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D Olive

Publications and source records attributed to D Olive.

At least 91 records · Page 5Linked to original sources
PubMed1998

Anti-GM-CSF monoclonal antibody therapy for refractory acute leukemia.

Several phase I trials and pilot studies using Monoclonal Antibody (MoAb) have been performed in B-cell neoplasms, but this approach has not until now been extensively tested in myeloid leukemias. Recently, we evaluated the use of anti-Granulocyte-Macrophage Colony-Stimulating Factor MoAb (Anti-GM-CSF MoAb) in acute myeloid leukemia (AML). Eight patients fulfilled inclusion criteria and received a single course of Anti-GM-CSF MoAb infusion during 5 to 15 days. Anti-GM-CSF MoAb was well tolerated and was detectable in pharmacokinetics studies. Using Human Anti-Rat Antibodies (HARA), we also observed an immunological response to the MoAb. Despite sufficient levels detected in the serum and biological activity of Anti-GM-CSF MoAb in vivo, no anti-leukemic effect was noted, except for one patient who had a decrease of 50% in the marrow blast cell mass. These observations indicate that leukemic proliferation in vivo involves a complex network spanning many mechanisms, and inhibition of leukemia is not effective if only one of these key targets is attacked. The development of these new approaches may be more effective in the future.

Adult↗
PubMed1998

A phase II study of interleukin-2 in 49 patients with relapsed or refractory acute leukemia.

In this report we present the results of a multicenter phase II study of high-dose recombinant Interleukin-2 (rIL-2) in patients with refractory or relapsed acute leukemia. Forty-nine patients with acute myeloid leukemia (AML: 30 patients) or acute lymphoblastic leukemia (ALL: 19 patients) were included. Median age was 30 years (range: 4-71). Four patients were treated for primary refractory disease and 45 for relapsed disease (16 patients > 2nd relapse). Twenty-four patients (49%) had previously received bone marrow transplantation (allogeneic: 5, autologous: 19). Patients were scheduled to receive three 5-day cycles of rIL-2 given every other week. rIL-2 was administered as bolus I.V. infusion of 8 x 10(6) UI/m2 every 8 hours during cycle I and every 12 hours during cycles 2 and 3. Patients received a mean of 76% of rIL-2 planned dose. Main toxicity was hematologic (grade IV thrombopenia: 84%). Hemodynamic and metabolic toxicities lead to treatment discontinuation in 10 patients (20%). Strong immune activation was achieved including a significant increase in activated T-cells and Lymphokine-Activating-Killer cell (LAK) activity. Twenty-seven out of 30 AML patients could be evaluated for response: 2(7%) achieved complete remission (CR) which lasted 3 and 4 months. No response was observed in the 18 assessable ALL patients, most of whom (77 %) presented absolute drug resistance. These results show that this high dose rIL-2 regimen induces significant biological effects and provides some anti-leukemic activity in patients with advanced leukemia. Considering the severe toxicity observed and the limited remission rate achieved here, rIL-2 does not appear to be a valuable therapeutic option for such patients. However, the undoubted anti-leukemic activity of this cytokine invites further investigation especially in the minimal residual disease situation.

Adolescent↗
PubMed1998

[Tumor antigens recognized by T-lymphocytes in human cancers. New advances and therapeutic perspectives].

The melanoma antigen coded by the MAGE-1 gene was the first tumor antigen described in human cancer. Genetic, biochemical, and "candidate peptide" strategies have been used to identify antigenic peptides presented to T-cells by class I major histocompatibility complex antigens. Antigens have now been characterized in a wide variety of tumor types. Five categories have been described based on expression profile. These antigens are detailed in this review. Among the tumor antigens produced as a result of intratumoral mutations, some are of special interest because of their potentially oncogenic effects. These new data can be expected to lead to the development of novel anticancer treatments based on specific immunotherapy. Pilot clinical studies are ongoing.

Antigen Presentation↗
PubMed1997

Temporal and subunit-specific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation.

Stimulation of highly purified primary T lymphocytes through CD2 and CD28 adhesion molecules induces a long-term proliferation, dependent on persistent autocrine secretion of interleukin 2 (IL-2), high and prolonged expression of inducible CD25/IL-2 receptor alpha chain (IL-2Ralpha), and secretion of growth factors such as the granulocyte-macrophage colony-stimulating factor (GM-CSF). CD28 costimulation appears to activate cytokine gene expression through conserved kappaB-related CD28 response (CD28RE) or cytokine 1 (CK-1) elements in addition to canonical NF-kappaB-binding sites. In this report, we assess: 1) the evolution of the expression, over an 8-day time period, of the Rel/NF-kappaB family of proteins in costimulated versus TcR/CD3-stimulated primary T cells; 2) the impact of changes on the in vitro occupancy of GM-CSF kappaB and CK-1, as well as IL-2Ralpha kappaB sites; and 3) the differential regulation of newly synthesized p65 and c-Rel by IkappaB proteins. We show that CD2+CD28 stimulation specifically induces, at maximal T cell proliferation phase, sustained nuclear overexpression of NFKB2 p52 and c-Rel subunits which might rely on long-lasting processing of p100 precursor for p52 and increased neosynthesis of c-Rel. This up-regulation correlates with sustained occupancy of GM-CSF kappaB and CK-1 elements by both proteins. Conversely, these subunits do not appear to bind to the IL-2Ralpha kappaB site. Costimulation, but not TcR/CD3 stimulation, appears supported by sustained down-regulation of both IkappaBalpha and -beta regulators. Furthermore, contrary to p65, c-Rel appears to display little affinity for p105, p100 and IkappaBalpha regulators.

CD28 Antigens↗
PubMed1997

Evidence that a kinase distinct from protein kinase C and phosphatidylinositol 3-kinase mediates ligation-dependent serine/threonine phosphorylation of the T-lymphocyte co-stimulatory molecule CD28.

The CD28 cytoplasmic tail contains several potential phosphorylation sites for the serine/threonine kinase protein kinase C (PKC) and/or proline-directed serine/threonine kinases, such as extracellular signal-regulated kinases. We demonstrate that ligation of CD28 by B7.1 results in strong serine/threonine phosphorylation of CD28. It is unlikely that ligation-stimulated phosphorylation of CD28 is mediated via activation of PKC, since it was not prevented by pre-treatment of Jurkat cells with inhibitors of PKC, and it was not mimicked by treatment with PKC activators such as PMA. Nevertheless, despite for lack of detectable effects of PMA treatment on CD28 phosphorylation, PMA did partially inhibit the association of CD28 with the putative signalling molecule phosphatidylinositol 3-kinase (PI 3-kinase) and the subsequent accumulation of PtdIns(3,4,5)P3. PI 3-kinase exhibits dual specificity as both a lipid kinase and a protein serine kinase, and site-specific mutagenesis of the Tyr173 residue in the CD28 cytoplasmic tail, which abolishes CD28 coupling to PI 3-kinase [Pages, Ragueneau, Rottapel, Truneh, Nunes, Imbert and Olive (1994) Nature (London) 369, 327-329], also prevents ligation-stimulated phosphorylation of CD28. However, the two PI 3-kinase inhibitors wortmannin and LY294002 had no effect on phosphorylation of CD28 after ligation by B7.1. This study therefore demonstrates that (1) a CD28-activated serine/threonine kinase distinct from both PKC and PI 3-kinase mediates ligation-stimulated CD28 phosphorylation, and (2) the PMA-stimulated down-regulation of the coupling of CD28 to PI 3-kinase is not due to PMA-stimulated phosphorylation of CD28.

B7-1 Antigen↗
PubMed1997

In vivo expression of the CTLA4 inhibitory receptor in malignant and reactive cells from human lymphomas.

The CTLA4 receptor is a CD28 homologue which induces inhibitory effect on activated T-cells. Peripheral T-cells proliferate spontaneously in CTLA4-deficient mice. These results led to an analysis of CTLA4 expression in human lymphomas (n = 82) including Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHLs), using immunohistochemistry. CTLA4 was present in neoplastic cells from most (10/11) T-cell malignancies, except for anaplastic and lymphoblastic subtypes (0/4). Malignant B-cells from rare (3/55) B-NHLs (all of follicular subtype) were also CTLA4-positive. Other B-NHLs (52/55) were negative in malignant B-cells and occasionally positive in T-cells. Reactive small lymphocytes, but not Reed-Sternberg cells, from all (12/12) HD cases were strongly CTLA4-positive. The CTLA4 ligands CD80 and CD86 were simultaneously expressed in most CTLA4-negative lymphoma cases. CTLA4 is thus expressed either in the reactive or in the malignant cell populations, depending on the lymphoma subtype. These results provide new insights leading towards therapeutic strategies based either on enhancement of anti-tumour immunity by CTLA4 blockade in reactive lymphocytes or on triggering of a CTLA4-mediated inhibitory pathway in lymphoma cells.

Abatacept↗
PubMed1997

CD28 can promote T cell survival through a phosphatidylinositol 3-kinase-independent mechanism.

Phosphatidylinositol 3(PI3)-kinase is implicated in various biological responses, including protection from apoptosis, although its role in antigen-induced T cell death and the molecular effectors it triggers remains ill-defined. Here, we investigated the role of PI3-kinase activity in the prevention of T cell receptor/CD3-induced cell death by CD28. PI3-kinase inhibitors blocked the up-regulation of Bcl-X(L) by CD28, without impairing the prevention of T cell receptor/CD3-triggered apoptosis by CD28, hence showing the existence of a cell-survival pathway independent of PI3-kinase activity and up-regulation of Bcl-X(L). Instead, we show that up-regulation of FasL which is instrumental in CD3-induced apoptosis was prevented upon CD28 co-stimulation. These results indicate that PI3-kinase couples CD28 to Bcl-X(L) up-regulation and provide a molecular basis for the role of CD28 in cell survival through a PI3-kinase-independent mechanism including FasL down-regulation.

Animals↗
PubMed1997

Alternative medical treatment for endometriosis.

Although a limited number of drugs make up the mainstay of treatment of endometriosis, many alternative medications have been used in an attempt to improve efficacy. Some have been rigorously evaluated and are of proven benefit, while others show promise in preliminary trials or in animal models. Proper methods of evaluating medical therapy and outcomes are essential. This chapter provides a review of new medical therapies for the treatment of endometriosis and their evaluation.

Complementary Therapies↗
PubMed1997

The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission.

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML = 22; ALL = 28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL-2 (RU 49637 from Roussel-Uclaf, Romainville, France) was started after hematological reconstitution an average of 72 +/- 22 days post transplant. The schedule consisted of a continuous infusion over 5 cycles (Cycle 1: 5 days starting on day 1; cycle 2-5: 2 days starting on day 15, 29, 43 and 57). Patients were treated at 4 different dosages (12 (N = 40), 16 (N = 3), 20 (N = 2), 24 (N = 5) x 10(6) IU/m2/day). Toxicities were mainly related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 +/- 49 10(6) IU/m2. Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimu-lation of both T-cells (P < 0.05) and natural killer (NK) cells (P < 0.05) and associated cytolytic functions (P < 0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 +/- 6% overall, 39 +/- 10% and 43 +/- 8% for AML and ALL respectively. Relapse probabilities at 3 years are 59 +/- 11% for AML and 57 +/- 8% for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early after reaching first complete remission.

Acute Disease↗
PubMed1997

Evaluation of Doppler ultrasonography as a means of monitoring in vitro fertilization and embryo transfer cycles: preliminary results and findings.

In vitro fertilization imposes an emotional and financial burden on infertile couples and has a relatively low success rate, but it offers their only means of conception. As uteroovarian perfusion varies during the menstrual cycle and may be related to uterine receptivity, we sought to identify hemodynamic parameters that would be of use in monitoring stimulated cycles and in making decisions about the timing of in vitro fertilization. Uteroovarian perfusion patterns in patients undergoing ovulation induction and embryo transfer were compared with normally cycling volunteers. Significant changes in ovarian perfusion were seen with suppression and stimulation. Despite manipulation, no difference in uterine perfusion was seen between the groups in the late luteal phase, the crucial time of implantation. We conclude that Doppler ultrasonography may be useful in monitoring artificial cycles and in predicting uterine receptivity.

Adult↗
PubMed1997

Clinical and biological effects of gamma interferon and the combination of gamma interferon and interleukin-2 after autologous bone marrow transplantation.

Interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) have shown synergistic immunomodulatory and anti-tumor effects in preclinical studies. The present study was designed to assess the effects of the combination of these cytokines after autologous bone marrow transplantation (ABMT). Ten patients received rIFN-gamma alone and 13 patients the combination of rIFN-gamma + rIL-2. Patients received transplants because of lymphoma (10 patients), acute leukemia (3 patients) or solid tumors (10 patients). Immunotherapy was started at a median of 67 days after ABMT. All patients received either 5 x 10(6) (8 pts) or 10 x 10(6) IU/m2 (16 pts) rIFN-gamma by subcutaneous injection 3 times weekly for 14 weeks. rIL-2 therapy consisted of 5 cycles of continuous intravenous infusion of 12 x 10(6) IU/m2/day starting 1 week after administration of rIFN-gamma. In the rIFN-gamma group, toxicity was mild and some biological changes were seen (NK/LAK activation, increase of phagocytosis and of NBT reduction). The combination of rIFN-gamma with rIL-2 did not increase the usual rIL-2 toxicity. NK/LAK cytotoxicity was strongly activated after the first cycle of rIL-2 and was maintained until the end of therapy. Granulocyte chemotaxis was defective after cycle 1 but recovered thereafter. We conclude that the administration of rIFN-gamma + rIL-2 is feasible after ABMT. Our data suggest that the combination may have prolonged the immunologic activation provided by rIL-2 and some improvement of the deleterious effects of rIL-2 on granulocyte functions was achieved. Controlled studies are warranted to assess the impact of this strategy on biological response and patient outcome.

Adjuvants, Immunologic↗
PubMed1996

Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association.

Through the interaction with its ligands, CD80/B7-1 and CD86/B7-2 or B70, the human CD28 molecule plays a major functional role as a costimulator of T cells along with the CD3-TcR complex. We and others have previously reported that phosphatidylinositol 3-kinase inducibly associates with CD28. This association is mediated by the SH2 domains of the p85 adaptor subunit interacting with a cytoplasmic YMNM consensus motif present in CD28 at position 173-176. Disruption of this binding site by site-directed mutagenesis abolishes CD28-induced activation events in a murine T-cell hybridoma transfected with human CD28 gene. Here we show that the last 10 residues of the intracytoplasmic domain of CD28 (residues 193-202) are required for its costimulatory function. These residues are involved in interleukin-2 secretion, p85 binding, and CD28-associated phosphatidylinositol 3-kinase activity. In contrast, the CD28/CD8O interaction is unaffected by this deletion, as is the induction of other second messengers such as the rise in intracellular calcium and tyrosine phosphorylation of CD28-specific substrates. Furthermore, we also demonstrate that, within these residues, the tyrosine at position 200 is involved in p85 binding, probably together with the short proline-rich motif present between residues 190 and 194 (PYAPP).

Amino Acid Sequence↗
PubMed1996

Physical and functional interaction of Nef with Lck. HIV-1 Nef-induced T-cell signaling defects.

The nef gene is unique to the primate lentiviruses and encodes a cytoplasmic membrane-associated protein that affects T-cell signaling and is essential for both maintenance of a high virus load in vivo and for disease progression. Here we investigated the perturbation of cell signaling by Nef in T-cells and found that Nef interacts with the T-cell restricted Lek tyrosine kinase both in vitro and in vivo. The molecular basis for this interaction was analyzed. We show that cell-derived Nef is precipitated in a synergistic manner by the recombinant Src homology 2 (SH2) and SH3 domains from Lck. A functional proline-rich motif and the tyrosine phosphorylation of Nef were evidenced as likely participants in this interaction. The precipitation of Nef by the Lck recombinant proteins was specific, since neither Fyn, Csk, p85 phosphatidylinositol 3-kinase nor phospholipase Cgamma SH2 domains coprecipitated Nef from T-cells. Finally, depressed Lck kinase activity resulted from the presence of Nef, both in vitro and in intact cells, and nef expression resulted in impairment of both proximal and distal Lck-mediated signaling events. These results provide a molecular basis for the Nef-induced T-cell signaling defect and its role in AIDS pathogenesis.

Amino Acid Sequence↗
PubMed1996

Signal transduction by CD28 costimulatory receptor on T cells. B7-1 and B7-2 regulation of tyrosine kinase adaptor molecules.

This study compares the biochemical responses in T cells activated with the CD28 ligands B7-1 and B7-2. The patterns of tyrosine phosphorylation induced in T cells by these two CD28 ligands are identical, but clearly different from the tyrosine phosphorylation induced by the T cell receptor (TCR). The TCR regulates protein complexes mediated by the adapter Grb2 both in vivo and in vitro. In contrast, there is no apparent regulation of in vivo Grb2 complexes in response to B7-1 or B7-2. Rather, B7-1 and B7-2 both induce tyrosine phosphorylation of a different adaptor protein, p62. The regulation of p62 is a unique CD28 response that is not shared with the TCR. These data indicate that B7-1 and B7-2 induce identical tyrosine kinase signal transduction pathways. The data show also that the TCR and CD28 couple to different adapter proteins, which could explain the divergence of TCR and CD28 signal transduction pathways during T cell activation.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Specific Th1 cytokine down-regulation associated with primary clinically derived human immunodeficiency virus type 1 Nef gene-induced expression.

HIV-1 infection is associated with a progressive and functional decline in the CD4+ lymphoid Th1 subset. Here, we propose that the HIV nef gene product may function as a specific regulator of Th1 cytokine production. By use of a T cell-specific inducible expression system, we show that upon T cell activation, induced nef expression down-regulated both IL-2 and IFN-gamma production in a dose-dependent manner, whereas IL-4, IL-9, IL-13, IL-8, and TNF-alpha production remained unaffected. In addition to this, independent transfected clones expressing various nef genes, including nef sequences amplified directly from an HIV-1 primary clinical isolate, displayed a similar pattern of cytokine expression. The specific Th1 impairment induced by nef, therefore, seems to be an important and conserved feature of HIV-1 infection and may represent a significant function of this viral gene in AIDS pathogenesis.

Base Sequence↗
PubMed1996

Comparison of CD28-B7.1 and B7.2 functional interaction in resting human T cells: phosphatidylinositol 3-kinase association to CD28 and cytokine production.

CD28 is a 44kDa homodimer present on T cells providing an important costimulatory signal for T cell proliferation, cytokine production and cytokine receptor expression. CD28 activation is mediated by interaction with its counter-receptors, B7.1/CD80 and B7.2/B70/CD86. The biochemical basis of these co-stimulatory signals are still poorly understood, particularly in resting T cells. However, various biochemical pathways such as tyrosine phosphorylation, phospholipase C, sphingomyelinase and phosphatidylinositol 3-kinase (PI3-K) activation have been reported to play a role in CD28 signaling in tumor T cell lines and CD28-transfected cells or pre-activated T cells. In addition, recent reports propose that CD28-B7.1 and B7.2 interaction could be involved in the production of Th1 and Th2 cytokines, respectively, but the putative biochemical basis for these different functions is still unknown. We have analyzed the functional and molecular consequences of CD28 activation by B7.1 and B7.2 in human resting T cells. We demonstrate in this report that both CD28-B7.1 and CD28-B7.2 interactions induce the association of PI3-K to CD28 in the CD4 subpopulation, whereas it was barely detectable in CD8 cells. This association involves the binding of the src homology domain 2 (SH2) of p85 to tyrosine-phosphorylated CD28 and does not require pre-activation by CD3-T cell receptor. Worthmannin, a specific inhibitor of PI3-K enzymatic activity within the nanomolar range also inhibits the interleukin-2 production induced by costimulation mediated by either the B7.1- and B7.2-transfected cells or CD28 monoclonal antibodies. The only slight difference between B7.1 and B7.2 costimulation is the IC50 of worthmannin being 25 and 110 nM, respectively, which could suggest differences in their activation of the T cell PI3-K.

Androstadienes↗
PubMed1996

Evidence for intact CD28 signaling in T cell hyporesponsiveness induced by the HIV-1 nef gene.

Infection by human immunodeficiency virus (HIV)-1 is associated with quantitative and qualitative T cell alterations that severely impair the host's immune defense system. The molecular basis for this immunosuppression remains unclear. Peripheral blood mononuclear cells (PBMC) isolated from patients show markedly decreased interleukin (IL)-2 secretion but unaffected or even increased T helper (Th)2 cytokine production. T cell functional defects were recently reported to correlate more with T cell receptor (TcR) signaling, whereas signals provided by ligation of co-receptors CD27 and CD28 appeared to be preserved. Among the various mechanisms proposed to be involved in HIV-1-induced T cell dysfunction, we and others have reported that the nef gene product exhibited significant immunosuppressive activity. By using an inducible stably integrated nef gene, we demonstrated that Nef specifically down-regulated IL-2 and interferon (IFN)-gama produced upon TcR triggering. Here, using the same experimental system, we extended our initial observations to additional mitogenic signals, and investigated the co-stimulatory function of CD28. Nef down-regulated IL-2, but not IL-4 produced upon induction by combinations of mitogens that mimicked TcR signals together with CD28 mAb or CD28's natural ligand (CD80 and CD86). However, the co-signals provided by CD28 to up-regulate IL-2 induction were unaffected by Nef, since IL-2 produced by nef-transfected cells was proportionally enhanced to the same extent as that of control cells, either upon stimulation by the CD28 mAb or CD80 and CD86. In addition, phosphatidylinositol-3 kinase recruitment induced upon CD28 triggering was also found to be unaltered by nef expression. Together with the observation that similar levels of the Nef protein were detected in nef-transfected cells and upon infection of PBMC, these data suggest a selective immunosuppression induced by nef in human T cells by altering TcR signaling without detectable impact on CD28 co-receptor function. These data agree with the T cell defects observed in PBMC isolated from HIV-infected individuals.

CD28 Antigens↗