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J Descotes

Publications and source records attributed to J Descotes.

At least 55 records · Page 3Linked to original sources
PubMed1995

Clinical toxicity of cytokines used as haemopoietic growth factors.

A number of cytokines are used as haemopoietic growth factors and this review focuses on toxicities associated with granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF and G-CSF, currently approved for clinical use, are generally well tolerated by the majority of patients during short term administration. Constitutional symptoms and bone pain are the most frequently reported adverse effects, but they are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and exacerbation of autoimmune thyroiditis or autoimmune haematological disorders have sometimes been described. Severe cardiovascular complications include the possibility for arterial thromboses and the vascular leak syndrome, which is more specifically observed with GM-CSF. Reports of several cases and small series of patients have suggested that growth factors might increase the pulmonary toxicity of chemotherapy, a possibility that remains debated and requires further attention. Generalised or local cutaneous reactions are frequently noted with GM-CSF. Leukocytoclastic vasculitis was observed with both growth factors, while neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G-CSF. The hepatotoxic potential of the growth factors is not clearly established, but the occurrence of coagulation abnormalities has recently been reported. Renal and biological disturbances are usually transient. Long term treatment with GM-CSF and G-CSF also seems to be well tolerated, but the possible occurrence of several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration of underlying disease, require further investigation in patients receiving prolonged treatment, as in myelodysplasia. Finally, antibodies against growth factors have been reported only with GM-CSF. Other cytokines are still under investigation. Flu-like and constitutional symptoms, sometimes dose-limiting, have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally associated with such adverse effects. More specific adverse events, also frequently considered as dose-limiting toxicities, include hypotension with IL-1, severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal lesions with IL-4. Severe capillary leak syndrome has been reported only with IL-4. M-CSF toxicity is minimal and limited to reversible but sometimes dose-limiting thrombocytopenia and ophthalmological symptoms with the recombinant product. Again, the safety of long term administration of these cytokines has not yet been determined, and IL-3-induced disease progression in myelodysplastic patients has been suggested.

Cytokines↗
PubMed1995

Assessment of immunotoxic effects in humans.

The immunotoxic effects of chemicals are varied and markedly different depending on the underlying pathogenesis, namely, direct immunotoxicity (including immunosuppression, immunodepression, and immunostimulation), hypersensitivity, and autoimmunity. A large number of immunological endpoints and functional assays have been proposed for use as biomarkers of immunotoxicity, but they often lack sensitivity or are poorly standardized, so that their relevance in assessing immunotoxic effects in humans is at best ill established. Examining sentinel immunopathological events in individuals with a defined history of chemical exposure is another approach, presumably more cost-effective at the present time. A multicenter collaboration is mandated, however, because these events are rare. We expect that progress in new technologies, e.g., molecular biology, will provide the sensitive and reliable biomarkers of immunotoxicity that are currently lacking.

Autoimmune Diseases↗
PubMed1994

Anaphylaxis models in the guinea-pig.

Immediate hypersensitivity (or anaphylactic) reactions can be caused by large molecules which are directly immunogenic or by smaller molecules which bind to macromolecular carriers and act as haptens. To reproduce these reactions in animals, either systemic or local models are used in actively or passively sensitized animals, respectively. Several attempts have been made to detect the potential of new drugs and chemicals to induce anaphylactic reactions. Protocols using the inhalation of reactive low-molecular-weight compounds produced clinical symptoms in the guinea-pig. An intralaboratory validation study was initiated using a panel of six positive and one negative model compounds in a guinea-pig model combining systemic and local anaphylaxis. Anaphylactic reactions to positive model compounds were obtained only when the molecular weight was approximately 3000 or more. Overall, published results indicate that the potential to induce immediate hypersensitivity reactions can be detected as far as large-molecular-weight molecules are concerned--in contrast to the majority of low-molecular-weight drugs and chemicals.

Administration, Cutaneous↗
PubMed1994

Contact sensitization assays in guinea-pigs: are they predictive of the potential for systemic allergic reactions?

Guinea-pig assays have been used extensively to detect contact sensitizers. In contrast, almost no reliable assays are available to detect the potential for low-molecular-weight drugs and chemicals to induce systemic allergic reactions in humans. Based on clinical data, and, to some extent, on recent immunological findings, it is proposed that guinea-pig assays can predict the hazard for systemic allergic reactions in man. Seventy drugs and chemicals were compared from published results in guinea-pig assays and in the clinic. A close correlation was found with 43 substances and a relatively good one with 16 substances. Conflicting results were found with 11 substances only. However, substances known to induce systemic allergic reactions in man were all detected as weak sensitizers, at least in guinea-pigs. Guinea-pig contact sensitization assays may therefore prove useful until more suitable and specific assays are available to predict the risk for systemic allergic reactions.

Allergens↗
PubMed1994

Lymphocyte activation by liposome-trapped streptozotocin in murine popliteal lymph node (PLN) test.

The lymphoproliferative potential of liposome-trapped streptoztocin (STZ) was compared to the effect of saline-dissolved STZ injected locally into the foot pad of CD-1 mice. Popliteal lymph node (PLN) enlargement and early cell activation of lymphocyte subsets were monitored during the onset of STZ-induced autoimmune-like reaction. Injection of the optimal STZ dose, 0.5 mg/foot pad, markedly increased the absolute PLN cell number as well as specific T-helper (CD4+), T-suppressor/cytotoxic (CD8+), and B-(Ig+) cell subsets stained with fluorescent monoclonal antibodies. Furthermore, there was a marked increase in the number of large/activated CD4+ and CD8+ cells and subsets bearing specific markers of early activation. These included cells stained with fluorescein-conjugated monoclonal antibodies against interleukin-2 receptor (CD25+) and early activation marker (EAM+) (CD69+), and with fluorescein-conjugated peanut agglutinin (PNA+). Surprisingly, the injection of liposome-trapped STZ, at a 1/10 of the optimal dose only, induced a marked PLN enlargement comparable to the effect of optimal STZ dose. The effect of liposome-STZ could be dissociated from the non-drug-containing MLV-related lymphocyte activation. The data suggest several possible advantages from the introduction of chemicals by the liposome route and the subsequent PLN test for chemical-induced autoimmunity. Toxicological advantages could involve better control of chemical exposure, controlled exposure to the water-insoluble substances, drastic reduction of xenobiotic dose, a stronger, clear PLN response and possible elimination or at least restriction of false-negative results, due to the liposome adjuvancity. Overall, application of liposomes as an exposure route potentialized the STZ-induced early lymphocyte activation.

Animals↗
PubMed1994

Morphology of popliteal lymph node responses in Brown-Norway rats.

The popliteal lymph node (PLN) assay has been proposed as a tool to predict in rodents those xenobiotics likely to induce autoimmune reactions in humans. To further validate this assay and to study the mechanisms involved, histologic changes in PLNs from rats injected with streptozotocin, diphenylhydantoin, pure acetone, or 50% ethanol were compared to a local graft-versus-host (GvH) reaction. This study suggests that routine histology of PLNs is instrumental to discard primary irritants. In addition, the hypothesis of a GvH-like mechanism in positive PLN responses is supported by the finding that the reference compounds streptozotocin and diphenylhydantoin produced histologic changes similar to a "true" local GvH reaction.

Acetone↗
PubMed1994

Methaemoglobinaemia due to amyl nitrite inhalation: a case report.

Methaemoglobinaemia is a potential toxic effect of aliphatic nitrites which are increasingly abused by male homosexuals and drug addicts because of marked vasodilating properties ('poppers'). In most instances, severe complications were described following the ingestion of large quantities of amyl, butyl or isobutyl nitrites. A deficiency in NADH-dependent haemoglobin reductase in some patients has been noted. This is the first report of symptomatic methaemoglobinaemia following the inhalation of amyl nitrite.

Administration, Inhalation↗
PubMed1994

Comparison of popliteal lymph node responses in various strains of rats.

Outbred (namely Wistar and Sprague-Dawley) and inbred (Wistar-Furth, Lewis, Fisher 344 and Brown-Norway) strains of rats were screened for their responses to reference compounds in the popliteal lymph node (PLN) assay. Streptozotocin and diphenylhydantoin gave positive responses as evidenced by increased weight and cellularity indices in all strains used whereas procainamide, isoniazid and barbital consistently gave negative responses. Although these findings overall are in agreement with previous investigations involving these compounds, the lack of marked interstrain differences in PLN responses argues against a strong immunogenetically controlled mechanism as could be assumed in presumably auto-immune reactions. The question is raised whether drug-induced side-effects predicted by the PLN assay are basically non-autoimmune as suggested by clinical and immunological findings in man.

Animals↗
PubMed1994

Clinical toxicity of the interferons.

Since their initial description in 1957, the interferons (IFNs) have been increasingly used to treat a wide array of diseases. Acute adverse effects, i.e. 'flu-like' syndromes, hypo- or hypertension, tachycardia, headache, myalgias and gastrointestinal disorders, occur within the first hour or day after starting treatment. They are seldom treatment-limiting and are easily manageable. Sub-acute and chronic effects develop after several days, usually within 2 and 4 weeks of therapy. The most typical is neurological toxicity, including fatigue/asthenia, and behavioural and cognitive changes. Such symptoms may seriously impair quality of life and result in treatment discontinuation. Seizures have seldom been described. Other infrequent central nervous system adverse effects include vertigo, cramp and oculomotor nerve paralysis. Distal paraesthesias and peripheral neuropathy have been reported. IFN-associated autoimmunity is quite rare but a matter of concern. Biological or clinical manifestations usually require several months to become apparent. Autoantibodies have been shown to develop in most patients but have been inconsistently associated with clinical symptoms of systemic lupus erythematosus, rheumatoid-like arthritis and thyroiditis. Both hypo- and hyperthyroidism have been described but are usually reversible. Other infrequent autoimmune reactions include diabetes, pemphigus and worsening of multiple sclerosis. Although several patients present with a pre-existing autoimmune disorder, no predisposing factor has been clearly established. While hypotension and tachycardia are the most frequent acute cardiovascular complications, a few additional cases of cardiac arrhythmias and myocardial ischaemia have been reported after a short course or several weeks of treatment. These latter complications do not appear to be dose-dependent or age-related. Isolated cases of congestive heart failure have also been described. Mild proteinuria has been observed in 15 to 25% of patients, but acute renal toxicity is uncommon. A transient rise in serum aminotransferase levels is frequently noted during the first stage of therapy, especially in patients receiving the highest dosages. Direct hepatotoxicity is extremely rare. Autoimmune hepatitis, which is ill-diagnosed as chronic viral hepatitis, and de novo induction of autoimmune hepatitis, account for the majority of liver diseases. Haematotoxicity is relatively common but mild to moderate, and develops gradually during the first weeks of treatment. Neutropenia is the most common haematological toxicity, but is usually not dose-limiting and resolves rapidly upon drug discontinuation. Myelosuppression, autoimmune and immune allergic haemolytic anaemias and thrombocytopenias have seldom been described. Cutaneous adverse effects comprised nonspecific erythema and hair loss and, less frequently, vasculitis, local ulcerations at the site of injection and exacerbation of psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Rapid gas chromatographic assay of diazinon: application to the study of diazinon kinetics in rats.

A rapid method was developed for the determination of diazinon in plasma using gas chromatography with electron-capture detection (GC-ECD). Following a single extraction with hexane from 100 microliters of plasma, diazinon was quantitated on a 3% OV-17 column. The detection limit was 10 ng/ml and linearity was obtained in the range of 25 ng/ml-2500 ng/ml. The applicability of the assay to single-dose kinetics in rats is illustrated.

Animals↗
PubMed1994

The status and future of toxicology in Europe.

This overview shows that toxicology in Europe is progressing well both quantitatively and qualitatively. However, a better recognition of key toxic issues is needed, particularly among health specialists. In this, teaching should play a pivotal role.

Europe↗
PubMed1993

Popliteal lymph node response to procainamide and isoniazid. Role of beta-naphthoflavone, phenobarbitone and S9-mix pretreatment.

The popliteal lymph node assay (PLNA) was proposed for the preclinical prediction of xenobiotics-induced autoimmune reactions in humans. Among the substances so far tested in this model, procainamide and isoniazid gave negative PLNA responses despite reports of lupus syndromes in man. To confirm the hypothesis that a metabolite instead of the parent molecule is involved, rats were pretreated with phenobarbital or beta-naphthoflavone, then injected with procainamide or isoniazid. In additional groups of animals, procainamide or isoniazid were injected together with S9-mix following various incubation times. Pretreated rats had a positive PLNA response when injected with procainamide, whereas preincubation with S9-mix resulted in a positive response to isoniazid. These results further support the validity of the PLNA.

Animals↗
PubMed1992

[Diagnosis of bacterial infections on vascular prosthesis. Histological and microbiological analysis].

A retrospective study of 212 vascular graft failures, using different criteria of infection evidenced a relatively high incidence of infectious complications. Vascular graft infection was assessed on one of the following criteria: clinical infection, positive bacteriological and/or virological examination of the graft, presence of characterized micro-organisms and of microstructures 0.1 to 0.5 micron in size at the blood/prosthesis surface at scanning electron microscopy, and presence of foci of persistent polymorphonuclear cells and lymphocytes at histological microscopy. In the absence of overlapping between these criteria, the present results raise the question of the adequacy of conventional bacteriological sampling on explanted artificial surfaces.

Blood Vessel Prosthesis↗
PubMed1992

The popliteal lymph node assay: a tool for studying the mechanisms of drug-induced autoimmune disorders.

Whereas it is still impossible to predict the risk for organ-specific drug-induced autoimmune disorders in animals, a large body of evidence suggests that the popliteal lymph node assay (PLNA) in mice or rats is instrumental to predict systemic drug-induced autoimmune disorders. Metabolites may be involved instead of the parent molecules in a few instances as shown by studies using animals pretreated with enzyme inducers. Histological examination can help distinguish primary irritants, contact sensitizers and 'autoimmunogenic' compounds. That a Graft-vs-Host (GvH)-like mechanism may be involved was further substantiated by the finding that histological features of a positive PLNA response to, e.g. streptozotocin, were quite similar to those of a 'true' local GvH response. In addition, this model is expected to be useful to improve our understanding of the mechanism(s) involved in systemic autoimmune reactions by studying the profile of PLN lymphocyte subpopulations and of released cytokines.

Animals↗
PubMed1992

Activation of CD4+ and CD8+ lymphocyte subsets by streptozotocin in murine popliteal lymph node (PLN) test.

Time-related and dose-related popliteal lymph node (PLN) enlargement and lymphocyte subset alterations owing to subcutaneous (s.c.) injection of streptozotocin (STZ) into the foot pad were determined in (C57BL/6 x DBA/2)F1 [B6D2F1] mice. Early cell activation and time-related changes in T and B lymphocyte subsets were monitored during the onset of STZ-induced lymphoproliferative reaction by flow cytometry and immunophenotyping of lymphocyte subsets stained with a panel of monoclonal antibodies. Examination of cell size and chromatin decondensing for T and B cell subsets revealed differences in their activation profiles during the early phase of STZ-induced lymph node enlargement. The kinetics of the reaction showed initial activation and proliferation of CD4+ cells associated with accumulation of CD8+ and B cells. Subsequently CD8+ cells were activated and proliferated, but there was no evidence of early or late B cell activation as shown by the lack of increase in cell size or nuclear decondensation and the low and transient synthesis of immunoglobulins. The activation characteristics for CD4+ and CD8+ cell subsets in STZ-induced node enlargement were found to be analogous with T cell activation in acute allogeneic graft-versus-host (GVH) reaction in which the F1 recipient differed from the parent at both class I and II MHC loci. Our data support a central role for T cell activation in the induction of STZ-related PLN enlargement and suggest that recirculatory host B cells can play a major role in early node enlargement.

Animals↗
PubMed1992

Activation of CD4+ and CD8+ lymphocyte subsets by streptozotocin in the popliteal lymph node assay. II. Comparison with acute graft-vs-host reaction in H-2 incompatible F1 mouse hybrids.

Changes in lymphocyte subsets during an acute GVH reaction were compared to STZ-induced PLN response in mice. The GVH reaction was induced locally by sc injection of parental C57Bl/6 [B6] spleen cells into (C57Bl/6 x DBA/2) F1 footpad [B6D2F1]. Early cell activation and time-related changes in T- and B-lymphocyte subsets were monitored during the onset of the GVH reaction by flow cytometry and immunophenotyping. Examination of cell size and chromatin decondensing for T- and B-cell subsets showed differences in activation profile during the early phase of the GVH reaction. The present study provides direct evidence for early in vivo activation of both CD4+ and CD8+ T-cells. Our data confirm the central role of T-cell activation in the induction of a GVH reaction and suggest that recirculatory host B-cells can play an important role in early GVH node enlargement. Overall, our comparative analysis supports the concept of polyclonal T-cell activation for both STZ-related and GVH-induced lymphoproliferation. Chemicals-induced lymphoproliferation leading to autoimmune reactions is a challenging issue. A number of drugs and chemicals have been tested in the PLNA assay for lymphoproliferative potential. We previously reported the activation and proliferation of T-cell subsets following STZ injection into murine footpads. The STZ-induced PLN enlargement and proliferation characteristics of T- and B-cell subsets were postulated to be similar to those of an acute allogeneic GVHR. In the present study, a cytometric analysis of T- and B-cell subsets in PLNs was performed during an acute allogeneic GVHR, for comparison purposes. Such a reaction results in a massive node enlargement five to ten times that seen after stimulation with conventional antigens. Acute GVHR is believed to be a direct consequence of the high frequency of alloreactive donor T-cells inducing a massive proliferation of B-cells, almost exclusively of host origin, in GVHR nodes. It is now widely accepted that donor T-cells activated as the result of exposure to foreign MHC antigens in the recipient, secrete various cytokines which assist the host B-cells and bypass the normal B-T cell cooperation. Induction of an acute GVHR, as in the parental B6--->recipient B6D2F1 model, requires the injection of CD4+ and CD8+ donor T-cells into an F1 recipient that differs from the parent at both MHC class I and II loci.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

[Polyaneurysmal dystrophy (ectatic medial dystrophy)].

Polyaneurysmal dystrophy is a novel form of arteriopathy which specific clinical, angiographic, anatomic and surgical features which distinguish it clearly from multiple atheromasclerotic aneurysm. It should be considered to be a local, multifocal accentuation of megadolicho-arteries, which constitute the lesions during the early stages of the disorder (fairly general elongation of the elastic arteries, with thin walls and regular increase in the caliber and multiple tortuousness). Arterial angiography identifies polyaneurysmal dystrophy; in the context of a twisted and sinuous system of large arteries, multiple spindle-shaped aneurysms can be distinguished which are frequently bilateral and symmetrical. The usual sites are the trunks of the aortic group and internal carotid, the ileo-femoral trunks and terminal aorta. The progress of the disorder is characterized by the possibility of rupture or thrombosis (particularly in the subcrural territory). The treatment is always surgical. The indication for surgery is inevitable in cases of severe ectasia, but may be avoidable in extensive forms of megadolicho-arteries with no clearly defined aneurysm: annual ultrasound monitoring is then called for. The disorder is of constitutional origin (and totally unrelated to atherosclerosis). Delayed dilatation of the aneurysms is due to the hemodynamic forces brought to bear on the fragile walls over a life-time. Multiple aneurysms occur mainly between the ages of 50 and 70 years, with a predominance of aorto-ileac sites in men, even though these subjects do not show any general elastic dysplasia. Half of the 45 patient undergoing surgery were hypertensive.

Aneurysm↗