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At least 19 recordsLinked to original sources

PubMed2026

Maternal disease control and pregnancy outcomes with anti-CD20 therapy versus natalizumab in multiple sclerosis: a systematic review.

BACKGROUND: Management of multiple sclerosis (MS) during pregnancy requires balancing maternal disease control with fetal safety. Among high-efficacy disease-modifying therapies, anti-CD20 monoclonal antibodies and natalizumab are commonly used in women with active disease, yet their comparative effectiveness and safety during pregnancy remain incompletely defined. This systematic review evaluated maternal disease activity and pregnancy-related outcomes associated with anti-CD20 exposure compared with natalizumab in pregnant women with MS. METHODS: PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library were searched from inception through February 2026. Eligible studies included pregnant women with MS exposed to anti-CD20 before or during pregnancy and reporting maternal disease activity compared to natalizumab. RESULTS: Seven studies were included, comprising six observational cohort studies and one pharmacovigilance disproportionality analysis. Across studies, anti-CD20 exposure was consistently associated with lower relapse activity than natalizumab, particularly in the postpartum period. Anti-CD20 strategies were also associated with markedly lower postpartum MRI activity and more favorable disability-related outcomes where reported. Meta-analysis of three studies demonstrated a significant reduction in postpartum MRI activity with anti-CD20 therapy compared with natalizumab (RR 0.06, 95% CI 0.02-0.24; I² = 0%). No clear increase in major congenital anomalies was identified, although some data suggested higher odds of small for gestational age and maternal antibiotic use with anti-CD20 exposure. CONCLUSIONS: Anti-CD20 therapy was associated with lower maternal disease activity than natalizumab during pregnancy, especially for relapse prevention and postpartum MRI suppression. However, evidence regarding fetal and neonatal safety remains limited, warranting cautious individualized treatment decisions and further comparative research.

Humans↗

PubMed1991

Activation of dense human tonsilar B cells. Induction of c-myc gene expression via two distinct signal transduction pathways.

Antibodies to surface Ig or to the B cell marker CD20 trigger resting human B cells in similar yet distinct ways. Either antibody induces five-fold increases in the expression of the protooncogene, c-myc, as detected with semi-quantitative Northern blot assays. The induction of c-myc mRNA by anti-IgM or anti-CD20 is blocked by inhibitors of protein kinase C (PKC) such as staurosporine and by pretreatment of B cells with phorbol esters to reduce cellular PKC levels. This suggests that PKC is involved in the pathways stimulated by both anti-IgM and anti-CD20. However, anti-CD20, unlike anti-IgM, does not activate significant increases in inositol triphosphate or intracellular-free calcium. Further, anti-CD20-triggered elevation of c-myc mRNA is inhibited by pertussis and cholera toxins, whereas the pathway initiated by anti-IgM if anything is stimulated by pertussis toxin and unchanged by cholera toxin. Further differences in the nature of these two signals were seen when the expression of adhesion/recognition molecules were examined. Anti-IgM consistently induces increased expression of the adhesion molecules CD54 (I-CAM-1) and B7/BB-1 on B cells, but anti-CD20 does not. Yet both anti-CD20 and anti-IgM increase class II MHC, CD18 (LFA-1 beta-chain) and LFA-3 levels. These data suggest that the way in which B cells are activated may influence their surface phenotype and possibly subsequent migration or cell-cell interactions.

Antibodies, Anti-Idiotypic↗

PubMed1992

Rescue from anti-IgM-induced programmed cell death by the B cell surface proteins CD20 and CD40.

Programmed cell death (PCD), or apoptosis, is characterized by several morphologic alterations and eventual cleavage of nuclear DNA into oligonucleo-some-length fragments. We defined a human B cell line, Ramos, that responds with PCD following ligation of surface IgM. Of the DNA in Ramos cells 3%-10% was fragmented as early as 4 h after IgM ligation. Propidium iodide staining demonstrated that 20%-40% of Ramos cells became apoptotic by 18 h and further established that cells transiting into the S phase of the cell cycle were susceptible to PCD. Addition of several agents to the Ramos cells abrogated anti-IgM-induced PCD, including the phorbol 12-myristate 13-acetate (PMA). In contrast to the effect of PMA, the 4 alpha PMA isomer of PMA neither activated protein kinase C (PKC) nor rescued the cells from anti-IgM-induced PCD, confirming a role for PKC in negating apoptosis. To explore the effect of physiologic signals on anti-IgM-induced PCD, antibodies against the CD20 or CD40 molecules were added in concert with anti-IgM. Both CD20 and CD40 synergize with anti-IgM to augment proliferation but neither molecule activates PKC in Ramos cells. Both anti-CD20 and anti-CD40 reduced the number of cells undergoing anti-IgM-induced PCD. Unlike the effect of anti-CD40, addition of anti-CD20 to anti-IgM-stimulated cells negated PCD only in a subset of cells. Maximal rescue occurred following the addition of anti-CD40 and occurred by 4 h and at least up to 20 h of culture. These data show that (a) PCD can be initiated in B cells entering the S phase of the cell cycle, (b) PCD can be triggered by engagement of surface IgM in the absence of ancillary signals or PKC activation, and (c) rescue from PCD can occur by several mechanisms, either PKC dependent or PKC independent.

Antigens, CD↗

PubMed1988

CDw40 and BLCa-specific monoclonal antibodies detect two distinct molecules which transmit progression signals to human B lymphocytes.

Two monoclonal antibodies (mAb), MA6 and G28-5, have the common property of detecting markers expressed on both B lymphocytes and carcinomas: BLCa (B lymphocyte carcinoma cross-reacting antigen) and CDw40 (Bp50). A comparison of the reactivity of these mAb revealed that MA6 and G28-5 detect distinct epitopes with different cell line and tissue distributions. L cell transfectants expressing CDw40 were not bound by MA6 anti-BLCa, but were bound by G28-5 anti-CDw40. G28-5 or a CDw40-specific heterantiserum could not block the migration of BLCa, while MA6 antibody could. These results indicate that CDw40 and BLCa are distinct surface molecules. Both G28-5 anti-CDw40 and MA6 anti-BLCa mAb could provide progression signals for B cells activated by appropriate B cell activators such as phorbol esters or anti-immunoglobulin; however, only G28-5 anti-CDw40 and not MA6 was co-stimulatory with the anti-CD20 competence signal, demonstrating a clear difference in the CDw40 and BLCa-mediated progression signals. Apparently, these molecules, although structurally distinct, have related functions in B cell activation.

Animals↗

PubMed1988

Triggering of neoplastic B cells via surface IgM and the cell surface antigens CD20 and CDw40. Responses differ from normal blood B cells and are restricted to certain morphologic subsets.

By raising monoclonal antibodies (MAbs) against B cells, a number of cell surface molecules have recently been identified which after binding by their specific antibody can trigger B cells, either alone or in co-operation with antibodies to surface immunoglobulin (sIg). The anti-CD20 (Bp35) MAb IF5 can deliver a strong activation signal to resting normal B cells, and the anti-CDw40 (Bp50) MAb G28-5 can promote activated G1 B cells to enter S phase. These antibodies were tested for their functional effects in vitro on suspended cells from 17 follicle-center-cell (FCC) lymphomas, 5 cases of chronic lymphatic B-cell leukemia (B-CLL) and 8 cases of various histological types. Changes in cellular volume, RNA and DNA synthesis were compared with the results obtained with a polyclonal anti-mu [F(ab')2] antiserum, a MAb to surface IgM (AF6), 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and B-cell growth factor (low-molecular-weight BCGF). Our data reveal differences in the requirements for triggering of various B-cell subsets: cells from CLL responded strongly to TPA but not to anti-mu, which is a potent stimulator not only of normal B cells but also of cells from individual cases of FCC lymphomas. Our observations suggest that the differentiation stage of B-CLL cells is distinct from that of small resting B cells from peripheral blood. Centrocytic lymphomas could not be activated by any of the reagents. CD20-mediated triggering was seen in neoplastic B cells from only 4 of 30 cases, indicating that most B-cell neoplasias were not responsive to this activation pathway. In contrast, the anti-CDw40 MAb consistently stimulated DNA synthesis together with anti-mu or TPA in cells from FCC lymphomas, but not from CLL. Together, these results suggest that activation in different neoplastic B-cell subsets depends on distinct signal transduction mechanisms.

Antigens, CD20↗

PubMed1992

The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.

Signals delivered to B cells via CD40 can synergize with those provided by other B cell surface receptors to induce B cell proliferation and antibody class switching as well as modulate cytokine production and cell adhesion. Recently, it has been shown that the ligand for CD40 is a cell surface protein of approximately 39 kDa expressed by activated T cells, gp39. Here we report on the isolation and characterization of a cDNA clone encoding human gp39, a type II membrane protein with homology to TNF, and the construction and characterization of a soluble recombinant form of gp39. COS cell transfectants expressing gp39 synergized with either anti-CD20 mAb or PMA to drive strong B cell proliferation and alone were able to drive B cells to proliferate weakly. In all cases the B cell proliferation induced by gp39-expressing COS cells was reduced to background levels by the addition of soluble CD40. Unlike gp39-expressing COS cells, recombinant soluble gp39 was not mitogenic alone and required co-stimulation to drive B cell proliferation. These results suggest that B cells require a second signal besides gp39-CD40 to drive proliferation and that soluble gp39 alone in a non-membrane bound form is able to provide co-stimulatory signals to B cells.

Amino Acid Sequence↗

PubMed1991

Myeloablative therapy with autologous bone marrow transplantation as consolidation of remission in patients with follicular lymphoma.

A study has been in progress since June 1985 to evaluate the use of myeloablative therapy (cyclophosphamide [60 mg/kg x 2] and total body irradiation [200 cGy x 6]) followed by reinfusion of autologous bone marrow in patients in second or subsequent remission of B-cell non-Hodgkin's lymphoma. The marrow mononuclear cell fraction is being treated in vitro with three cycles of the monoclonal antibody anti-CD20 (anti-B1, Coulter Immunology) and baby rabbit complement (Pel-Freez). Thirty-eight patients with follicular lymphoma (age range 29-61 years, median 43) have been treated to date. At the time of treatment, 28 patients were in second remission, 7 were in third, and 3 were in more than third remission. Twenty-three patients were in complete remission, 15 had residual disease (7 had lymph nodes less than 2 cm diameter, 4 had less than 10% bone marrow infiltration, 1 had involvement of lymph nodes and bone marrow, and 3 had involvement at other sites). Of the 38 study patients, 32 are alive; 6 have died, 4 in remission. Two of the deaths were treatment related: 1 resulted from cerebral haemorrhage at 29 days; 1 resulted from systemic fungal infection at three months). One patient died from secondary acute myelogenous leukaemia at four years, and another from an unrelated cause. Two patients died following relapse. The median time to engraftment was 28 days (range 15-45 days) for neutrophils greater than 0.5 x 10(9)/L and 28 days (range 15-46 days) for platelets greater than 20 x 10(9)/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity.

Adriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with an oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.

Animals↗

PubMed2026

Disease-modifying therapy uptake in a pediatric-onset multiple sclerosis population, British Columbia, Canada.

BACKGROUND: The treatment of pediatric-onset multiple sclerosis (POMS) is evolving as disease-modifying therapies (DMTs) undergo pediatric clinical trials. However, most DMTs remain off-label in children resulting in barriers to access and variability in treatment patterns across jurisdictions. The aim of this study was to describe trends in DMT uptake in POMS in British Columbia, Canada. METHODS: We utilized linked clinical and administrative datasets to identify MS with onset <18 years-of-age and assess DMT uptake from dispensed prescriptions between January 1, 1996 and March 1, 2020 in British Columbia, Canada. RESULTS: Of 173 POMS cases (median follow-up = 11.5 years), 32 (18%) filled a DMT prescription <18 years-of-age; 76 (44%) did so at any age. Moderate-efficacy therapies (beta-interferons/glatiramer acetate/teriflunomide/dimethyl fumarate) were the initial DMT in 60 cases (79%) overall, however by the end of follow-up a high-efficacy therapy was the most recent DMT dispensed for 52/76 cases (68%). After 2016, anti-CD20 monoclonal antibodies became the most common DMT class dispensed. CONCLUSIONS: Moderate-efficacy therapies were the more common initial DMT dispensed for individuals with POMS, but more than two-thirds eventually received a high-efficacy therapy. Only a minority of POMS cases were first dispensed a DMT under age 18 years.

Disease modifying therapies↗

PubMed2026

Obinutuzumab or Tacrolimus in Primary Membranous Nephropathy.

BACKGROUND: Studies of obinutuzumab, a type II anti-CD20 antibody, have shown efficacy in the treatment of hematologic cancers and autoimmune diseases. An evaluation of the efficacy and safety of obinutuzumab in patients with primary membranous nephropathy is needed. METHODS: In a phase 3 trial, we randomly assigned adults with primary membranous nephropathy in a 1:1 ratio to receive intravenous obinutuzumab or oral tacrolimus. The primary end point was complete remission (defined as a urinary protein-to-creatinine ratio of 0.3 or lower and a stable estimated glomerular filtration rate [eGFR]) at week 104. Key secondary end points were complete or partial remission at week 104, complete remission at week 76, a sustained reduction in the eGFR of at least 30%, duration of complete remission, and change in the Patient-Reported Outcomes Measurement Information System Fatigue T score from baseline to week 104. Fixed-sequence hierarchical testing was performed. Safety was assessed. RESULTS: A total of 142 patients underwent randomization. At week 104, complete remission was observed in 26 of 71 patients in the obinutuzumab group and in 4 of 70 patients in the tacrolimus group (37% vs. 6% with multiple imputation for missing data; adjusted difference, 31 percentage points; 95% CI, 18 to 44; P<0.001). The analyses of complete or partial remission at week 104 and complete remission at week 76 also showed a significant treatment effect. The analysis of a sustained eGFR reduction did not show a significant treatment effect; thus, subsequent end points in the hierarchy were not formally tested for significance. Adverse events of grade 3 or higher were reported in 16 patients (22%) in the obinutuzumab group and in 13 patients (19%) in the tacrolimus group; serious adverse events occurred in 12 (17%) and 10 (14%), respectively. There were 61 and 57 infections per 100 patient-years in the obinutuzumab and tacrolimus groups, respectively; 3 and 4 serious infections per 100 patient-years; and 11 and 14 serious adverse events per 100 patient-years. Adverse drug reactions with obinutuzumab included infusion-related reactions, respiratory tract infections, and neutropenia. One patient in each group died during escape therapy. CONCLUSIONS: Obinutuzumab was superior to tacrolimus in inducing complete remission in patients with primary membranous nephropathy. (Funded by F. Hoffmann-La Roche; MAJESTY ClinicalTrials.gov number, NCT04629248.).

Adult↗

PubMed2026

Histoplasmosis in children: emerging insights and evolving guidelines.

PURPOSE OF REVIEW: This review provides an update on the epidemiology, risk factors, clinical presentation, diagnosis, and management recommendations incorporating recommendations from recent publications including the Infectious Disease Society of America guidelines for the management of pulmonary and disseminated histoplasmosis. RECENT FINDINGS: Updates to the epidemiology of histoplasmosis indicate a broader geographic range than historically defined. Updated guidelines do not recommend routine treatment for asymptomatic, mild and moderate pulmonary histoplasmosis although itraconazole can be offered for immunocompromised children or for prolonged or worsening symptoms. Liposomal amphotericin B is recommended as initial treatment for severe histoplasmosis syndromes (severe pulmonary and disseminated histoplasmosis). Fibrosing mediastinitis, a late complication of histoplasmosis is treated with stenting of vessels and bronchi. Recent studies demonstrate that rituximab (anti-CD20 monoclonal antibody) may stop progression or lead to regression of progressive fibrosis. SUMMARY: Histoplasmosis has manifold manifestations, many of which are self-limited and do not require treatment. Severe histoplasmosis and its complications should be treated with liposomal amphotericin B followed by itraconazole. Clinical trials are needed to assess the efficacy of rituximab for the treatment of fibrosing mediastinitis.

Humans↗

PubMed1990

Inhibition of polyphosphoinositide breakdown and c-myc induction accompanying inhibition of human B-cell activation by two monoclonal antibodies against the leucocyte common antigen (CD45).

In this report we show that the two monoclonal anti-CD45 antibodies, EO-1 and FN-126, potently inhibit G0 to G1 transition and S phase entry in human B cells stimulated with anti-mu and low molecular weight B-cell growth factor. Both antibodies were found to inhibit anti-mu-induced inositol phospholipid breakdown and c-myc mRNA induction. In contrast, EO-1 and FN-126 only partially inhibited the early anti-mu-induced increase in cytoplasmic Ca2+ levels, both in normal and in Ca2(+)-depleted medium. B-cell activation provoked by 12-O-tetradecanoylphorbol 13-acetate (TPA) was not inhibited by these antibodies, except when using high concentrations of EO-1. In addition, both antibodies were found to inhibit G1 entry induced by the anti-CD20 antibody 1F5, which confers an activation of B cells without any detectable increase in [Ca2+]i or in phospholipid metabolism. This indicates that alternative mechanisms in addition to the inhibition of polyphosphoinositide (PI) breakdown are involved in the inhibitory action of these antibodies.

Antibodies, Monoclonal↗

PubMed1988

Immunological typing of acute leukemias: immunoenzymatic staining of fixed cells compared with immunofluorescence staining of unfixed cells in suspension.

A panel of 14 monoclonal antibodies (McAb) against hematopoietic cell surface antigens was applied on mononuclear blood or bone marrow cells from 40 cases of acute leukemia in order to compare immunoenzymatic staining (IE) (alkaline phosphatase) of fixed cells with immunofluorescence staining (IF) of unfixed suspended cells. According to the immunological results, 25 cases were phenotyped as ALL and 15 cases as AML. Cases with blast crisis secondary to chronic myelogenous leukemia (CML-BC) were not represented in this series. In all ALL cases the two methods gave an identical antigenic distribution. In 20 our of 21 cases of non-T-cell ALL, a B-cell progenitor origin was demonstrated by a positive staining reaction with the anti-CD19 McAb AB1 or HD37, and in 10 cases additionally with the anti-CD20 McAb B1 or 1F5. In contrast to the results obtained with IF, IE revealed a poor preservation of the AB1 epitope on CD19, whereas the HD37 epitope was equally well demonstrated by both methods. In 15 cases of AML the distribution of positive versus negative cells with IE or IF was identical for all McAb except J5 (anti-CALLA) (CD10) and B1 (CD20). Thus, 10/15 AML cases expressed CALLA with IE compared to 2/15 with IF. The corresponding figures for B1 were 5/15 and 0/15, respectively. Accordingly, normal myeloid precursor cells were CALLA-positive with IE but negative with IF. The discrepancy probably reflects the fact that, whereas both intracytoplasmatic and membrane-bound antigens are exposed in IE, only the latter are in IF. If the alteration of antigenic accessibility after fixation is considered, IE can safely be used for immunophenotyping of acute leukemia.

Antibodies, Monoclonal↗

PubMed2026

Prolonged SARS-CoV-2 infection in hematologic malignancies: clinical impact, risk factors and intra-host viral evolution.

INTRODUCTION: Prolonged SARS-CoV-2 infection in hematologic patients may go unrecognized. The aim of the study is to describe the incidence, risk factors, viral evolution and clinical outcomes of prolonged SARS-CoV-2 infection in patients with hematologic malignancies. METHODS: This is a prospective, observational study. We performed a longitudinal follow-up rRT-PCR with cycle threshold (Ct) assessment until negativization to 500 patients diagnosed with hematologic malignancies who suffered SARS-CoV-2 infection between March 2020 and August 2023. We considered prolonged COVID-19 to a positive rRT-PCR with a Ct <35 beyond 30 days after microbiological diagnosis with the same viral variant. RESULTS: Prolonged SARS-CoV-2 infection is a complication in 44.8% (156/348) of patients diagnosed with hematologic malignancies with a median time of rRT-PCR positivity of 58 days (IQR 43-88). Active treatment with bispecific antibodies, anti-CD20 antibodies, BTK inhibitors and immunosuppressive drugs for GvHD are significantly associated with prolonged viral shedding; as well as lack of vaccination, lesser booster vaccine doses, absence of anti-S seroconversion after immunization, severe acute infection and delayed antiviral treatment. A 56.4% (88/156) of patients exhibit a pattern of remitting and relapsing symptoms and fluctuant viral load. During those exacerbations, 70.5% of patients experienced an increase in the severity of the acute infection and 34% developed pneumopathy, particularly organizing pneumonia. Persistent COVID-19 caused 54.5% (85/156) of patients to interrupt and 19.9% (31/156) to suspend indefinitely their hematologic treatments. Viral intra-host mutations across the entire viral genome, predominantly within the spike were detected in most patients with prolonged COVID-19, especially in those who received anti-SARS-CoV-2 mAb as sotrovimab (E340, R346, K356) and tixagevimab/cilgavimab (R346, K444 and G446). These substitutions are associated with reduced viral susceptibility. DISCUSSION: Prolonged SARS-CoV-2 infection in hematologic patients is frequent and leads to persistent viral replication, significant morbidity and the emergence of intra-host viral mutations. Optimizing treatments and monitoring viral clearance are medical needs for high-risk patients.

Humans↗

PubMed1992

Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia.

This study for the first time elaborates on cells of the immune system present in benign prostatic hyperplasia (BPH). Compared with normal prostate, all BPH-derived specimens revealed a marked increase of CD45+ leukocytes, characterization of which demonstrated three major cell types, i.e., CD3+ T lymphocytes, CD11c+ macrophages and CD20+ B lymphocytes. Frequencies of CD3+ cells/mm2 of cryocut sections were increased at least 10 times in BPH specimens, and the CD8+:CD4+ T suppressor/cytotoxic:T helper cell ratio was reversed. The infiltrating leukocytes predominantly populate the interstitium and accumulate around epithelial ducts which, however, were found to be invaded and/or destroyed only in a number of cases. Phenotypic alterations of surface antigen expression on prostate epithelial cells in BPH that might be due to the presence of lymphocytes were examined by using monoclonal antibodies (mAb) directed against human leukocyte antigens (HLA). Whereas anti-HLA-DR reactivity in normal prostate is restricted to small numbers of macrophages and includes neither prostate epithelial cells nor prostate T cells, it was found to be dramatically increased in BPH, comprising CD45+ cells and prostate epithelial cells as demonstrated by double-staining with anti-cytokeratin or anti-prostate-specific antigen. A mean of 40% of analyzed epithelial glands in BPH reacted with anti-HLA-DR, but not with anti-DQ or -DP monoclonal antibodies. A new method for the enrichment of prostate-derived lymphocytes was established to facilitate phenotypic analysis by flow cytometry, demonstrating 70 to 80% of enriched CD45+ cells to stain for CD3, approximately 60% thereof for CD4, 30% for CD8, and the remaining 10% with anti-CD20, a pan-B-cell marker. Flow cytometry showed that, in contrast to peripheral T cells, both CD4+ and CD8+ prostatic T cells were positive for the T cell activation markers HLA-DR and interleukin-2-receptor.

Antibodies, Monoclonal↗

PubMed1992

Independent regulation of c-myc, B-myb, and c-myb gene expression by inducers and inhibitors of proliferation in human B lymphocytes.

Although a detailed picture is emerging about the nature of the second messengers involved in B cell activation and proliferation, little is yet known about the intracellular events taking place further downstream. The c-myb proto-oncogene, the structurally related B-myb gene, and c-myc probably code for transcription factors, have been demonstrated to be necessary for the proliferation of hemopoietic cells, and their expression is indeed induced after mitogenic stimulation of T and B lymphocytes. They are therefore likely to be key elements in the regulation of gene expression during proliferation. We have set out to study the regulation of the expression of these two myb genes and of that of c-myc in relation to entry into the different phases of the cell cycle during mitogenic stimulation of resting human B lymphocytes. Resting tonsillar B cells stimulated with the anti-CD20 antibody 1F5 alone are induced to enter the G1 but not the S phase of the cell cycle, whereas co-stimulation with the anti-CD40 antibody G28.5 further drives them to enter the S phase and proliferate. The G28.5 antibody alone has been reported to partially activate and increase the alertness of resting B cells without inducing them to enter G1. In this report we show that increasing the strength of the activating signal leads to progressive induction of the proliferation-related genes studied. Thus the G28.5 antibody alone induces c-myc mRNA only in resting B cells, 1F5 induces both c-myc and B-myb, and the full mitogenic signal given by both antibodies together is accompanied by increased expression of all three--c-myc, B-myb, and c-myb genes. In addition, using a semi-quantitative polymerase chain reaction method, we show that different inhibitors of B cell proliferation, namely, cyclosporin A, an anti-CD19 antibody (HD37), and transforming growth factor beta 1 (TGF-beta 1), inhibit differentially the induction of these same genes after mitogenic stimulation of B cells. Whereas cyclosporin A inhibits induction of all three genes, TGF-beta 1 specifically blocks B-myb induction and CD19 has little effect on either of the genes tested. We conclude that c-myb, B-myb, and c-myc are regulated independently from one another, that induction of c-myc and B-myb together is not sufficient to trigger B cell proliferation, and we suggest that expression of all three is a prerequisite for proliferation to occur.

Antigens, CD↗

PubMed1992

Therapy with unlabeled and 131I-labeled pan-B-cell monoclonal antibodies in nude mice bearing Raji Burkitt's lymphoma xenografts.

Clinical trials of radioimmunotherapy (RIT) of lymphoma have produced frequent tumor regressions and remissions, but it has been difficult to determine to what extent these tumor responses have been due to antibody-specific targeted radiation, nontargeted radiation, and/or cytotoxicity mediated by the carrier monoclonal antibody (MoAb). In this report, RIT was studied in athymic nude mice bearing s.c. Raji human Burkitt's lymphoma xenografts using two different pan-B-cell MoAbs, MB-1 (anti-CD37) and anti-B1 (anti-CD20), which differ in isotype (and thus the potential for interaction with host effector mechanisms) and isotype-matched control antibodies either in the unlabeled state or labeled with 131I. When a single i.p. injection of 300 microCi 131I-labeled MB-1 (IgG1) was compared to treatment with unlabeled MB-1 or 300 microCi 131I-labeled MYS control IgG1 MoAb, an antibody-specific targeted radiation effect of RIT was seen. 131I-labeled MB-1 produced a 44 +/- 19% (SEM) reduction in tumor size at 3 weeks posttreatment, while unlabeled MB-1 or 300 microCi 131I-labeled MYS control IgG1 antibody treatment resulted in continued tumor growth over this period of time. In vitro studies demonstrated that MB-1 was incapable of mediating antibody-dependent cellular cytotoxicity using Raji tumor cell targets and human peripheral blood mononuclear cells. Similar to the MB-1 studies, treatment with 300 microCi 131I-labeled anti-B1 produced a 64% reduction in mean tumor size, while 300 microCi of control antibody resulted in a 58% increase in tumor size over the same 3-week period. In contrast to MB-1, however, unlabeled anti-B1 (an IgG2a MoAb which in vitro studies showed to be capable of antibody-dependent cellular cytotoxicity) also had a substantial antitumor effect. Indeed, 300 microCi 131I-labeled anti-B1 and unlabeled anti-B1 treatment (using an equivalent amount of total protein in the treatment dose) produced a similar specific reduction in tumor size. Increasing the radionuclide dose of anti-B1 to 450 microCi in another experiment did not produce a significant difference in tumor regression compared to a 300-microCi dose. These results suggest that the antitumor effects of 131I-labeled anti-B1 treatment were dominated by antibody-mediated cytotoxicity mechanisms, such that an antibody-specific targeted radiation effect could not be distinguished. In contrast, antibody-specific targeting of radiation was the dominant mechanism of tumor killing with 131I-labeled MB-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Human atherosclerosis. III. Immunocytochemical analysis of the cell composition of lesions of young adults.

There have been only limited immunocytochemical studies of the cell composition of the early lesions of human atherosclerosis, and none that incorporate a comprehensive panel of antibodies to various cell types and subsets. The authors thus performed a prospective study of 27 lesions from 16 different individuals ranging in age from 15 to 34 years. These were all lesions that appeared grossly as slightly raised, yellow fatty streaks in the posterior ascending aorta, but on histologic examination had varying degrees of round-cell, spindle-cell, and foam-cell accumulation. Using a panel of antibodies, including monoclonal antibodies specific for smooth muscle cells [HHF35], human macrophages [HAM56], endothelial cells [monoclonal antibodies to F. VIII related antigen], lymphocytes [anti-CD45, anti-CD20, anti-CD45RO, anti-T-cell receptor], it was revealed that the predominant cell type in these early lesions was the smooth muscle cell, including the vast majority of the foam cells, which tended to appear in the deeper regions of the lesions. There were variable numbers of smooth muscle cells and lymphocytes; the latter were exclusively T cells. It is concluded that in atherosclerotic lesions of young adults, which may represent various stages of fatty streak formation and advanced fatty streaks, smooth muscle cell accumulation may be an early event.

Adolescent↗