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L Chatenoud

Publications and source records attributed to L Chatenoud.

At least 163 records · Page 9Linked to original sources
PubMed1991

Inter-mouse strain differences in the in vivo anti-CD3 induced cytokine release.

Triggering of the CD3 molecule by in vivo injection of the hamster anti-murine CD3 monoclonal antibody 145-2C11 in adult BALB/c mice leads to massive although transient T cell activation. High levels of tumour necrosis factor (TNF), interferon-gamma (IFN-gamma), IL-2, IL-3 and IL-6 are released into the circulation 1 to 8 h after a single 10 micrograms 145-2C11 i.v. injection. This release induces an impressive self-limited physical reaction associating hypothermia, hypomotility (as assessed by actimetry), diarrhoea, piloerection and even death when high doses (a single dose of greater than 100 micrograms/mouse injection) are administered. In vivo injection of 145-2C11 to other selected mouse strains, namely NZW, CBA/J and C3H/HeJ, induced both different cytokine release patterns and sickness. 145-2C11 induced significant release of TNF and IL-2 in all four strains. At variance, IFN-gamma was only detected in BALB/c mice sera which, in terms of physical reaction (hypothermia and hypomotility) were the most affected. Higher and long-lasting circulating IL-3/GM-CSF levels were present in CBA/J sera, correlating with a later recovery. These results underline heterogeneity in the in vivo cell activation pattern among different mouse strains, when triggering T lymphocytes via the CD3/Ti molecule as compared to exclusive targeting of monocyte/macrophages by means of lipopolysaccharide.

Animals↗
PubMed1991

[T lymphocyte activation induced by monoclonal anti-CD3 antibodies: physiopathology of cytokine release].

Anti-CD3 monoclonal antibodies are largely used as therapeutic agents in clinical transplantation. Constrating with their potent immunosuppressive activity anti-CD3 antibodies also transiently express T cell activating properties. In vitro they promote T cell mitogenesis and in vivo, the self-limited cytokine release (including TNF, IFN gamma, IL-2, IL-3, IL-6) observed following the first anti-CD3 injection, is responsible for an acute clinical syndrome. Clinical studies as well as the experimental data obtained in mice, confirmed that TNF plays a fundamental role in the anti-CD3 induced syndrome. The administration of anti-TNF monoclonal antibodies prior to the first anti-CD3 injection prevents the syndrome not only by blocking TNF bioactivity but also, by modulating the circulating levels of the other anti-CD3-induced cytokins. In particular, this model allowed the description of regulatory pathways existing between TNF and IFN gamma, which in turn regulate IL-3 and IL-6 release.

Animals↗
PubMed1990

In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids.

A massive and self-limited release of tumor necrosis factor and interferon gamma was detected in the systemic circulation in 35 consecutive renal allograft recipients by specific radioimmunoassays very soon following the first injection of the monoclonal antibody OKT3 (anti-CD3). Peak serum TNF and IFN gamma levels were reached, respectively, at 1 and 4 hr following the first OKT3 injection. Abnormally high serum interleukin 2 levels were also observed 4 hr following the first OKT3 injection in a minority of patients (5 cases). OKT3 had no effect on interleukin 1 beta, interferon alpha, and granulocyte/macrophage colony stimulating factor serum levels, which in all patients remained within the normal range throughout the study. This selective OKT3-induced cytokine release, which only followed the first injection, was transient (i.e., lasting a few hours). It tightly paralleled the spontaneously reversible clinical syndrome characterized by high fever, headaches, and gastrointestinal symptoms that is invariably associated with the first OKT3 administration. Importantly, when administered in adequate dosages and with adequate timing, corticosteroids influenced both the cytokine release and the systemic reaction. Thus, the highest TNF, IFN gamma, and IL-2 serum levels were detected in patients who did not receive corticosteroids. Patients who received high-dose corticosteroids (1 g solumedrol bolus) concomitantly with the first OKT3 injection still had high TNF and IFN gamma levels. Conversely, when the same corticosteroid dose was injected 15-60 min prior to the first OKT3 injection, in all cases the increase of serum TNF and IFN gamma was significantly lower as compared with the above-described groups; IL-2 levels did not rise. These data offer a direct explanation for one major side effect of OKT3 and thus provide the basis for devising means to prevent its occurrence.

Antibodies, Monoclonal↗
PubMed1990

Reduction of morbidity and cytokine release in anti-CD3 MoAb-treated mice by corticosteroids.

In keeping with the in vitro mitogenic properties of anti-CD3 MoAbs, the first injections of anti-CD3 are invariably responsible for an in vivo cellular activation. This activation induces a massive cytokine release in the circulation (TNF, IFN gamma, IL-2, IL-6, and IL-3). Paralleling this release, a severe clinical reaction occurs in OKT3-treated patients and in 145 2C11-treated mice. Corticosteroids both in vitro and in vivo inhibit the production of several cytokines involved in the anti-CD3 reaction. A single 1 mg hydrocortisone dose was administered to 145 2C11-treated mice according to different kinetics schedules. When given 1 hr prior to the anti-CD3 MoAb, hydrocortisone exerted a beneficial effect on the mouse physical reaction. Hypothermia was totally abrogated at the 4-hr time point. Diarrhea decreased by 50%. Hypomotility improved although not significantly. This improvement correlated with a major modification in the anti-CD3 pattern of cytokine release. At the 90-min blood withdrawal time point cytokine serum levels showed a 100% decrease for IFN gamma, an 88% decrease for IL-6, and 85% decrease for IL-2, and a 75% decrease for TNF. At 4 hr IL-2 serum levels were diminished by 65%; IL-6, IL-3, and IFN gamma serum levels were comparable to controls; and, interestingly, TNF was still detected, whereas it has already disappeared when 145 2C11 was administered alone. Importantly, when given more than 1 hr prior to anti-CD3 injection, corticosteroids were ineffective. To conclude, high doses of corticosteroids must be given with a precise kinetics--i.e. 1 hr prior to anti-CD3 MoAb--to achieve their maximal beneficial effect in the prevention of the anti-CD3 reaction.

Adrenal Cortex Hormones↗
PubMed1990

[Inflammation and rejection].

The inflammation represents an important cause of allograft tissue lesions during ongoing rejection episodes. Such inflammation is mediated, at least in part, via the release of different soluble mediators. Some of these endogenous inflammation mediators are well known and include prostaglandins, leukotriens, histamine or histaminergic compounds and factors induced by the activation of the complement cascade (C3a, C5a). More recently, different molecules have been characterized, namely cytokines that are potent mediators of both immune and inflammatory reactions. Cytokines are produced by a wide variety of cells types (i.e., inducing immune and non immune cells) and expressing pleiotropic effects. The synergism between these various inflammation mediators finally provoke the anatomopathological lesions characteristic of a rejection process that are vascular lesions, edema formation and white blood cell chemotaxis leading to massive cellular infiltration. The aim of this brief review is to analyze the more recent data of the literature concerning cytokines that, applied to the field of organ transplantation, may provide further insights onto the relationships existing between inflammation and allograft rejection.

Cytokines↗
PubMed1990

The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells.

OKT3 exerts its in vivo immunosuppressive effects by inducing major peripheral T cell depletion as well as antigenic modulation of the T3/Ti T cell receptor complex. Modulated cells, which reversibly lose the expression of the CD3 T cell receptor molecular complex but still share the CD4 and CD8 antigens, have been shown to be functionally immunoincompetent. Antigenic modulation is maintained as long as significant OKT3 serum levels are present. Cells infiltrating renal allografts from seven OKT3 treated patients were studied by double immunofluorescence to assess whether antigenic modulation could affect cells located in profound organs such as renal allografts. Needle biopsies were obtained in patients given OKT3 (5 mg/day) for at least 10 consecutive days in association with conventional immunosuppressive drugs for treatment of a rejection episode (5 cases) or prophylactically (2 cases). In all patients at the time of biopsy, CD3 positive cells were absent from the circulation, significant OKT3 serum levels were present, and neither IgG nor IgM anti-OKT3 antibodies were detected. Infiltrating cells were double-labeled using a combination of either anti-CD3 and anti-CD4 or anti-CD3 and anti-CD8 monoclonal antibodies. Following 7-14 consecutive days of treatment, all patients given OKT3 for a rejection episode showed a significant decrease in the number of graft-infiltrating lymphocytes. Importantly, all T cells still infiltrating the allograft were CD3-CD4+ or CD3-CD8+ cells, which is exactly the same phenotypical pattern of CD3 circulating modulated T cells. In 6 out of the 7 patients, this phenotypical pattern was associated with clinically normal graft function. These results further underline the fact that antigenic modulation is an important mechanism mediating the immunosuppressive effect of OKT3 both in peripheral blood and in renal allografts.

Antibodies, Monoclonal↗
PubMed1990

Monoclonal antibodies to CD3 as immunosuppressants.

Murine monoclonal antibodies specifically directed at the CD3 molecular complex are widely used in clinical transplantation. They are potent inhibitors of immune function and may be administered in association to conventional immunosuppressants. The main purpose of this review is to summarize our present knowledge on the CD3 molecule, to discuss the available data on the clinical use of anti-CD3 MAb (therapeutic effectiveness, mode of action and side effects) and the recent information derived from the use of anti-CD3 MAb in experimental models that are opening new perspective in the applications of anti-CD3 and will hopefully lead to the extension of its clinical use to settings different from transplantation.

Animals↗