Antibodies to HTLV-I in Sjögren's syndrome.
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Genes, env↗
Biomedical subjects
J C Brouet
Publications and source records attributed to J C Brouet.
High-dose therapy and autologous blood stem cell transplantation in multiple myeloma: preliminary results of a randomized trial involving 167 patients.
Since 1986, we have treated young patients with aggressive multiple myeloma (MM) by high-dose chemotherapy (HDC) and total body irradiation (TBI) followed with autologous blood stem cell transplantation (ABSCT). To evaluate this strategy: 1) We conducted a phase II trial that included 63 patients. Within a median follow-up of five years after transplantation, overall survival was 60% and median event-free survival was four years, and 2) In the early 1990s, we initiated a prospective trial where, after collection of chemotherapy-mobilized ABSC, patients under 55 years of age with newly diagnosed MM were randomly assigned either to HDC and TBI supported with ABSCT (high-dose therapy [HDT] arm) or to a conventional vincristine, melphalan, cyclophosphamide and prednisone (VMCP) regimen (VMCP arm). In the latter, HDT with ABSCT was performed as a rescue therapy, in case of primary resistance to VMCP or at relapse in responders. As of June 1994, 167 patients have been enrolled since a median time of 26 months. Fourteen (8%) could not be randomized. Among the randomized patients (n = 153), 30 deaths were observed, 13 in the HDT group and 17 in the VMCP group (p = 0.28, two-sided log rank test). Overall survival rates at two years were estimated at 78% for all 167 patients, at 82% in the HDT group and at 67% in the VMCP group. ABSC, provided they are collected early in the disease course, allow a great majority of myeloma patients to receive HDT.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
BCMAp: an integral membrane protein in the Golgi apparatus of human mature B lymphocytes.
BCMA is a human gene expressed preferentially in mature B lymphocytes as a 1.2 kb mRNA, which encodes a 184 amino acid peptide (BCMAp). The study of BCMA mRNA expression, using human malignant B cell lines characteristic of different stages of B lymphocyte differentiation, demonstrated that the BCMA mRNA is absent in the pro-B lymphocyte stage. It is expressed faintly at the pre-B cell stage and its expression increases with B lymphocyte maturation. Polyclonal antibodies were used to show, by cellular fractionation and immunoprecipitation, that BCMAp is a non-glycosylated integral membrane protein. Furthermore, BCMAp inserts, in vitro, into canine microsomes, as a type I integral membrane protein. Cell surface labeling showed that BCMAp is not expressed in the plasma membrane of mature B lymphocytes. Immunofluorescence studies revealed that BCMAp lies in a cap-like structure near the nucleus, that was identified as the Golgi apparatus by co-localization of BCMAp with CTR433, a marker of the medial cisternae of the Golgi apparatus. Confocal scanning laser microscopy of U266 plasma cells labeled with markers of various Golgi apparatus subcompartments strongly suggests that BCMAp is located in the cis part of the Golgi apparatus. Thus, BCMAp is the first Golgi resident protein with a tissue specificity and whose expression is linked to the stage of differentiation of B lymphocytes. The location of BCMAp in the Golgi apparatus and its high expression in plasmocytes (secreting large amounts of Ig) suggest that BCMAp is implicated in the intracellular traffic of Ig.
B-Cell Maturation Antigen↗
Plasma exchange and chlorambucil in polyneuropathy associated with monoclonal IgM gammopathy. IgM-associated Polyneuropathy Study Group.
The study compared chlorambucil alone with chlorambucil in combination with plasma exchange in patients with polyneuropathy associated with monoclonal IgM. Forty four patients were prospectively randomly assigned, in a comparative open trial, to receive either 0.1 mg/kg/day chlorambucil orally, for 12 months or chlorambucil associated with 15 courses of plasma exchange, during the first four months of treatment. They were evaluated by a neuropathy disability score and nerve conduction studies. No difference was found between the two treatment groups. The average neuropathy disability score improved by 2.1 points from baseline (21.0 to 18.9) in the chlorambucil group and by 1.8 points (20.4 to 18.6) in the chlorambucil + plasma exchange group (P = 0.70). The mean motor nerve conduction velocity decreased from 20.0 to 18.2 m/s in the chlorambucil group and increased from 20.5 to 22.5 m/s in the chlorambucil + plasma exchange group (P = 0.51). A slight improvement of the sensory component of the neuropathy disability score (from 10.5 to 8.3) was noted in both groups (P = 0.01). At the end of the study and according to self evaluation, 15 patients--eight from the chlorambucil group and seven from the chlorambucil + plasma exchange group--reported clinical improvement, whereas 15--eight from the chlorambucil group and seven from the chlorambucil + plasma exchange group--reported clinical worsening. Neuropathy remained stable in the others. Thus plasma exchange seemed to confer no additional benefit in the treatment of polyneuropathy associated with monoclonal IgM.
Aged↗
Marrow transplantation for myeloma.
High-dose therapy with hemopoietic stem cell support in multiple myeloma (MM) has been used for 10 years. This approach is currently the most promising form of treatment for this disease. We review here its rationale and the results of clinical trials according to the source of hematopoietic stem cells [allogeneic or autologous, bone marrow or blood]. Finally, we discuss the ongoing uncertainties regarding the utility of this treatment and the future prospects for high-dose therapy in MM.
Antineoplastic Combined Chemotherapy Protocols↗
Iliac artery dissection in alpha 1-antitrypsin deficiency.
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Adult↗
[Cost of intensive treatment followed by autograft of circulating stem cells. Application to multiple myeloma].
OBJECTIVES: Legitimate efforts to reduce health care costs, especially of intensive protocols including transplantation for haematological diseases, require realistic economic evaluations. We determined the direct cost of intensive chemotherapy associated with total body irradiation and autologous blood stem cell transplantation in patients with multiple myeloma. METHODS: Ten consecutive patients (7 males, 3 females) with Stage II or II multiple myeloma, who had received no prior treatment and were under the age of 55, were included in the study. Peripheral blood stem cells were collected by successive cytaphereses after a short period of aplasia induced by a CHOP protocol. During this period, the patients were in normal hospital rooms. A VAMP protocol was then administered in three 4-day sessions. Intensive therapy was started 1 month later with CCNU, etoposide, cyclophosphamide and melphalan. Total body irradiation (12 Gy) was performed on days -3, -2, -1. Autologous grafting was done on day 0. The intensive therapy was followed by a period of aplasia and the patients were protected in laminar flow rooms. Regular antibiotic and haematologic protocols were applied. Growth hormone was not given. The patients were seen regularly for follow-up and interferon alpha 2b was prescribed for 5. RESULTS: The mean cost of the two year treatment was 468,392 +/- 167,467 French francs. Personnel accounted for 36% of the total cost, marrow collection 13%, blood products 9.8%, laboratory tests 8.2% and drugs 7.2%. Little data are available in the literature of comparable cost analyses in other French hospitals or in other countries. CONCLUSION: Controlled cost/benefit studies should be conducted to enable a rigorous comparison between different therapeutic strategies.
Adult↗
Modulation of spontaneous B-cell differentiation in macroglobulinemia by retinoic acid.
We previously showed that clonal blood B cells from patients with macroglobulinemia spontaneously differentiate in vitro to plasma cells. This process is dependent on an interleukin (IL)-6 autocrine pathway. We investigate here whether all-trans-retinoic acid (RA) interferes with B-cell differentiation either in patients with IgM gammapathy of undetermined significance (MGUS) or Waldenström's macroglobulinemia (WM). RA at a concentration of 10(-5) to 10(-8) mol/L inhibited by 50% to 80% the in vitro differentiation of purified B cells from four of five patients with MGUS and from one of five patients with WM as assessed by the IgM content of day 7 culture supernatants. We next determined whether this effect could be related to an inhibition of IL-6 secretion by cultured B cells and/or a downregulation of the IL-6 receptor (IL-6R), which was constitutively expressed on patients' blood B cells. A 50% to 100% (mean, 80%) inhibition of IL-6 production was found in seven of 10 patients (five with MGUS and two with WM). The IL-6R was no more detectable on cells from patients with MGUS after 2 days of treatment with RA and slightly downregulated in patients with WM. It was of interest that B cells susceptible to the action of RA belonged mostly to patients with IgM MGUS, which reinforces our previous data showing distinct requirements for IL-6-dependent differentiation of blood B cells from patients with VM or IgM MGUS.
B-Lymphocytes↗
The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed.
In a previous study of a t(4;16)(q26;p13) translocation, found in a human malignant T-cell lymphoma the BCMA gene, located on chromosome band 16p13.1, has been characterized. In this study we show that the BCMA gene is organized into three exons and its major initiation transcription site is located 69 nucleotides downstream of a TATA box. RNase protection assays demonstrated that the BCMA gene is preferentially expressed in mature B cells, suggesting a role for this gene in the B-cell developmental process. A cDNA complementary to the BCMA cDNA was cloned and sequenced and its presence was assessed by RNase protection assay and anchor-PCR amplification. This antisense-BCMA RNA is transcribed from the same locus as BCMA, and exhibits mRNA characteristic features, e.g. polyadenylation and splicing. It also contains an ORF encoding a putative 115 aa polypeptide, presenting no homology with already known sequences. RNase protection assays demonstrated the simultaneous expression of natural sense and antisense-BCMA transcripts in the majority of human B-cell lines tested.
Amino Acid Sequence↗
Extensive small intestinal T-cell lymphoma of low-grade malignancy associated with a new chromosomal translocation.
BACKGROUND: Primary T-cell lymphoma of the small intestine is rare, and most cases have proved rapidly fatal. METHODS: We describe a case of lymphoma involving the small intestine uniformly and extensively in a 28-year-old man on initial examination seen with long-standing diarrhea, malabsorption, and recurrent episodes of intestinal obstruction. Clinical remission was obtained with pentostatin (2'-deoxycoformycin, supplied by Professor Catovsky, London UK) after the patient had failed to improve under conventional chemotherapy. Tumor specimens as well as mesenteric lymph node, liver, and bone marrow specimens were studied with conventional pathology and immunochemistry. Additionally, mesenteric lymph nodes and peripheral blood cells were studied for T-cell receptor (TCR) gene rearrangement and karyotype. RESULTS: Lymphoma cells were small T-lymphocytes with irregular pleomorphic nuclei, bearing the CD3, CD4 and TCR alpha-beta phenotype. Peripheral-blood cytology and bone marrow biopsy were normal. Southern blot analysis of the TCR beta-chain gene revealed the same monoclonal rearrangement in the mesenteric lymph nodes and peripheral blood lymphocytes. An as yet undescribed t(4;16)(q26;p13) translocation, involving the region where the interleukin-2 (IL-2) gene has been mapped, was present in the mesenteric lymph nodes and peripheral blood lymphocytes. CONCLUSION: We believe this is the first description of an extensive, small intestinal lymphoma of low-grade malignancy made up of monoclonal T-cells with a TCR alpha-beta and helper/inducer phenotype, associated with a novel chromosomal translocation.
Adult↗
Monoclonal IgM from patients with peripheral demyelinating neuropathies cross-react with bacterial polypeptides.
Human monoclonal IgM associated with a demyelinating peripheral neuropathy often feature a distinct antibody activity directed against a glucuronyl sulphate epitope shared by myelin-associated glycoprotein (MAG), nerve glycolipids and low molecular weight peripheral nerve polypeptides. Earlier studies showed that these IgM use a diverse repertoire of VH and VL genes which exhibit somatic mutations, possibly indicative of an antigen-driven process. Here, we investigated whether such monoclonal IgM may react with environmental bacterial antigens. We found that six patients' sera and purified monoclonal IgM, as well as IgM from supernatants of three clonal anti-MAG-secreting cell lines reacted with unique 90-100 kD polypeptides from extracts of two out of 10 bacterial species. Purified MAG was able to inhibit this reactivity. These results indicate molecular mimicry as a possible mechanism of this immunomediated neuropathy and associated clonal lymphoid disease.
Antibodies, Bacterial↗
Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein.
In this study, we show that IL-10 enhances in vitro the viability of purified splenic B cells. There was a two- to threefold increase in recovery of viable cells during a 15-d culture period in the presence of IL-10. This effect was abolished by neutralizing antibodies to IL-10. The survival of large splenic B cells, which mostly represent follicular center cells, was similarly increased. The in vitro rescue from spontaneous death of the latter cells is known to involve a bcl-2-dependent pathway. We therefore investigated whether IL-10 might affect bcl-2 expression. Unseparated B cells as well as large splenic B cells displayed a strong expression of bcl-2 protein by immunofluorescence at days 2-7 of culture in the presence of IL-10. Other lymphokines such as IL-2 and IL-4 were able to trigger only a transient and faint expression of bcl-2; moreover, this effect was abolished by anti-IL-10 mAb. Inasmuch as activated B cells can produce their own IL-10, this lymphokine may play a crucial role in relieving from apoptosis those B cells that encounter their antigen in B cell follicles.
B-Lymphocytes↗
Myeloma cell contamination of peripheral blood stem cell grafts in patients with multiple myeloma treated by high-dose therapy.
In order to assess the contamination with malignant cells of peripheral blood stem cell (PBSC) transplants used to support high-dose therapy in multiple myeloma (MM), we used the immunoglobulin heavy chain gene radioactive fingerprinting polymerase chain reaction (PCR) method to detect clonal cells in PBSC from 10 patients. The sensitivity of the technique allowed the detection of one clonal cell among 10(4) normal blood mononuclear cells. A clonal band was detected in 4 of 11 leukaphereses samples. The level of contamination was low because a clonal band could never be identified on ethidium bromide-stained agarose gels whose sensitivity is between 1 and 5%. The use of granulocyte-colony stimulatory factor (G-CSF) in combination with chemotherapy in three cases did not seem to increase the contamination of PBSC grafts; in one patient, G-CSF was used during a second course of leukapheresis which was free of detectable clonal cells whereas the first one performed after chemotherapy alone contained clonal cells. Thus, PBSC grafts may rarely be completely devoid of clonal potentially malignant cells but the level of contamination is much lower than in BM grafts. Whether graft contamination is an important adverse prognostic factor for patients with MM undergoing intensive treatment and autografting is still unsettled.
Antineoplastic Agents↗
Recovery from pulmonary hypertension with steroid therapy in a patient with Sjögren's syndrome and polymyositis.
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Adult↗
Interferon therapy in multiple myeloma.
Alpha-interferon is an active agent in multiple myeloma. It proved to be beneficial in some but not all studies both in combined therapy with alkylating agents or as a single agent to prolong the plateau phase in patients in partial remission. The best strategy of administration has yet to be established.
Alkylating Agents↗
Autoantibodies sequencing may help to understand the physiopathology of some monoclonal lymphoid proliferations and autoimmune diseases.
Nucleotide sequences of variable regions of autoantibodies may help to understand the origin of B cells secreting autoantibodies, both in the context of monoclonal lymphoid proliferations and polyclonal autoimmune diseases. We established the nucleotide sequence of variable genes of four monoclonal IgM secreted by lymphoplasmacytic proliferations and directed to myelin-associated glycoprotein, of five anti-lamin B autoantibodies in patients with a lupus like vasculitis, and of one monoclonal IgM secreted in a chronic lymphocytic leukemia patient and directed to the cardiolipin/beta 2 glycoprotein I complex. A selection process (antigen-driven?) was probably implicated in the origin of autoantibodies in the first two situations although a random process occurred in the last one.
Antibodies, Monoclonal↗
High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients.
Sixty-three patients with high tumor mass multiple myeloma were treated with high-dose chemotherapy and total body irradiation supported by autologous blood stem cell transplantation. After high-dose therapy, they were monitored for a median of 44 months. Seven patients died early from toxicity. All the other patients, including those whose disease was resistant to previous therapies, showed a tumor mass reduction. At 6 months postengraftment, 40 (71%) of the surviving patients had minimal residual disease and 11 (20%) were in apparent complete remission. During follow-up, 25 out of the 63 (39%) patients relapsed and 16 of these died; 31 (49%) had a sustained remission. The median overall and event-free survival times after transplantation were 59 and 43 months, respectively. The initial serum beta 2-microglobulin value (> or < 2.8 mg/L) and length of previous therapy (> or < 6 courses of chemotherapy) were the only significant prognostic factors. In all surviving patients, blood stem cell autograft provided satisfactory and sustained haematopoietic reconstitution most often within 15 days. High dose chemoradiotherapy followed by autologous blood stem cell transplantation is thus an important therapeutic option for young patients with aggressive multiple myeloma.
Adult↗
[Alpha heavy chain disease. Molecular analysis of a new case].
The NH2-terminal structure of serum abnormal protein, as well as the sequence of the corresponding mRNA, were determined in a new case of alpha heavy chain disease. The patient presented with typical clinical features of the disease. Intestinal and mesenteric lymphoplasmic infiltration was monoclonal as assessed by the study of the configuration of heavy and light chain genes. The serum abnormal alpha chains included two molecular species: one starting at the beginning of the hinge region and the other being two amino acids shorter, missing the two first amino acids of the hinge region. The sequence of the mRNA displayed a leader exon, a 93 bp sequence of unknown origin and the second and third constant exons of human alpha 1 chain. These data are discussed in the light of previously reported molecular studies in heavy chain diseases.
Adult↗