Extensive genomic polymorphism in mouse 21-hydroxylase region.
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Animals↗
Biomedical subjects
L Degos
Publications and source records attributed to L Degos.
Double-blind, placebo-controlled lithium treatment in chemotherapy induced aplasia for AML: reduced antibiotic requirement.
A double-blind placebo-controlled study on lithium (Li) therapy after chemotherapy-induced bone marrow aplasia was undertaken in 53 patients with acute myeloblastic leukemia (AML). No difference was observed between the two groups for the duration of aplasia, the number of units of platelets or RBC transfused, the complete remission rate or the disease free survival. However, a statistically significant reduction in the number of days of antibiotic therapy required was found in the treated group (10.55 +/- 2.72 vs 12.73 +/- 3.60, P less than 0.05).
Adolescent↗
Action of interferon-alpha on hairy cell leukemia: expression of specific receptors and (2'-5')oligo (A) synthetase in tumor cells from sensitive and resistant patients.
IFN-alpha induces tumor regression with a high percentage of complete remissions in hairy cell leukemia. We have recently reported that hairy cells express specific IFN-alpha receptors which are down-regulated upon therapy. We show here that the activity of 2-5 A synthetase, an IFN-induced enzyme, is 2 to 7-fold stimulated in hairy cells from responsive patients within 12-24 h after the first IFN dose. This in-vivo enzyme induction paralleled the kinetics of receptor down-regulation. In one patient who was unresponsive to IFN-alpha treatment neither expression of IFN-alpha receptor nor change in 2-5 A synthetase were expressed and modulated as in sensitive patients. In-vitro treatment of hairy cells with recombinant interferons showed that IFN-beta 1 was able to induce this enzyme to the same extent than IFN-alpha 2, whereas IFN-gamma was inactive despite the presence of specific IFN-gamma receptors. Our results indicate that IFN-alpha can exert its therapeutic effects by acting directly on the hairy cells through interaction with surface membrane receptors. Induction of 2-5 A synthetase can be one of the steps involved in this action. However, both mechanisms, as well as receptor down-regulation are not sufficient to explain the responsiveness of hairy cell leukemia to IFN-alpha.
2',5'-Oligoadenylate Synthetase↗
HLA class I molecules are associated with CD1a heavy chains on normal human thymus cells.
The molecules encoded by the major histocompatibility complex play a pivotal role in regulatory interactions between cells of the immune system, which can result in the activation and function of T cells. The function of the CD1 molecules, which are homologous to the major histocompatibility complex-encoded molecules but are encoded on human chromosome 1, is not known. HLA class I molecules and CD1a heavy chains share the ability to associate with several different cell-surface molecules. We show here, by several technical approaches, that HLA class I molecules are associated with CD1a heavy chains on the surface of normal thymus cells. The functional significance of this association during T-cell differentiation is discussed.
Antibodies, Monoclonal↗
Immune response to H-2 class I antigens on platelets. I. Immunogenicity of platelet class I antigens.
Purified allogeneic murine platelet suspensions were found unable to induce primary anti-H-2 class I antibody or T cell proliferative responses. In contrast, the same platelet suspensions could elicit secondary anti-class I responses. The secondary responses were not due to contaminating leucocytes. Possible explanations, the lack of acolyte determinants (class II or non- H-2) on platelets or inappropriate layout and/or structure of their class I antigens, are discussed. These findings emphasize the importance of sufficient leucocyte depletion before platelet transfusion in the human.
Animals↗
Immune response to H-2 class I antigens on platelets. II. Specific decrease of H-2 class I-specific antibody response induced by treatment with allogeneic platelets.
Mice pretreated with injections of allogeneic platelets were found to mount a decreased antibody response upon challenge by lymphocytes of the same donor strain. This decrease was mediated by platelets themselves, and not by leucocytes and red cells contaminating the platelet suspension. It affected specifically antibodies reactive with H-2 class I antigens present on donor platelets. This phenomenon may be related to the lack of class II or some non-H-2 antigens on platelets, and/or to properties of their class I antigens (soluble molecules adsorbed from the plasma). These findings emphasize the potential usefulness of purified platelet transfusions preceding organ transplantation in man.
Animals↗
Erythema multiforme is associated to HLA-Aw33 and DRw53.
Erythema multiforme is an acute eruption of the skin and mucous membranes of various aetiologies. Forty-one unrelated patients were HLA typed for 53 specificities of the HLA-A, B, C, DR and DQ series. Frequencies of Aw33 and DRw53 were significantly increased: Aw33, 17.0% in patients vs 2.8% in controls (corrected p = 0.01, relative risk = 7.2); DRw53, 70.7% in patients vs 30.5% in controls (corrected p = 0.0005, relative risk = 5.5).
Adult↗
Predominant expression of circulating CD3+ lymphocytes bearing gamma T cell receptor in a prolonged immunodeficiency after allogeneic bone marrow transplantation.
The cell surface expression of alpha:beta heterodimer was studied using WT31 monoclonal antibody, in peripheral blood lymphocytes (PBL) from a patient who developed a prolonged immunodeficiency after allogeneic bone marrow transplantation. This patient, grafted for chronic myelogenous leukemia, received T cell depleted bone marrow from her HLA, A, B, D matched sibling. The late occurrence of opportunistic infection, led us to analyze the phenotype of patient PBL. 70% of PBL were CD3+ and 29% WT31+, indicating that the majority of CD3+ PBL did not express the alpha:beta heterodimer. Transcription of the genes encoding the alpha, beta, and gamma chains was assessed in cell lines derived from PBL, by Northern blot analysis. We showed that the CD3+ WT31- subset expressed a truncated, beta mRNA (1.0 kb) and also truncated alpha transcript (1.4 kb). To determine the CD3-associated structure on CD3+ WT31- cell line, immunoprecipitation assays were performed using monoclonal anti-CD3 and an hetero antiserum against gamma peptides. These CD3+ WT31- cells expressed a disulfide linked dimer, composed of products of gamma gene (37 kD, 40 kD) and of undefined delta chain (45 kD). Functional analyses were performed in PBL before and after sorting with WT31 and anti-CD3 antibody. These circulating CD3+ WT31- cells were unable to proliferate when triggered with anti-T3 beads and they seemed to mediate a suppressor activity on CD3+ WT31+ cells.
Adult↗
[Autografts of blood cells at various stages].
Thirty-nine patients with acute myeloblastic or lymphoblastic leukaemia had peripheral blood mononuclear cells collected by 3 continuous-flow leukapheresis as they entered first remission after induction chemotherapy. CFU-GM were assayed as a measure of the number of haemopoietic stem cells in each collection. Numbers of CFU-GM harvested varied among the patients (for example 0.27 to 155.10(4)/kg for ANLL patients). Nineteen patients underwent peripheral blood stem cells autografts after a conditioning regimen with high dose cyclophosphamide and TBI. The patients were transfused with a median of 2.2.10(4)/kg CFU-GM cells (0.28 to 100.10(4) CFU-GM/kg). Only 1 patient had a graft failure. The rate of haemopoietic recovery was studied for our patients and those reported in the literature. A strong correlation exists between the numbers of CFU-GM transfused and the rate of granulocytes and platelets recovery. Very rapid recovery are regularly obtained when the number of CFU-GM transfused is superior to 5.10(4)/kg.
Adult↗
The human T-cell V gamma gene locus: cloning of new segments and study of V gamma rearrangements in neoplastic T and B cells.
The authors have analyzed the involvement of V gamma and J gamma segments in TRG gamma rearrangement from a series of 40 acute lymphoblastic leukemia (ALL), including 25 T- and 15 B-lineage cases, in which TRG gamma are rearranged. Sixty-five rearranged alleles were studied. The authors first describe the cloning and sequencing of two variable segments, V gamma 11 and psi V gamma 12, which rearrange in T- and B-neoplastic cells. To date three subgroups of translatable V gamma segments have been described. The authors show that V gamma 11 is the unique member of a new fourth V gamma subgroup that also rearranges in normal polyclonal T cells and that psi V gamma 12 is located at 5-kilobase (kb) downstream to V gamma 11. As shown by DNA sequence analysis, V gamma 11 shares a 60% homology with V gamma 10 (third subgroup) and a 50% homology with V gamma 9 (second subgroup) but no appreciable homology with the V gamma segments from the first family. In contrast to psi V gamma 12, V gamma 11 is translatable. In this paper the authors have also attempted to determine which V gamma segments were rearranged in the ALL cases by hybridization with a J gamma probe and genomic probes specific of the four subgroups. In the 54 instances in which the rearrangement was consistent with J gamma 1 or J gamma 2 involvement, the authors have identified the corresponding V gamma segments and have not found any other rearrangements suggestive of the existence of further V regions. The V gamma segments, belonging to the first subgroup, were the most frequently used (41 alleles). V gamma 9, V gamma 10, V gamma 11, and psi V gamma 12 were found rearranged in cases 3, 4, 5, and 1, respectively. No cases using the pseudo psi V gamma 1, psi V gamma 5, and psi V gamma 6 segments were found. Pseudo V gamma segments were not found rearranged in T cells, while V gamma 2 and V gamma 4, segments are frequently used. In contrast to the V gamma I gene rearrangement, the involvement of the V gamma II, V gamma III, and V gamma IV subgroups was most frequently observed in T-ALL with stage II differentiation (CD7+, CD4+, and/or CD8+, CD3-), than in those with stage I (CD7+, CD4-, CD8-, CD3-), than in those with stage I (CD7+, CD4-, CD8-, CD3-) and stage III (CD7+, CD4+/-CD8+/-CD3+).(ABSTRACT TRUNCATED AT 400 WORDS)
Antigens, Differentiation, T-Lymphocyte↗
Prominent expansion of circulating lymphocytes bearing gamma T-cell receptors, with preferential expression of variable gamma genes after allogeneic bone marrow transplantation.
The presence of two distinct T-cell receptors (TCR) alpha/beta dimers or gamma/delta dimers, was systematically analyzed in peripheral blood lymphocytes form 26 recipients of allogeneic bone marrow transplants for leukemia. When using monoclonal antibody WT31, which recognizes a common epitope on the alpha/beta heterodimer, the expansion of peripheral CD3+, WT31- cells to 40% of the PBLSs was detected in two patients. In patient 2, the presence of circulating TCR gamma-bearing cells was directly demonstrated with monoclonal antibody Ti gamma A directed against the V gamma 9 J gamma p gene products. From CD3, WT31- clones derived from patients 1 and 2, sequential immunoprecipitations were performed with anti-CD3 and anti-C gamma to determine the CD3-associated structure. Molecular weights of gamma subunits were different in both patients, thus indicating structural heterogeneity. The ability of TCR gamma clones to proliferate when stimulated with anti-CD3 beads was observed for clones from patient 2, whereas this response required exogenous interleukin-2 for clones from patient 1. We have already shown that the TCR gamma cells from patient 1 might have played a role in the immunodeficient state. Similar conclusions cannot be drawn from patient 2. Southern blot analysis of total PBL gamma cell lines and clones indicated that this major circulating subset of TCR gamma cells retained a TCR beta gene in germline configuration and preferentially expressed a single V gamma gene, V gamma 5 for patient 1 and V gamma 9 for patient 2.
Antibodies, Monoclonal↗
[Treatment of malignant tumors by interleukin 2 and LAK cells].
Lymphokine-activated killer (LAK) cells are cells able to lyse fresh tumor cells. In vivo treatment using LAK cells and interleukin 2 is highly toxic because of increased capillary permeability. International discussion is underway on this promising or too toxic therapy. However, such treatment opens a new way for ex vivo manipulation of cells.
Capillary Permeability↗
Human T cell clones use a CD3-associated surface antigen recognition structure to exhibit both NK-like and allogeneic cytotoxic reactivity.
In the present study, we developed human non-MHC-restricted CTL clones from human peripheral blood mononuclear cells activated in vitro with recombinant IL 2 and subsequently expended with PHA. The CD3/Ti+ clones were selected for their ability to exhibit non-MHC-restricted CTL reactivity by killing various tumor cell lines in culture, including the line K562 which does not express MHC antigens. We report that, at least for some of the NK-like T cell clones, it is possible to establish an allo-CTL activity, and that the CD3-associated surface antigen recognition structure might be involved in both reactivities.
Antibodies, Monoclonal↗
Human T cell gamma genes are frequently rearranged in B-lineage acute lymphoblastic leukemias but not in chronic B cell proliferations.
T cell rearranging gene gamma (TRG gamma) and T cell antigen receptor beta (TCR beta) chain gene rearrangement and transcription were studied in a series of patients with B-lineage acute lymphoblastic leukemia (ALL), in which the Ig H chain genes are rearranged and the surface phenotype reproduces the stages of normal pre-B maturation. For comparison, polyclonal T cells from peripheral blood of healthy donors and blast cells from 19 cases of T lineage ALL were also studied. In this study we demonstrate the presence of a clonal rearrangement of the TRG gamma in 18 of the 22 B-lineage ALL cases and establish that this rearrangement, which generally involves the J gamma 1 region, is often monoallelic and appears different from the biallelic J gamma 2 rearrangement frequently seen in T-cell ALLs. In 9 of 22 cases, we found rearrangement of the genes of the TCR beta chain, which never involved the J beta 1 region. Conversely, the TRG gamma were seen in germline configuration in all 19 cases of B chronic lymphoid malignancies. In none of the 9 AML cases studied was TRG gamma and TCR beta chain gene rearrangement found. The TCR beta chain genes were rearranged in one B cell chronic lymphocytic leukemia (CLL). We also show that in B-lineage ALL, the cells probably use the same V gamma genes for TRG gamma rearrangements as the malignant cells in T-ALL and the polyclonal T cells. In none of the 13 B-lineage ALL cases investigated by Northern analysis was TCR beta mRNA expression detected, whereas a weak expression of TRG gamma transcripts was found in two of these cases. The correlations between surface phenotype, rearrangement of TRG gamma, TCR beta, and Ig H chain genes were analyzed. The significance of rearrangement of TRG gamma and TCR beta chain genes in B or pre-B cells is also discussed.
B-Lymphocytes↗
Molecular localization to a unique DR beta-chain of the restriction element of an anti-influenza T cell clone.
The DR beta-chains of a panel of DRw13 cells were characterized by two-dimensional polyacrylamide gel electrophoresis in order to identify the molecule bearing the restriction element of a DR-restricted proliferative and cytotoxic T cell clone COT C2 specific for DRw13 and the influenza A virus. Because in different DRw13 haplotypes one DRw13 beta-chain can be associated with other distinct DRw13 beta-chains, such complex associations allowed us to determine the ability of a given DR beta-chain to present the antigen or COT C2. The presence of the DR beta-chain 6B5, and only this chain, is associated with the ability to induce the proliferation of clone COT C2 whatever the second DR beta-chain associated with 6B5 is, namely 6B4 or 6B3. The DRw13 cells that express 6B4 or 6B3 but not 6B5 could not present the antigen to COT C2. Moreover, ILR2, a monoclonal antibody that precipitated 6B5, blocked the proliferation of COT C2, whereas 7.3.19.1, a monoclonal antibody that precipitated only 6B4 and 6B3, could not block the proliferation of this clone. Thus, the DRw13 beta-chain 6B5 appears as the unique class II element that restricts the response of the T cell clone COT C2.
Antibodies, Monoclonal↗
Alpha-interferon in hairy cell leukaemia: direct effects on hairy cells or indirect cytotoxicity?
This report presents the results of a clinical trial on 53 patients with hairy cell leukaemia using low-dose alpha-interferon as therapy. Improvement of cytopenia and/or bone marrow hairy cell infiltration occurred in all but one patient. Often, blood and bone marrow improvements were dissociated and, after 7 or 13 months of therapy, complete remission was only observed in about 40% of patients. Recurrence of the disease was observed in some cases after cessation of therapy. A summary of the following results is presented: alpha-interferon receptor analysis, oncogene expression, study of the sensitivity of hairy cells to natural killer cells, and the effects of interferon on T-cell receptor gene rearrangement and on the function of T-cell clones. Results are also presented which show that myelofibrosis may be due to a release of platelet derived growth factor. The immunological findings and oncogene expression in 2 patients with a variant form of hairy cell leukaemia for which resistance to therapy was observed are also described. All the results show that interferon acts on hairy cells and are consistent with a direct effect by interferon in the treatment of hairy cell leukaemia.
Blood Platelets↗
Hairy-cells are not lysed by NK-cells.
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Cytotoxicity, Immunologic↗
Role in T-cell activation for HLA class I molecules from accessory cells: further distinction between activation signals delivered to T cells via CD2 and CD3 molecules.
The immunological function of major histocompatibility complex molecules, including HLA class I molecules, is to present antigens and/or their processed peptides to various lymphocyte subpopulations. Thus, they play a pivotal role in regulatory interactions between cells of the immune system, which can result in the activation and function of T cells. We looked for a role of major histocompatibility complex molecules during T-cell activation induced by monoclonal antibody (mAb) or combinations of mAb recognizing the two well-characterized T-cell surface molecules CD3 and CD2. To activate T-cell peripheral blood lymphocytes, we used a CD3 mAb or two different pairs of CD2 mAb, CD2 "GT2 + T11(1)" and CD2 "D66 + T11(1)," which, as we have previously shown, deliver different signals of activation to T cells. Anti-HLA class I mAb blocked the activation induced by CD3 mAb or by CD2 GT2 + T11(1), but it did not block activation induced by CD2 D66 + T11(1). We observed this pattern of inhibition according to the stimulus used to activate T cells both when the anti-HLA class I mAbs were added to cultures of whole peripheral blood mononuclear cells and when they were fixed to monocytes only. In the latter case, purified monocytes were first incubated with the anti-HLA mAb (whether whole immunoglobulin or Fab fragment) and then fixed with paraformaldehyde before culture with autologous purified T cells. Anti-HLA class I fixed on monocytes prevented both interleukin 2 (IL-2) receptor expression and IL-2 synthesis on T cells. The inhibitory effects of anti-class I mAb bound to monocytes were not reversed by adding large amounts of recombinant IL-2 or recombinant IL-1, a finding consistent with the observations that accessory cells surface components can fully complement the signals directly delivered to T cells by CD2 or CD3 mAb. We conclude that HLA class I from accessory cells plays an important role in the early phase of T-cell activation when direct contacts between accessory cells and T cells are required.
Antibodies, Monoclonal↗