Biomedical subjects
L Chatenoud
Publications and source records attributed to L Chatenoud.
In vivo T cell preactivation in chronic uremic hemodialyzed and non-hemodialyzed patients.
The production and targeting of a major T cell derived lymphokine, Interleukin 2 (IL-2), were studied in 23 uremic patients undergoing regular hemodialysis treatment and 20 uremic patients prior to the onset of renal replacement therapy. In hemodialyzed patients, abnormally increased proportions of circulating T cells spontaneously expressing high affinity IL-2 receptors (IL-2 Rec) were detected: they bound a monoclonal antibody specifically directed to the IL-2 Rec 55 kDa chain (Tac antigen) (mean +/- SEM: 7.12 +/- 0.81% in patients vs. 2.15 +/- 0.39% in normal controls, P less than 0.0001) and significantly proliferated in presence of human recombinant IL-2 alone (mean +/- SEM: 5438 +/- 729 cpm in patients vs. 1647 +/- 244 cpm in normal controls). Hemodialyzed patients also exhibited significantly increased serum levels of soluble IL-2 receptor (mean +/- SEM: 4036 +/- 947 U/ml in patients vs. 253 +/- 29 U/ml in normal controls. P less than 0.001). Moreover, a significantly decreased IL-2 activity was detected in the supernatants of stimulated T cells from hemodialyzed patients (mean +/- SEM: 0.93 +/- 0.12 U/ml in patients vs. 2.49 +/- 0.22 U/ml in normal controls, P less than 0.0001). In nine hemodialyzed patients who were analyzed before and immediately after the hemodialysis session no acute modifications of the various parameters analyzed were detected. Although less profound, a similar pattern of T cell abnormalities was observed in the uremic non-hemodialyzed patients studied.(ABSTRACT TRUNCATED AT 250 WORDS)
Suppression of the humoral response to anti-CD3 monoclonal antibody.
Anti-CD3 monoclonal antibodies are used clinically to treat organ allograft rejection. Their administration can result in reversal of rejection even in episodes resistant to other modes of therapy. A major limitation to their use has been the humoral response of the patients against the mAbs, resulting in loss of therapeutic efficacy. We have established an animal model for anti-CD3 treatment using the antimurine CD3 mAb, 145-2C11. Exposure of mice to this mAb, like exposure of humans to its antihuman analog OKT3, results in suppression of graft rejection but also stimulates a strong humoral response that abrogates the efficacy of further treatments. Administration of an additional dose of anti-CD3 mAb did not prolong skin graft survival--and, in some instances, resulted in a lethal anaphylactic reaction. In an attempt to suppress the humoral response against the anti-CD3 mAb, anti-CD4 mAb was administered prior to the anti-CD3 mAb treatment. Pretreatment of mice with anti-CD4 mAb (GK1.5) almost completely suppressed the humoral response to anti-CD3 mAb, and permitted readministration of the anti-CD3 mAB without loss of efficacy as assessed by prolongation of skin graft survival. The data suggest that the use of anti-CD4 mAb to suppress the humoral response against anti-CD3 mAb should be attempted clinically, as it might permit repeated courses of anti-CD3 administration, thus significantly improving the efficacy of these agents in the therapy of organ allograft rejection.
Aberrant T cell-mediated immunity in untreated schizophrenic patients: deficient interleukin-2 production.
The authors examined the immune status at the cellular and humoral levels of 16 untreated schizophrenic patients. No abnormality in the distribution of T cell subsets (CD4+, CD8+) was detected. The proliferative response to the T cell mitogen phytohemagglutinin was normal. No increase in the number of T cells showing activation markers, such as human leukocyte antigens and interleukin-2 receptors, was noted. Conversely, function studies revealed a clear deficiency in interleukin-2 production by purified T cells. This lower production was probably intrinsic to the patients' T cells, since interleukin-2 production showed normal sensitivity to prostaglandin E2-mediated down-regulation by autologous monocytes.
Effect of cyclosporin on interleukin 2-related T-lymphocyte parameters in IDDM patients.
Seventy patients aged 15-40 yr with recent-onset insulin-dependent diabetes mellitus (IDDM) were entered into a double-blind trial, in which they were randomly assigned to either cyclosporin (7.5 mg.kg-1.day-1) or to placebo and were monitored for 1 yr for various phenotypic and functional parameters of T-lymphocyte-mediated immunity. Before treatment, the proportions of total T-lymphocytes (CD3+) and helper-inducer T-lymphocytes (CD4+) were normal, whereas significantly decreased values of suppressor/cytotoxic T-lymphocytes (CD8+), as compared with normal controls, were found in 31% of the patients. The interleukin 2 (IL-2)-receptor expression was significantly increased in IDDM patients compared with control subjects, although the single values were low: patients, 2.02 +/- 0.41%; controls, 0.88 +/- 0.25% (means +/- SE). Circulating levels of soluble IL-2 receptor were also significantly increased in IDDM patients compared with controls: patients, 372.3 +/- 25.4 U/ml; controls, 235.5 +/- 29.3 U/ml (means +/- SE). However, no major abnormalities were found in mitogen (phytohemagglutinin)-induced IL-2 production, cell proliferation, or IL-2-receptor expression. After 6 mo of cyclosporin treatment, no major modifications of any of the parameters analyzed were noted, even in patients who had cyclosporin blood trough levels greater than 300 ng/ml, i.e., the threshold value associated with clinical efficacy. One explanation for the absence of a major effect of cyclosporin, in contrast with its demonstrated clinical effectiveness, is the reversibility of its activity. Our results preclude the use of the described tests to reliably monitor IDDM patients undergoing immunosuppressive therapy.
Suppression of the humoral response to anti-CD3 mAB by pretreatment with anti-CD4 mAB.
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A randomized trial comparing the efficacy of OKT3 used to prevent or to treat rejection.
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In vivo infusion of anti LFA-1 antibody in HLA non-identical bone marrow transplantation in children: serum concentrations and biological effects.
The mouse monoclonal antibody 25-3 specific for the alpha subunit of LFA-1 (CD11a) has been infused to children undergoing HLA non-identical bone marrow transplantation because of lethal inherited diseases or of leukemia in order to prevent graft failure. We have assessed the serum concentrations of the antibody infused according to two regimens: 0.1 mg/kg five times, every alternate day (eight patients) or 0.2 mg/kg daily for 10 days (30 patients). Serum trough levels of 25-3 antibody in the first group were constantly found to be low (less than 0.6 micrograms/ml) while 25-3 serum concentration in the second group rose progressively to a mean value of 2.2 micrograms/ml. Serum antibody concentrations were significantly lower in patients with greater antigenic mass, i.e. with splenomegaly, or non conditioned. The engraftment rate was slightly higher in patients treated by the daily infusion of 25-3 for 10 days. No immunization against 25-3 antibody occurred. One patient who subsequently received other mouse anti-B cell antibodies eventually produced anti-isotype antibodies. The consequences of 25-3 infusion on leukocyte counts has been evaluated in the group of patients (n = 6) with severe combined immunodeficiency who did not receive any chemotherapy and in one who was treated with 25-3 because of acute graft-versus-host disease. In none of the cases did 25-3 antibody infusion modify blood leukocyte counts. In addition, it was shown that saturation of LFA-1 on leukocytes was a transient phenomenon, since it could not be found 24 h following infusion of 25-3 antibody.(ABSTRACT TRUNCATED AT 250 WORDS)
In vitro and in vivo action of cyclosporin A on the induction of human interleukin-2 receptor alpha and beta chains.
To compare in vitro and in vivo cyclosporin A (CyA) effects on early events involved in human T cell activation, lymphocytes obtained from healthy donors and from diabetic patients undergoing CyA therapy were studied for their interleukin 2 (IL-2) responsiveness, surface IL-2 receptor (IL-2R) expression and IL-2R mRNA accumulation, following stimulation with mitogen or anti-CD3 monoclonal antibody. T cells recovered from eight in vivo CyA-treated patients and stimulated in vitro for 4 h with mitogen or anti-CD3 (in the absence of CyA) showed significant (50-60%) inhibition of Tac mRNA accumulation, as assessed and quantified by scanning densitometry. Conversely, these cells showed no modification in their expression of membrane alpha (p55, Tac) or beta (p70) chains of IL-2R in binding experiments performed with both iodinated anti-Tac and IL-2 following 18 h stimulation with either mitogen or anti-CD3. Normal lymphocytes treated in vitro with CyA showed significant inhibition of alpha chain IL-2R expression both at the mRNA and the membrane level. At variance, expression of the IL-2R beta chain was unaffected; a significant number of high-affinity IL-2 binding sites was still detectable after in vitro CyA treatment. These results suggest that: (1) a residual immunosuppressive effect of CyA on T cell activation may be evidenced in in vivo treated cells by measuring very early events triggered following short-term stimulation; (2) CyA activity on T cell activation seems similar in vivo and in vitro; and (3) the described approach would be potentially useful to monitor the individual in vivo immunosuppressive capacity of CyA.
[Diagnostic and therapeutic use of monoclonal anti-T lymphocyte antibodies].
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The therapeutic use of monoclonal antibodies.
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One-month prophylactic use of OKT3 in cadaver kidney transplant recipients.
Fifty-five recipients of first cadaveric renal allografts were randomly assigned to three treatment groups in order to compare the safety and efficacy of a mouse antihuman T cell monoclonal antibody (OKT3) given prophylactically for a one-month period. This long period of administration was made possible by concomitant administration of azathioprine. The immune response against the foreign immunoglobulin was thus delayed and decreased in both intensity and severity, and OKT3 treatment could be given during almost the entire month in the majority of patients. The 18 patients who were enrolled in this treatment group had significantly (P less than 0.01) fewer rejection episodes during the first month posttransplantation than the 19 patients allocated to the high-dose (HD) steroid control group or the 18 patients allocated to the low-dose (LD) control group. Actual 2-year as well as actuarial 4-year graft survival rates were 89% in the OKT3 group, whereas they were 70% and 67% respectively in the steroid control groups. Four-year serum creatinine levels were normal and doses of steroids and other immunosuppressive agents were lower in the OKT3 group as compared with the control groups. Tolerance to OKT3 was good, and while viral infections were more frequently observed in OKT3 treated patients, the total number and the severity of infectious episodes were similar in all groups. The combination of one-month OKT3 plus azathioprine prophylaxis followed by conventional azathioprine plus low-dose steroid maintenance produced very satisfactory long-term results comparable to the best results now being obtained with cyclosporine regimens.
[Immunology of transplantation].
Immunologic events leading to the acute rejection of a grafted organ follow three sequential stages: 1) recognition of the antigens fully specific expressed by the allograft; 2) proliferation and differentiation of the T lymphocytes; 3) destruction of the graft mediated by various cellular types: sensitized cytotoxic T lymphocytes, lymphokine activated lymphocytes or macrophage cells, and, more hypothetically, by the so-called "killer" cells. The T lymphocytes infiltrating the grafts during rejection include functionally distinct subsets: inducer T cells (CD4+ cells) and suppressor/cytotoxic cells, T cells (CD8+ cells). In reversible acute rejections the role of activated cytotoxic cells (CD3+ CD8+) seems to be predominant. The functional nature of the lymphoblasts infiltrating the allograft is heterogeneous. It includes cell-mediated cytotoxicity, the proliferative response to alloantigens and the production of lymphokines. Finally, the role of the T cell receptor for the recognition of the antigen appears to be essential. The necessity for the immune system to build up a large repertoire of different T receptors is dependent on a mechanism of genetic coding similar to the one used by immunoglobulins. In the near future, one may hope to alter specifically the repertory of the T receptors used by the lymphocytes responsible for rejection. This would represent the dawn of a new era in transplantation immunity with the beginning or specific immunosuppression.
Therapeutic use of the OKT3 anti-T cell monoclonal antibody: mode of action and side effects.
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[T lymphocyte activation induced in vivo by the first injection of OKT3 monoclonal antibodies].
One of the major side effects induced by the in vivo administration of the murine monoclonal antibody OKT3 is a spontaneously reversible clinical syndrome associating in variable proportions depending on the patient: fever, chills, headaches, diarrhea and seldomly meningismus. Sera from 3 renal allograft recipients treated with OKT3 were studied and showed that a massive although transient release of some cytokines namely, Tumor Necrosis Factor alpha, Interleukin 2 and Interferon gamma is observed following the first OKT3 injection.
The effect of cyclosporine A on humoral and cellular immunity in insulin-dependent (type I) diabetes mellitus.
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In vivo cyclosporine A treatment inhibits spleen cell mitogen-triggered free [Ca2+] increase.
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Polyclonal and monoclonal antibodies directed against SK & F 94461, a specific H1 histamine receptor ligand.
SK & F 94461, an aminopentyl analogue of mepyramine, is a recently described H1 receptor antagonist. At variance with the other available H1 receptor ligands, SK & F 94461 offers the possibility of coupling to a protein carrier to render the molecule immunogenic. SK & F 94461 coupled to succinylated bovine serum albumin was used as an immunogen to raise polyclonal antibodies in rabbits and BALB/c mice. In parallel, spleen cells from immunized mice were used to produce hybridomas by somatic cell fusion. Thus, six different murine monoclonal antibodies sharing anti-SK & F 94461 specificity were selected for further detailed characterization of their binding properties. Pharmacologic studies of competitive inhibition using a set of 11 histaminergic agents allowed analysis of the fine specificity of anti-SK & F 94461 antibodies. Both polyclonal and monoclonal anti-SK & F 94461 antibodies showed very high affinity for the immunizing molecule (i.e., Ka values for monoclonal antibodies 8 and 12 were, respectively, 3 X 10(10) and 1.4 X 10(10) M-1). Both types of antibodies bound with high affinity (IC50 ranging from 10(-10) to 10(-12) M) to mepyramine, which has a chemical structure closely resembling that of SK & F 94461. Moreover, these antibodies displayed clear-cut stereoselectivity inasmuch as they bound the d-configuration of chlorpheniramine with significantly higher affinity than the l-form. Thus, all six monoclonal antibodies showed IC50 values 1 to 6 log units lower for d- than for l-chlorpheniramine. For some monoclonal antibodies, spectroscopic and fluorescence spectra studies showed that their different binding capacities correlated with their optical properties. Similarly, polyclonal anti-SK & F 94461 antibodies showed a 500-fold lower affinity for l- than for d-chlorpheniramine. All these results indicate that the polyclonal and the majority of monoclonal anti-SK & F 94461 antibodies recognized with high affinity structural configurations known to be important for the pharmacologic activity of H1 ligands, namely the presence of the dimethylaminoethyl side chain and, with stereochemical selectivity, the d-configuration of chlorpheniramine. These data extend for the first time to an H1 histamine receptor ligand results reported in other hormone systems.