Inhibition of interleukin-3-dependent growth of CD34+ acute myelogenous leukemia cells by recombinant soluble CD23.
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Antibodies, Monoclonal↗
Biomedical subjects
P Debre
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MHC-restricted cytotoxicity against HIV.
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Epitopes↗
[Inhibitor effect of CD8+CD57+ lymphocytes on cell-mediated cytotoxicity: characterization of suppressor factor].
We report a new suppressor function of CD8+CD57+ lymphocytes from HIV-seropositive patients or allotransplanted recipients, on the cytolytic activity of allospecific CTL, NK and LAK cells. This inhibitory effect is mediated by a non-antigen specific soluble factor distinct from PGE2, TGF beta and TNF alpha beta. A preliminary biochemical characterization indicates that the CD8+CD57+ inhibitory activity 1. is heat and trypsin resistant, 2. specifically binds to Concanavalin A suggesting its glycosylation, 3. is mediated by a 20-30 kD molecule.
Bone Marrow Transplantation↗
IL-4 inhibits the expression of high affinity IL-2 receptors on monoclonal human B cells.
In the presence of anti-mu antibodies (anti-microAb), monoclonal B lymphocytes from patients suffering from B type chronic lymphocytic leukemia (B-CLL) can respond to IL-2. In contrast to the effect it exerts on normal B cells, IL-4 does not promote DNA synthesis by B-CLL lymphocytes. Rather this interleukin inhibits the response to IL-2 in all patients' cells that responded to this interleukin. We thus examined whether IL-4 would modulate the number and/or the affinity of IL-2 receptors. A 3-day activation of cells by anti-microAb induced a few hundred high affinity IL-2 receptors (HA-IL-2R) on B-CLL cell surface, as determined by Scatchard analysis. Treatment of cells with IL-4 caused a marked decrease in the number of HA-IL-2R without interfering with the binding ability of IL-2. In contrast with this profound suppressive effect, IL-4 did not down-regulate the expression of each chain, alpha and beta (p55 and p75, respectively), of the HA-IL-2R heterodimer. In fact, the expression of alpha and beta induced by anti-microAb was enhanced by IL-4. Altogether, IL-4 exerts a critical influence on the function and the configuration of HA-IL-2R without inhibiting the expression of two subunits, alpha and beta.
B-Lymphocytes↗
CD1 stimulation of human T cell lines induces a rapid increase in the intracellular free Ca2+ concentration and the production of IL-2.
The effect of a battery of CD1 mAb on intracellular free Ca2+ concentration and IL-2 production has been examined on different T cell lines in this study. Both 0249F and NU-T2 two CD1b specific mAb tested, induced a rapid increase in the intracellular Ca2+ concentration on HPBALL T cells whereas only one (L161) among three different CD1c mAb (L161, 10C3, and M241) produced a similar effect. In contrast the addition of four different CD1a mAb directed against two different epitopic groups of this molecule were uneffective in modifying the intracellular Ca2+. Both L161 and 0249F also induced a comparable increase in the intracellular Ca2+ concentration on MOLT 4 and JURKAT, two other T cell lines of similar phenotype. The effect of L161 mAb on the IL-2 production of the IL-2 producing T cell line JURKAT was also examined. The association of the latter with PMA strongly induced the production of IL-2 on this cell model while either L161 or PMA alone had no effect. Although the natural ligand and the function of CD1 molecules are still unknown, the accumulation of these data strongly suggest that CD1b and CD1c might represent two activatory pathways for immature T cells operating before the classical CD2 and CD3 activation pathways.
Antibodies, Monoclonal↗
CD2 triggering stimulates a phospholipase A2 activity beside the phospholipase C pathway in human T lymphocytes.
In previous studies we demonstrated the triggering of the phospholipase C (PLC) pathway during the activation of an Ag-specific human CD4+ T lymphocyte clone by a mitogenic pair of CD2 (X11,D66) mAb. Similar conditions were applied to investigate a possible involvement of a phospholipase A2 (PLA2) acting as an additional alternative pathway during human T cell activation. Our results show that arachidonic acid or its derivatives are released after CD2 triggering. This release is largely independent of PLC activation and is mediated by a PLA2 because: 1) phosphatidylcholine is the preferential source of [3H]arachidonate release; 2) [3H]arachidonic acid release and phosphatidylcholine hydrolysis are blocked by two inhibitors of solubilized PLA2, mepacrine, and 4-p-bromophenacylbromide; and 3) we evidenced a PLA2 activity in cell homogenates. Extracellular calcium appears to play a critical role because the effects of CD2 mAb were inhibited in a Ca2(+)-depleted medium. In contrast, protein kinase C is not implicated since PMA, a protein kinase C activator, neither stimulated arachidonic acid release nor modulated CD2-induced arachidonic acid release. Cyclic AMP which has been proved to regulate the activity of the PLC in T lymphocytes does not appear to play an important role in the regulation of PLA2 activity since PGE2 has only a minimal effect on [3H]-arachidonate release. Altogether, these findings suggest that CD2 triggering stimulates a PLA2 activity in T lymphocytes via an extracellular Ca2(+)-dependent PLC protein kinase C independent mechanism.
Antigens, Differentiation, T-Lymphocyte↗
Soluble CD23 (Fc epsilon RII) and interleukin 1 synergistically induce early human thymocyte maturation.
The ability of human thymus-derived CD7+CD2-CD3- cells to acquire mature T cell antigens was assessed. Purified CD7+ thymocytes were incubated with rIL-1, rIL-2, and/or recombinant soluble CD23 (rsCD23). Short-term incubation of these cells with only rsCD23 + rIL-1 induced mature T cell antigen expression on at least half of the cells. The induction of CD2 was functionally significant, as these cells became able to respond to CD2 triggering and could proliferate in response to IL-2. Possible sources of CD23 in the thymus are under investigation.
Antigens, Differentiation, B-Lymphocyte↗
Isolation of an early T-cell precursor (CFU-TL) from human bone marrow.
CD2-CD3-CD4-CD8- human bone marrow (BM) cells were previously shown to generate T-cell clones in vitro. This capacity was abolished after treatment of this population with anti-CD7 monoclonal antibody and complement. In this study, using rosetting with sheep erythrocytes, complement-dependent cytotoxicity, and specific immunoadherence method, we isolated a minor BM subset that contained more than 80% CD7+CD2-CD3-CD4-CD8- cells with small lymphoid cell morphology. They comprised most early T-cell precursors (CFU-TL) as they displayed high capacity to generate T-cell clones when cultured in limiting dilutions. CFU-TL nature of these cells was also confirmed by the sequential expression of mature T-cell specific markers on their surface after in vitro induction. This BM subset also contained 2% to 3% CFU-GM precursors. Together, these results pointed to the existence of BM CD7+CD2- precursors with high differentiation potential and showed the commitment of most of them to T-cell lineage.
Antigens, CD↗
Reactivity of lymphocytes to a progesterone receptor-specific monoclonal antibody.
In this study we present evidence for reactivity of pregnancy lymphocytes, but not nonpregnancy lymphocytes, with the progesterone receptor-specific monoclonal antibody mPRI. Using an avidin-biotin peroxidase detection system, we found a nuclear staining in 14.6 +/- 3.7% (mean +/- SEM, N = 27) of pregnancy lymphocytes, while only 0.47 +/- 0.33% (mean +/- SEM, N = 15) of nonpregnancy lymphocytes reacted with the antibody. To characterize the receptor-bearing subset, CD8+ and CD4+ cells were depleted by complement-dependent lysis. Depletion of CD8+ cells was accompanied by 62 +/- 18% loss of progesterone receptor-bearing cells, while depletion of CD4+ cells resulted in a twofold increase in the number of positively staining lymphocytes. In nonpregnancy lymphocytes a 3-day PHA treatment, as well as allogeneic stimulation, resulted in a significant increase in the number of receptor-containing cells. These results suggest that pregnancy, but not nonpregnancy, lymphocytes contain progesterone binding structures, and that these are inducible by mitogenic or alloantigenic stimuli.
Antibodies, Monoclonal↗
B8.7 antigen expression on B-CLL cells and its relationship to the LMW-BCGF responsiveness.
In this work, we studied the expression of B8.7 antigen on B lymphocytes from patients suffering from B type chronic lymphocytic leukemia (B-CLL) as well as on non Hodgkin lymphoma cells (NHL). B8.7 is an activation marker, which has been reported to be associated with the capacity of activated B cells to respond to LMW-BCGF. B lymphocytes of 11 out of 22 patients tested were B8.7 positive. With the exception of one case, LMW-BCGF is able to induce DNA synthesis by these cells in the absence of costimulation by anti-mu antibodies (anti-mu Ab). The LMW-BCGF dependent proliferation of these malignant cells is inhibited by the anti-B8.7 monoclonal antibody (anti-B8.7 MoAb), in the same line as that of normal B cells. These results obtained with monoclonal B cells confirm that the B8.7 molecule is involved in the signalling pathway of the LMW-BCGF.
Aged↗
A human TCR-Ig chimeric protein used to generate a TCR alpha chain variable region-specific mAb.
In a recent report, a construction containing the alpha chain-variable region (V alpha) coding sequence of a cDNA clone derived from a diphtheria toxoid-specific human T cell (P28), fused to a human immunoglobulin kappa light chain constant region (Ck), was used stably to transfect a murine myeloma cell. In the present study, these transfected cells were employed as an immunogen to raise a mAb, termed 1C5V alpha, specific both for the V alpha Ck chimeric protein secreted by the transfectant and the P28 T cell antigen receptor-V alpha region. mAb 1C5V alpha specifically immunoprecipitates the V alpha Ck protein as a family of 32-35 kDa bands present in the 35S-methionine-labeled culture supernatant from the transfected cells. It specifically binds clone P28. Surface molecules recognized by mAb 1C5V alpha are physically linked to the CD3 molecules since cell treatment with either 1C5V alpha or anti-CD3 mAbs caused the simultaneous down-regulation of the CD3/TCR molecular complex. This link is further supported by immunoprecipitation experiments. Thus, both the 1C5V alpha and the anti-CD3 mAbs precipitate the 16-28 kDa CD3 molecules and the disulfide-linked form of P28 TCR from 125I-labeled P28 T cells. Studies performed in order to define whether a stimulus directly acting on the TCR-V alpha region may trigger the intracellular events observed during human T cell activation showed that (a) mAb 1C5V alpha efficiently triggers the phospholipase C transduction pathway revealed by an accelerated phosphoinositides turn-over and an increased production of phosphorylated derivatives of inositol phosphates; (b) mAb 1C5V alpha induces an up-regulation of IL2R mRNA, accompanied by a slight increase of IL2 and IFN alpha mRNA transcripts evidently amplified in the presence of PMA; (c) soluble mAb 1C5V alpha is strongly mitogenic together with PMA. These results provide the first evidence for the structural authenticity of a secreted water-soluble chimeric form of the variable region of a human TCR alpha chain. They further demonstrate that such chimeric proteins may be valuable tool to further dissect the various functional structure of the human TCR.
Antibodies, Monoclonal↗
Induction of mouse syngeneic MLR by in vivo xenogeneic immunization with HLA-DR antigens.
To study in mice the effects of in vivo xenogenic immunization with human major histocompatibility complex (MHC) class II antigens, the animals were injected with HLA-DR antigens and their proliferative responses tested in vitro. The results showed that small amounts of HLA-DR proteins, acting as nominal antigens, were not only able to prime mice for a secondary in vitro xenogenic mixed lymphocyte reaction but also induced a syngeneic mixed lymphocyte reaction. In contrast, allogeneic or syngeneic immunization of mice with soluble MHC class II molecules failed to stimulate an autoreactive response. The syngeneic mixed lymphocyte reaction was primarily directed against syngeneic MHC class II molecules since the murine T lymphocytes reacted against MHC class II-positive dendritic spleen cells and MHC class II-transfected mouse fibroblasts. A self-reactive T-cell line induced under these experimental conditions did not react in xenogeneic and allogeneic mixed lymphocyte reactions. However, these T lymphocytes proliferated when human peripheral blood lymphocytes of various haplotypes were presented in the context of syngeneic mouse antigen presenting cells.
Animals↗
Increased lung epithelial permeability in HIV-infected patients with isolated cytotoxic T-lymphocytic alveolitis.
HIV-related lymphocytic alveolitis is common in HIV-seropositive patients without lung infection or tumor. In some of them a fraction of alveolar lymphocytes are HIV-specific cytotoxic T-lymphocytes (CTL) bearing the CD8 and D44 cell surface markers and capable of killing HIV-infected alveolar macrophages. In order to evaluate the in vivo effect of these CTL on lung function, we measured the pulmonary clearance of aerosolized 99mTc-diethylene triamine penta-acetate (DTPA-CI) on 24 occasions in 22 patients with lymphocytic alveolitis. DTPA-CI has been selected as a highly sensitive test to detect injury of the lung epithelium. In 13 of the patients, we found a high DTPA-CI of 4.56 +/- 2.54%.min-1 (mean +/- SD), suggesting an increase of the epithelial permeability. The lymphocytic alveolitis was then characterized by a high cellularity, a high proportion of lymphocytes (59 +/- 18%), mainly composed of CD8+D44+ T-lymphocytes (149 +/- 109 cells/mm3), which spontaneously exhibited a cytolytic activity against the autologous alveolar macrophages in a standard 51Cr release assay. In the remaining 11 patients, DTPA-CI was normal (less than 1.78%.min-1), lymphocytic alveolitis being characterized by a low number or an absence of CD8+D44+ alveolar lymphocytes (9 +/- 13 cells/mm3) with no significant cytolytic activity. In the whole group, a significant correlation (r = 0.74, p = 0.0004) was found between the DTPA-CI and the number of CD8+D44+ lymphocytes and their cytotoxic activity against alveolar macrophages. Altogether, these results suggest that an injury of the lung epithelium could result from a HIV-specific CTL-induced immunologic conflict.
Adult↗
Human immunodeficiency virus-1 glycoproteins gp120 and gp160 specifically inhibit the CD3/T cell-antigen receptor phosphoinositide transduction pathway.
The interference of the recombinant HIV-1 glycoproteins gp160 and gp120 with the CD3/T cell antigen receptor (TcR)-mediated activation process has been investigated in the CD4+ diphtheria toxoid-specific human P28D T cell clone. Both glycoproteins clearly inhibit the T cell proliferation induced in an antigen-presenting cell (APC)-free system by various cross-linked monoclonal antibodies specific for the CD3 molecule or the TcR alpha chain (up to 80% inhibition). Biochemical studies further demonstrate that exposure of the T cell clone to both glycoproteins (gps) specifically inhibits the CD3/TcR phospholipase C (PLC) transduction pathway, without affecting the CD3/TcR cell surface expression. Thus, inositol phosphate production, phosphatidic acid turnover, intracellular free calcium, and intracellular pH increase induced by CD3/TcR-specific MAbs are specifically impaired in gps-treated P28D T cells. Addition of purified soluble CD4 prevents binding of gps to T cells and overcomes all observed inhibitions. Maximal inhibitions are obtained for long-term exposure of the T cell clone to gps (16 h). No early effect of gps is observed. By contrast, gp160 and gp120 fail to suppress the CD2-triggered functional and biochemical P28D T cell responses. These results demonstrate that, in addition to their postulated role in the alteration of the interaction between CD4 on T lymphocytes and MHC class II molecules on APC, soluble HIV-1 envelope glycoproteins may directly and specifically impair the CD3/TcR-mediated activation of PLC in uninfected T cells via the CD4 molecule.
Antigens, CD↗
Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes.
CTL specific for HIV have been described in lungs of infected patients at early stages of HIV disease. In order to characterize the evolution over time of HIV-specific CTL, we have analyzed the cytotoxic function and the cell surface phenotype of the alveolar lymphocytes from 41 patients at various stages of HIV disease. We demonstrated a progressive decline of alveolar anti-HIV CTL activity and detected Ts cells from the lungs of patients with advanced HIV disease. These alveolar T cells strongly suppressed the effector phase of anti-HIV CTL lysis. They lacked a marked specificity of function because they also block anti-HLA CTL response and were not restricted by the HLA-class-I transplantation Ag. They displayed the CD3, CD8, and HNK1 markers, were CD4 and CD16 negative, and lacked NK activity. The presence of Ts cells at late stages of HIV disease could thus partly explain the inefficiency of host defenses against HIV.
AIDS-Related Complex↗
Immunoregulatory effects of a suppressor factor from healthy pregnant women's lymphocytes after progesterone induction.
Progesterone-treated pregnancy lymphocytes release an immunologic blocking factor. The mode of action of this substance was investigated. The supernatant of progesterone-treated pregnancy lymphocytes was highly suppressive of natural cytotoxicity toward human embryonic fibroblast target cells as well as of natural killer cell activity. The effect was not observed when progesterone induction was performed in the presence of RU 486, a progesterone receptor blocking agent. The factor was able to inhibit mixed lymphocyte reactions (MLRs), and transfer coculture experiments revealed that this effect was dependent on major histocompatibility complex nonspecific, nonrestricted suppressor T cells. The activation/expansion of suppressor inducer and suppressor effector T cells was further proved by fluorescence-activated cell sorter analysis of the populations from MLRs cultured in the presence of the inhibitory factor. These changes were not observed with MLRs performed in the presence of supernatants from progesterone + RU 486-treated peripheral blood lymphocytes. The inhibitory material, on the other hand, did not affect either production or function of IL-2. We conclude that in the presence of high local concentrations of progesterone, a suppressive pathway dependent on specific progesterone-CD8+ lymphocyte interaction might be established. This mechanism might play an important role in the maintenance of pregnancy.
Antibodies, Monoclonal↗
Phenotype and function of peripheral blood and bone marrow T-cell colonies: identification of DC3-, 4-, 8-autoreactive T cells.
The existence of immature autoreactive T cells has been examined in peripheral blood (PB) and bone marrow (BM) derived T-lymphocyte colonies (TLC) that have previously been shown to be potentially generated from CD3-negative BM-T cells. An extensive phenotypical analysis of total and T-depleted TLC showed that both PB- and BM-derived TLC contained a mean of 5% immature T lymphocytes (ITL), which were negative for the CD3, CD4, and CD8 antigens but displayed the CD2 and CD7 antigens. The only detectable immune functions of these isolated ITL were an allo- and an autoreactivity without cytolytic activity. The self-reactivity of ITL was not detected in bulk non T-depleted TLC cells and seemed to be actively suppressed by autologous mature T cells. In addition, the auto-MLR of ITL was totally inhibited by anti-HLA class II but not by anti-class I monoclonal antibody (MoAb) and only partially by anti-CD4 moAb, whereas the anti-CD3 and anti-CD2 MoAbs gave no inhibition. Once activated, ITL could acquire in culture a mature T cell CD3 + CD4 + phenotype. The CD3-, 4-, 8-auto-reactive T cells present in T colonies could represent pre- or post-thymic cells that have not yet undergo or that have escaped the thymic selection.
Antigens, Differentiation, T-Lymphocyte↗
Diagnostic and prognostic significance of myelomonocytic cell surface antigens in acute myeloid leukaemia.
Thirty-six cases of acute myeloid leukaemia (AML) were tested with a large battery of monoclonal antibodies (moAbs) detecting surface markers normally expressed by myelomonocytic, T and B lymphoid, megakaryocytic and erythroid lineages. Differences in antigenic expression were observed among the various FAB subgroups: HLA-class II molecules were found in almost all AML cases but not in the promyelocytic subgroup (M3); CD14 and CD36 antigens were detected in monocytic leukaemias (M4 and M5); the CD34 moAb (MY10) recognizing an epitope described on myeloid stem cells was positive in 88% of the M1 and 80% of the M3 cases. By a multivariate analysis, only the CD14b (MY4) discriminated significantly between M1-M2 and M4-M5 subgroups. Using Cox's model to assess the prognostic importance of variables including immunophenotyping on survival, we undertook a one by one analysis and found that the presence of CD17 antigen predicted for a shorter survival (P = 0.03). In addition this marker appeared more significant than other clinical and biological parameters.
Adolescent↗