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Biomedical subjects

C Ferran

Publications and source records attributed to C Ferran.

At least 19 recordsLinked to original sources
PubMed1992

Evidence that antihuman tumor necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome.

We have used an antihuman tumor necrosis factor monoclonal antibody, CB006 (murine IgG1), to prevent the OKT3-induced acute clinical syndrome. This syndrome is due to the massive, although transient release in the circulation of various cytokines (TNF, interferon gamma, interleukin 2, interleukin 6) and represents one important side effect linked to in vivo use of OKT3. Fourteen kidney allograft recipients undergoing prophylactic OKT3 therapy were treated with CB006 in a single i.v. injection of either 0.4 mg/kg (group I, 7 patients) or 2 mg/kg (group II, 7 patients), 1 hr before the first OKT3 administration. Nineteen consecutive patients formed a historical control group. None of the CB006-pretreated patients showed any of the common, severe OKT3-associated symptoms (hypotension, respiratory distress, or neurotoxicity), which were observed in 10% of the historical controls. In addition, CB006-treated patients showed a lower frequency of pyrexia (> or = 39 degrees C) and gastrointestinal symptoms. None of the CB006-treated patients presented severe vomiting or diarrhea, defined as repeated episodes inducing significant fluid and electrolyte loss. Two out of the 7 patients in group I and group II had mild transitory diarrhea. Mild single vomiting episodes occurred in 2 group I patients and 3 group II patients. At variance in all controls, gastrointestinal symptoms were long lasting and associated with major prostration due to electrolyte and fluid loss. Importantly, CB006-treated patients who presented mild symptoms had detectable bioactive circulating TNF, showing incomplete inactivation of OKT3-induced TNF by CB006. CB006 was perfectly well tolerated, did not induce xenosensitization, and did not affect the biological or clinical effectiveness of OKT3.

Acute Disease↗
PubMed1991

[Acute clinical syndrome associated with OKT3 administration. Prevention by single injection of an anti-human TNF monoclonal antibody].

This study analyzed the capacity of an anti-human tumour necrosis factor (TNF) monoclonal antibody, CB006 (murine IgG1, Celltech), to prevent the OKT3-induced acute clinical syndrome. Fourteen renal allograft recipients undergoing prophylactic OKT3 therapy were included. CB006 was administered as a single i.v. injection, 0.4 mg/kg (Group I, 7 patients) and 2 mg/kg (Group II, 7 patients), one hour prior to the first OKT3 administration. Nineteen consecutive patients that were part of a randomized multicenter trial constituted the historical control group. In all patients CB006 was perfectly well tolerated and significantly decreased the frequency of the common OKT3-associated acute symptoms. None of the CB006 pretreated patients showed severe life threatening symptoms (hypotension, respiratory distress or neurotoxicity), observed in 10 per cent of historical controls. At variance with controls, in CB006 treated patients gastrointestinal symptoms (vomiting, diarrhea) and pyrexia (body temperature greater than or equal to 39 degrees C) appeared in low frequency, were mild and short lasting, never promoting major prostration of the patients due to electrolytes and fluid loss. Importantly, the presence in some patients of these mild symptoms, correlated with detectable bioactive TNF in the circulation thus reflecting incomplete blockade by CB006 of OKT3-induced TNF. CB006 pharmacokinetics data further stressed the need for adequate dosage adaptation. CB006 did not affect the biological or clinical effectiveness of OKT3. None of the patients showed evidence of anti-CB006 xeno-sensitization.

Antibodies, Monoclonal↗
PubMed1991

Cascade modulation by anti-tumor necrosis factor monoclonal antibody of interferon-gamma, interleukin 3 and interleukin 6 release after triggering of the CD3/T cell receptor activation pathway.

In addition to being potent immunosuppressants, anti-CD3 monoclonal antibodies (mAb) are powerful mitogens in both humans and mice. The first antibody injection consistently induced an initial monocyte-dependent T cell activation with subsequent release of both monocyte- and T cell-derived cytokines [mainly tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL) 2, IL 3 and IL 6) into the circulation. This cytokine release is associated with a self-limiting, often severe, acute physical reaction in both patients and mice. We report here that a single injection of anti-TNF mAb prior to anti-CD3 administration not only neutralizes the biological activity of TNF but also strongly affects the release of other cytokines, with notably an up-regulation of IFN-gamma release and a down-regulation of IL 3 and IL 6 release. Conversely, pretreatment with anti-IFN-gamma mAb increases IL 3 and IL 6 production but does not affect TNF levels. Taken together, these data point to a pivotal role of IFN-gamma in the anti-CD3-induced cytokine cascade and reveal new regulatory pathways between TNF and IFN-gamma. With regard to the clinical implications of these findings, as anti-TNF mAb prevents anti-CD3-induced sickness in mice, whereas anti-IFN-gamma does not, such a therapeutic approach might be of value in OKT3-treated patients.

Animals↗
PubMed1991

Corticosteroid inhibition of the OKT3-induced cytokine-related syndrome--dosage and kinetics prerequisites.

The data presented extend to a larger series of 27 consecutive renal allograft recipients treated prophylactically with OKT3 our previous observation that the acute OKT3-induced clinical syndrome is related to massive release in the circulation of some cytokines, among which are tumor necrosis factor and interferon gamma. In addition, a pilot randomized study was set up including 12 consecutive patients receiving high-dose corticosteroid treatment (0.5 g solumedrol) either before or at the same time as the first OKT3 injection. Results confirm that when corticosteroids are given in sufficient amount and, importantly, 1 hr before the first OKT3 injection, they significantly decrease the release of both tumor necrosis factor and interferon gamma. In addition, the pretreatment with corticosteroids may totally abolish the IL-2 release induced by OKT3. Given the key role the massive although transient cytokine release plays in determining the OKT3-induced acute syndrome, these results provide the biological basis supporting a precise kinetics of administration of high-dose corticosteroids to better decrease the severity of the clinical reaction.

Adrenal Cortex Hormones↗
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

Plasmid-mediated sucrose metabolism in Escherichia coli: characterization of scrY, the structural gene for a phosphoenolpyruvate-dependent sucrose phosphotransferase system outer membrane porin.

The scrY gene, part of the pUR400-borne sucrose regulon, appeared to be transcribed from its own promoter, with the transcriptional start site located 58 bp upstream from the initiation codon. An open reading frame encoding a polypeptide of 505 amino acid residues (Mr 55,408) was identified. The first 22 amino acid residues formed a leader sequence typical of those found in other procaryotic outer membrane and periplasmic proteins. A frameshift mutation in the scrY gene resulted in a dramatic decrease in sucrose transport with no effect on in vitro phosphorylation activity associated with enzyme IISer. The rate of diffusion of sucrose was 96 times greater than the rate of diffusion of lactose or maltose in liposomes containing the ScrY protein. This increase in sucrose permeability provided strong evidence that the ScrY protein functions as a sucrose porin. There was 23% amino acid sequence identity between the ScrY protein and LamB, a maltose porin from Escherichia coli.

Amino Acid Sequence↗
PubMed1990

Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation.

In vivo injection of the hamster anti-murine CD3 monoclonal antibody 145 2C11 into BALB/c mice induces a massive systemic release of several cytokines. Very high circulating levels of tumor necrosis factor are detected both by enzyme-linked immunosorbent assay and L-929 bioassay 90 min following a single injection of 10 micrograms/mouse 145 2C11. Peak circulating levels of exclusively T cell-derived products such as interferon-gamma, interleukin 2 and interleukin 3 are also detected 90 min to 8 h post-injection. Importantly, this cytokine release is transient since none of these cytokines are still present 12 to 24 h post-injection. In parallel to cytokine release, 145 2C11-treated mice (10 micrograms/mouse) exhibit somnolence, hypomotility (quantified by actimetry), hypothermia, diarrhea and piloerection. At this dosage, the physical reaction is not lethal and reverses in all mice by 48 h post-injection. Severe but again reversible anatomopathological changes are also observed: massive cellular depletion, necrosis and edema of lymphoid organs, leakage syndrome and inflammatory cell infiltrates of the lung, cell vacuolization, necrosis and vascular congestion of the liver. All these data are similar to the clinical and immunological manifestations of the OKT3-induced reaction in patients and, thus, provide an invaluable experimental tool to study its mechanisms and explore its prevention.

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↗