nonphenotyped blood transfusions set up at least 20 days before grafting in a control cohort (group A) and was compared with a single pretransplant HLA haplo- or semi-identical blood transfusion in a successive group of patients (group B). Our results suggest that both protocols were associated with similar 1-year graft survivals (> 96% in both groups) and number of patients experiencing rejection episodes (20.7% in group A; 9.6% in group B; P NS). HLA haplo- or semi-identical transfusion was significantly beneficial in naive patients without previous alloantigen contact by pregnancy or blood transfusions during dialysis. Naive patients in group B did not develop post-transfusion anti-HLA antibodies compared to naive patients in group A (16.6%; P < 0.001), and they experienced significantly less acute rejection episodes (2.7%) compared to group A naive patients (20.8%; P = 0.02).

Blood Transfusion↗
PubMed1995

Malignant B lymphocytes from non-Hodgkin's lymphoma induce allogeneic proliferative and cytotoxic T cell responses in primary mixed lymphocyte cultures: an important role of co-stimulatory molecules CD80 (B7-1) and CD86 (B7-2) in stimulation by tumor cells.

We analyzed the stimulating capacities of malignant B cells from non-Hodgkin's lymphomas (NHL) to induce an allogeneic response in primary mixed lymphocyte reaction (MLR). T cells purified from a single healthy donor (KS) were used to compare the responses induced by either malignant or hyperplastic cells. Malignant B cells induced strong proliferation of KS cells independently of their level of expression of adhesion molecules. The KS cells after MLR were predominantly CD3+, CD25+, HLA-DR+, Ki67+ and CD45RO+ T cells, and the CD4/CD8 ratio was heterogeneous (from 0.8 to 2.7). To investigate the role of co-stimulatory molecules CD80 and CD86 for the stimulatory capacities of B cells, the expression of both molecules was analyzed before and during the MLR. Most fresh malignant B cells were negative for CD80 and CD86, whereas co-cultured B cells expressed high levels of both molecules. This expression was crucial for T cell proliferation, since monoclonal antibodies directed against CD80 and CD86 completely abrogated the MLR. We also report that KS responding cells at the end of co-culture were able to lyse fresh B cells used as stimulator cells to different extents (from 10 to 51%), and the level of lysis was enhanced after PMA activation of the target cells. Inhibition experiments using CD8 and CD4 mAb showed that effector cells were mainly CD8+. This report is the first to describe the accessory function of human malignant B cells from NHL and their sensitivity to lysis mediated by CD8+ T cells, and suggests new strategies for the development of antitumor immunity in NHL.

Adolescent↗
PubMed1995

Neutrophil activation by anti-beta 2 glycoprotein I monoclonal antibodies via Fc gamma receptor II.

Murine monoclonal antibodies (mAbs) to human beta 2-glycoprotein I (beta 2GPI), a plasma protein required for the binding of some antiphospholipid antibodies, have been shown to possess lupus anticoagulant properties and to activate platelets via Fc gamma receptor (Fc gamma R) crosslinking. Here we investigated their ability to induce polymorphonuclear leukocyte (PMN) functional responses. The six mAbs (IgG1 isotype) tested in combination with beta 2GPI led to a concentration-dependent activation of human PMNs as appreciated by granule release, H2O2 production, and cytosolic Ca2+ increase. This activation process was accompanied by the enhancement of PMN-mediated heparan sulfate loss from the endothelial cell line EA.hy 926 without evidence for cell lysis or detachment. F(ab')2 fragments of one of the mAbs bound to PMNs in a beta 2GPI-dependent manner but were devoid of activating effects. Carbamylated beta 2GPI was unable to mediate PMN-antibody binding and subsequent activation. In addition, cationization of beta 2GPI or removal of its sialic acid groups led to higher efficiency in binding to the PMN surface and triggering activation in comparison with the untreated protein. Thus, the process of PMN activation depends on mAb binding to these cells through both Fab (via beta 2GPI) and Fc domains, as confirmed by the suppression of all responses upon treatment with an anti-Fc gamma RII, but not anti-Fc gamma RIII, antibody. Our data suggest a model of cellular activation by beta 2GPI-dependent antiphospholipid antibodies.

Antibodies, Monoclonal↗
PubMed1995

Autotumour reactive T-cell clones among tumour-infiltrating T lymphocytes in B-cell non-Hodgkin's lymphomas.

Seventy-three T-cell clones (TCC) were established from tumour-infiltrating lymphocytes-T (TIL-T) derived from lymph nodes involved by B-cell non-Hodgkin's lymphomas (B-NHL) in nine patients with different histological subtypes and clinical stages. 40 TCC (55%) expressed the CD25 Ag and were also able to proliferate in the presence of irradiated autologous B-NHL cells. Among them, 23 autotumour (AuTu) proliferative TCC were found not to proliferate to autologous EBV-transformed B-cell lines, indicating that the proliferative reactivity of these TCC was preferentially directed at autologous B-NHL cells. Tested against autologous B-NHL cells, only three AuTu proliferative TCC (CD8+) showed a significant level of cytotoxicity (specific lysis > 15%). In blocking experiments, the AuTu proliferative reactivity of three TCC from one patient was strongly inhibited by anti-DR and anti-DQ mAbs, whereas that of three TCC from another patient was not affected by either anti-MHC class I or class II (DR, DP, DQ) mAbs. These findings suggest that the recognition of autologous B-NHL cells by AuTu proliferative TCC may occur through MHC-restricted as well as MHC-unrestricted mechanisms.

Cell Division↗
PubMed1995

Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants.

Some lupus anticoagulants (LA) have been shown to be directed against phospholipid-bound prothrombin. While developing an ELISA to detect anti-prothrombin autoantibodies in patient serum or plasma, no or very low signal was observed using human prothrombin immobilized on plain polystyrene plates. In contrast, the same LA-positive samples bound specifically to prothrombin coated on gamma-irradiated plates, depending on the radiation dose, in the absence of added calcium and phospholipid. Optimization of the assay required the addition of 0.1% Tween 20 to the buffers. Antibody specificity for immobilized prothrombin was ascertained by competition using liposome-bound prothrombin, since fluid-phase prothrombin competed poorly. Seventy-seven of 139 patients (55.4%) with LA related to a variety of underlying diseases possessed anti-prothrombin antibodies (27 IgG, 35 IgM and 15 both isotypes), either isolated or more often associated with anti-beta 2 glycoprotein I (beta 2GPI) antibodies. These included 67-71% of the patients with systemic lupus erythematosus and related disorders, primary antiphospholipid antibody syndrome or drug-induced LA (autoimmune groups), but only 19-20% of those with infection or malignancy (p < 0.001). As previously shown for anti-beta 2GPI antibodies, IgG2 was the predominant IgG subclass reactive with prothrombin. Thus, autoimmune patients with LA have a high incidence of antibodies to beta 2GPI and prothrombin, the binding of which could similarly require high antigen density and/or exposure of cryptic epitopes resulting from protein interaction with an irradiated (i.e. more anionic) polystyrene surface.

Autoantibodies↗
PubMed1994

[Is there a relationship between the presence of autoantibodies or mixed cryoglobulinemia and the clinical and histological characteristics of chronic viral hepatitis C?].

The purpose of this prospective work was to study a possible relationship between autoantibodies, cryoglobulinaemia and liver histologic lesions in chronic hepatitis C. Ninety three patients (mean age: 43.3 years) with histologically proven chronic hepatitis were studied. Chronic hepatitis was associated with cirrhosis in 18 cases. Auto-antibodies detection was performed in the serum of all patients and cryoglobulinaemia detection was performed in 47 patients. The prevalence of auto-antibodies was also studied in 45 blood donors (control group) and 30 patients with chronic hepatitis B. Histologic study included Knodell score and semi-quantitatively expressed histologic lesions considered as more specific of chronic hepatitis C. Twenty six of the 93 patients (28%) had at least an autoantibody with a level > or = 1/100. The autoantibodies prevalence was: smooth muscle: 15%, antinuclear: 15%, LKM 1: 1.2%, mitochondrial: 0. A mixed cryoglobulinaemia was present in 23 of 47 patients (49%). The prevalence of anti-smooth-muscle autoantibodies was significantly increased in hepatitis C patients compared with the control group (P < 0.05). The histologic Knodell score was 7.3 +/- 3.6. The histologic lesion prevalence was: portal tract lymphoid follicles: 97%, acidophil bodies: 85%, intra-sinusoidal lymphoid infiltrates: 71%, steatosis: 61%, microgranulomas: 54%, biliary duct tract damages: 53%. No statistical significant correlation was found between autoantibodies prevalence and liver histologic lesions. The Knodell score was only significantly increased in patients with mixed cryoglobulinaemia (8.4 +/- 3.6 vs 6.2 +/- 2.8) (P < 0.05). These results suggest that the autoantibodies presence in chronic hepatitis C does not change hepatic histologic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Evaluation of monoclonal antibodies with specificity for the human platelet HPA-1 allotypes.

Two mouse monoclonal antibodies have been characterized. Both antibodies specifically recognized the amino acid sequences which are responsible for the presence of the HPA-1a and HPA-1b alloantigens at the surface of human platelet. The monoclonality allied with an exquisite specificity of these antibodies allow a perfect typing of platelet HPA-1 status. A fast and reliable Elisa assay which fulfills all the needs and requirements of hematology laboratories has been set up and is described here. The Elisa assay has been tested on a population of 689 blood donors. The results agreed with the known phenotypic frequencies of the HPA-1 alloantigens.

Amino Acid Sequence↗
PubMed1992

CD45RA expression by CD4 T lymphocytes in tumors invaded by B-cell non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD).

Little is known about the role of tumor infiltrating T lymphocytes (TIL-T) in the pathogenesis of malignant diseases and collaboration between normal and malignant cells has not yet been proved. In the present work, we have investigated whether immune T lymphocytes exist in tumors invaded by B-cell non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). Therefore, we have studied the reactivity of the CD45RA monoclonal antibody, which discriminates between naive and memory CD4 T lymphocytes. Our results showed far lower percentages of CD4+ CD45RA+ in malignant lymphoma (30.3 +/- 15.0% in B-cell NHL, and 37.4 +/- 18.6% in HD) than in reactive hyperplasia (54.7 +/- 13.2%), leading to the conclusion of an accumulation of immune cells in tumor microenvironment. A further heterogeneity in the relative proportion of naive and memory TIL-T was also observed within lymphoma (range: 11 to 68% in B-cell NHL, 5 to 69% in HD). In B-cell NHL, it was related to histological features, as documented by the Kiel classification (P = .028), and to a stronger extent to cytological characteristics analysed with the Grenoble classification (P less than .0001): class 1 NHL, which are essentially indolent NHL displayed lower naive cells (22.2 +/- 7.4%) than class 3 NHL, which are more aggressive (40.1 +/- 16.1%). Among the monoclonal antibodies (mAb) defining the B-cell clone phenotype or activation state (CD19, CD20, CD21, CD22, CD23, CD24, CD5, CD10, CD11a, and Ki67), only CD23 (P = .0003) and Ki67 (P = .0007) revealed statistical association with the percentage of naive CD4 lymphocytes. No correlation could be demonstrated with the proportion of whole TIL-T, activated CD3 DR TIL-T, or CD4 subset.

Adult↗