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Biomedical subjects

L Degos

Publications and source records attributed to L Degos.

At least 145 records · Page 8Linked to original sources
PubMed1991

Recognition of HLA-B27 by mouse cytotoxic T-cell clones: a transgenic mouse model.

As a basis for the characterization of mouse T cells involved in the recognition of xenogeneic HLA molecules, a panel of HLA-B27-reactive cytotoxic T-cell clones was generated upon stimulation by cells from HLA-B27-transgenic mice. The HLA-B27-induced T-cell response was found to comprise two categories of clones: some recognizing HLA-B27 independent of H-2 molecules expressed by the target cells (unrestricted clones), others recognizing HLA-B27 in an H-2-restricted manner. The unrestricted clones exhibited diverse specificities, as judged from their various cross-reactivities with other xenogeneic (HLA) or allogeneic (H-2) molecules. In addition, although most of the unrestricted clones were able to react with both mouse and human HLA-B27-transgenic mice. The HLA-B27-induced T-cell which reacted only with HLA-B27-positive mouse, and not human cells. These findings illustrate that both H-2-restricted and unrestricted T cells with diverse specificities contribute to HLA-B27-xenorecognition.

Animals↗
PubMed1991

Modulation of allogenic reaction by ticlopidine treatment.

Ability of response in proliferation and cytotoxicity of lymphocytes, after in vitro allogeneic reaction was tested in three independent series of experiments, before and after seven days of ticlopidine treatment (500 mg daily) taken by normal adult individuals. In the third experiment, blood samples were taken twice before treatment and twice during the treatment. In two of the three series of experiments the ability of proliferation of responding cells in a mixed lymphocyte reaction was decreased (P less than 0.01). Cytotoxicity was reduced in the three series of experiments when the combination effector/target cells after treatment was compared with the combination before treatment (P less than 0.01 - 0.001), at various effector to target cells ratios for one target (50:1 and 100:1).

Adjuvants, Immunologic↗
PubMed1991

Analysis of primary HLA-specific cytotoxic T cell response in graft-draining lymph nodes--a transgenic mouse model for in vivo recognition of human MHC antigens.

In order to characterize primary anti-HLA cytotoxic T cells and especially those involved in graft rejection, we have utilized a transgenic mouse model. Mice (non-transgenic and HLA-transgenic) were grafted with spleen cells originating from H-2-matched transgenic mice expressing HLA-B27 molecules, and cells from graft-draining lymph nodes were tested in CML assay to investigate the primary in vivo induced CTL responses. The results showed that HLA-B27 molecules were able to raise strong primary xenogeneic CTL responses. Results from split-well analysis indicated that although recognition of HLA-B27 by primary CTL induced in nontransgenic recipients is predominantly unrestricted by H-2, a small fraction (ranging from 2% to 27%) of the primary in vivo induced CTL is able to recognize HLA-B27 in an H-2-restricted manner. HLA-specific H-2-restricted CTL had never so far been demonstrated in the primary T cell response. Thus the protocol used in our study for the generation of a primary CTL response seems to provide not only a more appropriate representation of cytotoxic T cells sensitized by a graft, but also to be a more sensitive approach than the usually used in vitro mixed lymphocyte culture.

Animals↗
PubMed1991

HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme.

Erythema multiforme (EM) is an acute, episodic inflammatory disorder of the skin and mucous membranes of various etiology that could be related to immunologic hypersensitivity response. EM has been previously reported to be associated with serologically defined HLA-DRw53 and DQw3 antigens. In this report, we reevaluate the role of HLA class II alleles in EM manifestations. With use of the polymerase chain reaction, followed by sequence-specific oligonucleotide hybridization, 35 unrelated Caucasian EM patients and 80 randomly selected healthy subjects were studied, and the DRB3, DRB4, DQA1, and DQB1 alleles were analyzed. The comparison of frequencies of these alleles indicates that (i) susceptibility to EM disease is more associated with the HLA-DQ than the HLA-DR subregions and (ii) that the DQB1*0301 is the most frequent allele among EM patients. Sixty-six percent of the patients had the DQB1*0301 allele compared to 31% of the controls (RR = 4.1; p less than 0.001). An even stronger DQB1*0301 association was found in the patient group with herpes-associated EM (76%; RR = 6.5; p less than 0.001). Our data demonstrate a clear association between an HLA-DQB1 allele and susceptibility to EM.

Adolescent↗
PubMed1991

All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells.

We have recently demonstrated that all-trans retinoic acid (RA), the active metabolite of vitamin A, is an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (AML3). We have further shown that, in these AML3 cells, the gene of the retinoic acid receptor-alpha (RAR alpha) is translocated from chromosome 17 to chromosome 15, and fused to a new gene, PLM. This results in the expression of both normal and chimeric RAR alpha transcripts in AML3 cells. The PLM-RAR alpha protein may account for the impairment of differentiation and thus leukemogenesis, but not for the paradoxical efficacy of RA in these cells. In an attempt to elucidate RA's differentiative effect in AML3 patients, the present work examined the in vitro and in vivo modulation of the normal RAR alpha transcripts by all-trans RA in seven cases of AML3. In all samples, Northern blot analysis revealed a low expression of the two normal RAR alpha transcripts compared with other human myeloid leukemic cells. No modulation was observed after 4-8 d of in vivo therapy with all-trans RA 45 mg/m2 per d. In vitro incubation with all-trans RA, however, increased the level of expression of the normal RAR alpha transcripts in AML3 cells but not in other AML leukemic subtypes. This modulation of the two normal RAR alpha transcripts appeared to be an early and primary event of RA's differentiating effect. We therefore suggest that up-regulation of the normal RAR alpha gene expression by pharmacological concentrations of all-trans RA may restore the normal differentiation pathway in these cells.

Carrier Proteins↗
PubMed1991

Phenotypic reversion in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 t (15; 17) and with a bleeding diathesis previously attributed to a disseminated intravascular coagulation which is recently also related to a primary fibrinolysis. The high percentage of early deaths, around 20% experienced by APL patients, is generally due to the haemorrhagic syndrome. A new feature is the highly effectiveness of all-trans retinoic acid treatment, a vitamin A derivative, for inducing complete remission in patients. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore recent molecular studies revealed that the breakpoints of the t(15; 17) translocation are clustered in the gene of retinoic acid receptor a, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for the leukemogenesis. The abnormal program made by the aberrant transcript might be overcome by pharmacological concentration of RA which induces an over expression of the normal allele and a normal activity of the aberrant product.

Carrier Proteins↗
PubMed1991

Granulocytic colony-stimulating factors (G-CSF and GM-CSF) in the treatment of adult acute myeloid leukemia.

Large randomized trials have shown that granulocytic colony-stimulating factors (G-CSF and GM-CSF) may be interesting in vivo in promoting neutrophil recovery after high-dose myelosuppressive therapy in some clinical settings. However, any beneficial effect on survival was not yet demonstrated. Granulocytic CSFs act as growth and viability factors on myeloid leukemic cells and their use in acute myeloid leukemias (AML) is theorically not without risk. Paradoxically, these CSFs will maybe be usefull in the future as a part of AML treatment. First, the high early mortality rate in elderly AML patients after intensive chemotherapy should allow a demonstration of a CSF-induced improvement of survival. Secondly, GM-CSF should increase the efficacy of cell cycle dependent cytotoxic drugs based on recruitment of quiescent leukemic cells. Third, granulocytic CSFs should be used to induce programmed cell death in myeloid leukemic cells.

Acute Disease↗
PubMed1991

Production of a monoclonal antibody (2B44) reactive on a shared epitope on dendritic reticulum cells, smooth muscle cells of vessels and Reed-Sternberg cells.

Lymph node cells from a patient with Hodgkin's disease (HD) were cultured without Epstein-Barr virus (EBV) or leukine adjuvant. A cell line (719-AB) emerged from the culture after four weeks. The cell line express CD20 (79%), CD 21 (30%), CD30 (63%), CD 35 (61%) antigens and weakly CD25 (19%). using Southern Blot technique, the existence of specific EBV DNA and polyclonal immunoglobulin genes rearrangement were observed in the cell line. In order to obtain a monoclonal antibodies (MoAb), mice Balb/C were immunized with this cell line. The splenic cells suspension of immunized animals were fused with the mouse myeloma NS1. Antibody IgM kappa from secreting clones 2B44 was studied using both indirect immunofluorescence with labeled anti-mouse immunoglobulin and immunohistochemistry based on alkaline phosphatase/antiphosphatase complex (APAAP) and ModAMeX technique on a panel of normal or pathological cells. Normal peripheral lymphocytes, monocytes, polymorphonuclear cells, and erythrocytes, did not react. The MoAb 2B44 recognized the dendritic reticulum cells and the smooth muscle cells of vessels on frozen section and paraffin section from HD or reactive lymph nodes. On specially processed paraffin sections (ModAMeX) Reed-Sternberg cells (RSC) were reactive with 2B44 MoAb (in 2 cases out of 5 tested). The molecular weight of the antigen recognized by 2B44 MoAb is of 37 kd. The description of a new epitope shared by different histological components might be of interest for defining a new cluster and better understanding the nature of RSC.

Antibodies, Monoclonal↗
PubMed1991

Pharmacokinetics of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.

It has been shown that patients with acute promyelocytic leukemia (AML3 subtype) treated with all-trans retinoic acid (all-trans RA), 45 mg/m2/day, achieve complete remission through differentiation of the leukemic clone to mature myeloid cells, which die spontaneously. The pharmacokinetics of all-trans RA given by mouth were studied in 15 AML3 patients. Blood samples were drawn for 24 h following a single oral dose of 45 mg/m2 and assayed for all-trans RA and 13-cis retinoic acid (13-cis RA) plasma concentrations by specific high-performance liquid chromatography. In one patient all-trans RA and 13-cis RA levels were below the detection limits at all times. In the other patients, the time to peak concentration of all-trans RA was between 60 and 210 min (median 90 min) after ingestion, with maximum concentrations between 0.03 and 2.5 micrograms/ml (median 0.4 micrograms/ml). These concentrations were within the in vitro differentiating concentration range of all-trans RA for these patients' cells. In nine patients, enterohepatic cycling was suggested by the presence on the concentration versus time curve of a secondary peak that occurred at meal times. The apparent plasma elimination half-life was between 16.8 and 77.4 min (median 30 min). Detectable plasma levels of 13-cis RA in 12 patients indicated in vivo isomerization of all-trans RA. Despite the high inter-individual variability of all-trans RA pharmacokinetics in these patients, high blast cell counts and failure to respond to differentiation treatment tended to be associated with low all-trans RA Cmax values and high clearance estimates.

Administration, Oral↗
PubMed1991

[Biological parameters of the efficiency of retinoic acid in acute leukemia].

We have previously shown that all-trans retinoic acid therapy is an alternative therapy for acute promyelocytic leukemia (AML3) via differentiation of the leukemic cells. The t(15;17) translocation is specifically found in this leukemia. We and others have shown that through this translocation the RAR alpha gene is rearranged and its expression altered in AML3 cells. The gene is truncated and fused to a novel gene (PLM). This results in a fusion protein whose transactivating properties may be implicated in the leukemogenesis of this disease. Retinoic acid cytoplasmic binding proteins (CRABP and CRBP) are not detected by PAGE chromatography in normal or malignant hematopoietic cells. During all-trans RA therapy, a) all-trans RA plasma concentrations are within in vitro differentiating concentration (med. 0.4 microgram/ml); b) increased expression of the normal remaining RAR alpha allele is rapidly observed and may explain the paradoxical induction of RA differentiation in these cells; c) CRABPII is induced in the bone marrow cells of AML3 patients and remains detectable 1 month after withdrawal of RA. AML3 in relapse after RA therapy is always less sensitive to RA in vitro and in vivo. Our data suggest that modification of the metabolisation pathways of RA may be one of parameters linked to this resistance. It appears that the efficacy of all-trans RA is the resultant of multiple parameters (RA concentration, ratio of PML/RAR alpha transcripts to normal RAR alpha, CRABP) which need to be defined to efficiently monitor all-trans RA therapy in APL.

Drug Administration Schedule↗
PubMed1991

Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinoic acid.

Two recent reports have described major clinical benefits from all-trans-retinoic acid (tRA) therapy of patients with promyelocytic leukemia (APL). This paper describes the first patient with a blast crisis of chronic myelogenous leukemia (CML-BC) who responded to oral tRA therapy. In vitro marrow studies, including clonogenic assays, immunopheno-typing, cytogenetics and premature chromosome condensation together with chromosome painting provided evidence for the in vivo differentiation and maturation of the malignant cells. The patient achieved a partial remission with reversal of all clinical features of disease, including normalization of peripheral blood counts, complete resolution of fever, fatigue and splenomegaly, and marked maturation of the bone marrow. This response to tRA in CML-BC is unique, and broadens the spectrum of diseases which may respond to retinoids.

Antineoplastic Agents↗
PubMed1990

All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results.

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases--were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.

Adult↗
PubMed1990

All-trans retinoic acid in acute promyelocytic leukemias. II. In vitro studies: structure-function relationship.

All-trans retinoic acid induces leukemic cells from patients with acute promyelocytic leukemia (M3) to differentiate in vitro to mature granulocytes which express the CD15 antigen and are capable of respiratory burst function. Of 35 M3 samples, only one failed to respond. In eight cases, we compared the efficacy of two naturally occurring isomers of retinoic acid, all-trans RA and 13-cis RA. Both isomers induce maximal differentiation at 10(-6) mol/L. The maximal response was maintained at 10(-7) mol/L for the all-trans but not for the 13-cis RA. We also observed that the metabolites 4-oxo-all-trans and 4-oxo-13-cis were effective at 10(-6) mol/L. This 1 order of magnitude difference in the in vitro differentiating potencies of all-trans RA and 13-cis RA in the blasts of promyelocytic leukemias predicts a difference in the clinical efficacy of the two drugs.

Cell Transformation, Neoplastic↗
PubMed1990

The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.

Retinoic acid is a vitamin A derivative with striking effects on development and cell differentiation. Several nuclear retinoic acid receptors (RARs), acting as ligand-inducible transcription factors, have been characterized and indirect evidence suggests that they have distinct roles. One of the most intriguing properties of retinoic acid is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. Because the RAR alpha gene maps to chromosome 17q21 (ref. 14), close to the t(15;17) (q21-q11-22) translocation specifically associated with APL, we analysed RAR alpha gene structure and expression in APL cells. We report here that, in one APL-derived cell line, the RAR alpha gene has been translocated to a locus, myl, on chromosome 15, resulting in the synthesis of a myl/RAR alpha fusion messenger RNA. Using two probes located on either side of the cloned breakpoint, we have found genomic rearrangements of one or other locus in six patients out of eight, demonstrating that the RAR alpha and/or myl genes are frequently rearranged in APL and the breakpoints are clustered. These findings strongly implicate retinoic acid receptor alpha in leukaemogenesis.

Base Sequence↗