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J Descotes

Publications and source records attributed to J Descotes.

At least 19 recordsLinked to original sources
PubMed2001

Induction of delayed-type hypersensitivity to sulfamethoxazole in mice: role of metabolites.

Although cutaneous adverse drug reactions (ADRs) are relatively frequent and potentially severe, their mechanisms are poorly understood and no validated predictive experimental model is available. Sulfamethoxazole (SMX) is commonly used to treat infections in HIV-positive patients and severe cutaneous ADRs have been described. This study was undertaken to test whether sensitization to SMX could be achieved in mice using a combination of in vivo and in vitro endpoints. No delayed-type hypersensitivity (DTH) response could be evidenced following SMX injection in the back and subsequent challenge into the footpad or onto the ear. Pretreatment with the enzymatic inducers phenobarbitone and betanaphtoflavone, or depletion in CD4(+) T-lymphocytes were not successful either. In contrast, the injection of SMX/S9 mix in the back and challenge with SMX/S9 mix induced a significant increase in footpad thickness. A significant proliferation of spleen cells from SMX- or SMX/S9 mix-treated mice was evidenced following incubation with SMX/S9 mix, but not SMX alone. This study provides indirect evidence that SMX metabolites are involved and confirms previous in vitro results obtained with lymphocytes from patients with a history of SMX-induced ADRs cultured with murine microsomes. Further investigations using other drugs known to induce similar ADRs are warranted to establish the predictive value of this murine model.

Animals↗
PubMed2001

Drug allergy diagnosis in humans: possibilities and pitfalls.

Due to the potential hazards of drug allergies, an early and reliable diagnosis is crucial. The use of in vivo tests is not recent but, because of the hazards of skin testing in patients with a history of anaphylaxis, they had been abandoned for a while. Recent reevaluations have shown that for some drugs, e.g. antibiotics-reliable skin tests can ensure the diagnosis of drug allergy in up to 70% of cases. Many in vitro tests based on well-defined mechanisms, e.g. the basophil degranulation test have been used for the diagnosis of totally unrelated allergic mechanisms. It is almost impossible to interpret their validity as diagnosis tools. Nevertheless, other tests, e.g. the lymphocyte transformation test which have been evaluated in well-conducted recent studies, seem to have a good predictive value. Their use is still restricted to clinical trials or research studies. A reliable clinical approach as well as a detailed examination of the drug intake remains obligatory to diagnose drug allergy. Available in vivo and in vitro tests are sometimes used to confirm the diagnosis. The sensitivity and specificity of these tests is evaluated in clinical studies. Research to improve the existing tests and to develop new diagnostic tools is still of paramount importance.

Animals↗
PubMed2001

Gell and Coombs's classification: is it still valid?

The Gell and Coombs's classification divides drug allergies into four pathophysiological types, namely anaphylaxis (type I), antibody-mediated cytotoxic reactions (type II), immune complex-mediated reactions (type III), and delayed type hypersensitivity (type IV). Although this classification was proposed more than 30 years ago, it is still widely used. As only a limited number of drug allergies fit into this classification which does not include our current understanding of the immune response, its use is not recommended, particularly in the context of the preclinical safety evaluation of new therapeutic agents. In fact, three different situations can be identified, namely pseudo-allergic reactions, primarily antibody-mediated reactions and cell-mediated reactions, which could serve as a basis for modern and more adequate classifications

Anaphylaxis↗
PubMed2000

The popliteal lymph node response to streptozotocin is under type 1, MHC class-I restricted, CD8(+) T-cell control.

The popliteal lymph node (PLN) assay has been proposed to predict the 'autoimmunogenic' potential of xenobiotics. A better understanding of the processes involved in PLN responses is needed to establish the value of this assay for preclinical safety evaluation. In order to determine whether PLN responses involve CD4(+) or CD8(+) T-cells, the effects of streptozotocin (STZ), a prototypic immunotoxic compound, were analyzed after injection into the hind footpad of C57 BL/6 mice and major histocompatibility complex (MHC) class I or II deficient mice. The involvement of type 1 or type 2 cell control on the production of cytokine mRNAs was analyzed in lymph node cells by quantitative RT-PCR, together with the analysis of a wide range of cytokine mRNAs after STZ injection (IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma, IL-2, IL-2 receptor, IL-4, IL-5, IL-6, IL-10 and IL-12). We have found that mice depleted in CD8(+) T-cells did not respond to STZ, whereas mice depleted in CD4(+) T-cells exhibited the expected positive PLN responses, with increased weight and cellularity indices. STZ induced a low production of interleukin (IL)-2 mRNAs, a mild increase in IL-1alpha and IL-6 mRNAs production, and a dramatic increase in IFN-gamma, IL-1beta, TNF-alpha, IL-12 and IL-2 receptor mRNAs, which correlated with positive PLN responses. No effects on IL-4, IL-5 and IL-10 mRNAs synthesis were noted. In CD8(+) T-cell deficient mice, there was no production of IFN-gamma or IL-6 mRNAs. These results suggest that PLN responses to STZ are under the control of type 1, MHC class-I-restricted, CD8(+) T-cells. This is in accordance to the known physiopathology of STZ-induced diabetes. Additional studies are necessary to establish the mechanism of CD8+ T-cell activation.

Animals↗
PubMed2000

Autoimmunity and toxicity testing.

Major difficulties when addressing autoimmunity today within the context of regulatory toxicology are the following: (i) the incidence of auto-immunity related to chemical exposure is not known; (ii) the mechanisms involved are not understood in most instances; and (iii) no fully validated models are available. Although no relationship has been firmly established between the serum levels of autoantibodies and the development and/or the severity of autoimmune diseases, these are considered the hallmarks of autoimmunity. It has proved impossible so far to detect reproducibly autoantibodies indicative of organ-specific autoimmune reactions induced by chemicals in conventional toxicity testing. The detection of autoantibodies suggestive of a systemic autoimmune reaction has been successful with very few compounds only, and most often using non-conventional strains of animals. Genetically-deficient animal strains were sometimes helpful, but these models should be standardised and validated. This also applies to experimental autoimmune disease models. The popliteal lymph node (PLN) assay is potentially helpful, but more research and validation efforts are warranted. From a regulatory toxicology perspective, the search for serum autoantibodies, as it is performed today, does not seem to be a reliable tool, and progress is more likely to be expected from the design, standardisation and validation of dedicated models.

Animals↗
PubMed2000

Endocrine and neurological adverse effects of the therapeutic interferons.

There is experimental evidence that the nervous central and the neuroendocrine systems can influence the immune system, which can in turn influence the brain activity. Endogenous cytokines are known to play a critical role in the pathophysiology of many diseases. The recently acquired experience on the adverse effects of therapeutic cytokines, particularly neurological and endocrine adverse effects, are further illustrative of these interferences. Interferons-alpha have been used in thousands of patients, so that the information accumulated with this group of closely related products is essential to delineate the potential and severity for non-immunological, but largely immune-mediated adverse effects to develop in patients treated with immuno-activating agents.

Animals↗
PubMed2000

[Respiratory distress in three newborns after mask disinfection with Endosporine. Probable role of glutaraldehyde].

BACKGROUND: Disinfectants for medical devices are uncommonly a cause of iatrogenic adverse effects. Nevertheless, when misused, they can induce severe complications. Three cases of acute respiratory distress in newborns probably induced by glutaraldehyde are reported. CASE REPORTS: Three children born by Caesarean section between 8 and 19 May 1999 in the same hospital presented acute respiratory distress requiring hospitalization in the neonatal intensive care unit; one child was premature. The clinical appearance, which was initially normal, deteriorated with a respiratory distress in 30 to 60 minutes. Recovery was uneventful in all cases. The diagnosis considered was a hyaline membrane disease. The enquiry conducted after this cluster onset identified, as a main contributing factor, the disinfection procedure recently introduced in the surgical theater. CONCLUSION: Review of toxicologic data on glutaraldehyde shows this is a highly irritating chemical for the respiratory tract, even at low concentrations. Clinical and radiologic features in these three neonates are compatible with a pulmonary sub-edema on an immature alveolar setting. The hypothesis proposed is that glutaraldehyde, the active ingredient of the biocidal formula used to disinfect the respiratory masks, was massively desorbed from the rubber and foam of which masks are made.

Disinfectants↗
PubMed1999

Preclinical safety evaluation of human gene therapy products.

Human gene therapy products include naked DNA and viral as well as non-viral vectors containing nucleic acids. There is limited experience on the preclinical toxicity studies necessary for the safety evaluation of these products, which have been outlined in several recently released guidelines. Requirements for the preclinical safety evaluation of human gene therapy products are both specific and non-specific. All key preclinical studies should be performed in compliance with Good Laboratory Practices. Non-specific requirements are in fact common to all pharmaceutical products. Critical specific issues to be addressed are: the safety evaluation of the vector and the toxicity of the expressed protein(s), which are the two components of gene therapy products, the quality of the test article, the selection of animal species, and the verification that the administration method successfully transports the gene of interest, with the vector, to the target site(s). The treatment schedule should mimic the intended human therapeutic design. The host's immune response against the gene therapy product has to be evaluated to detect possible adverse effects and immune neutralization by antibodies. The biodistribution of the gene of interest is also essential and can be evaluated by molecular biology techniques, such as PCR. Specific confinement is required for the safe manipulation of viral vectors.

Animals↗
PubMed1998

Value of animal models for predicting hypersensitivity reactions to medicinal products.

Although hypersensitivity reactions induced by medicinal products and chemicals are relatively common, few predictive models are available. A major difficulty is our currently limited understanding of the mechanisms involved, and efforts should be paid to better defining drug immunogenicity, hapten formation and immune effector mechanisms. A second difficulty is the multiplicity of clinical manifestations presumably due to varying mechanisms. Available models can only predict a few of these reactions. Anaphylaxis models in guinea-pigs can be only used for the safety assessment of macromolecules which are neither humanized or of human origin, whereas guinea-pig or mouse models can detect the majority of human contact sensitizers. In addition to the extensive validation of existing models, promising avenues of research are expected to be found in the use of novel animal models, particularly those using genetically modified animals, such as transgenic and knock-out mice.

Allergens↗
PubMed1998

[Acute alveolitis after using a waterproofing aerosol: apropos of 2 cases].

INTRODUCTION: Waterproofing sprays for leather clothing have seldom been involved in severe accidents. In some circumstances, their pulmonary toxicity is marked, as shown by two case reports and a review of the literature. EXEGESIS: Acute alveolitis is described in two young adults without previous respiratory illness, following the use of a waterproofing spray for leather clothing. Clinical features typical of a flu-like reaction (malaise, fever and chills) were associated with dyspnea and with hemoptysis in one patient. X-ray examination evidenced lesional edema which quickly resolved after symptomatic treatment. The toxic mechanism is debated, but experimental data and clinical findings suggest the causative role of recently introduced fluoropolymers. CONCLUSIONS: Waterproofing sprays for leather clothing may induce severe respiratory illness after massive inhalation in confined area. Treatment is supportive.

Acute Disease↗
PubMed1997

The popliteal lymph node assay: results of a preliminary interlaboratory validation study.

The popliteal lymph node (PLN) assay was proposed to predict possible autoimmune effects of xenobiotics. A preliminary interlaboratory validation study of the PLN assay was conducted in Wistar rats. Three laboratories tested in blind fashion four compounds, namely chlorpromazine, zimeldine, hydrazine and streptozotocin, which were reported to cause autoimmune-like reactions in humans, and one compound, i.e. barbital, which was not, using strictly the same experimental procedure. All tested substances were injected into the hind footpad of rats on day 1, and PLN weight and cellularity were measured on day 8. Comparison of the controlateral PLN was used to calculate weight and cellularity indices. The results were independently analyzed in a fourth laboratory. All four positive compounds were detected by the three laboratories using both weight and cellularity indices, and the negative compound consistently proved negative. Despite variations in absolute values between laboratories, although not significant, these results provide further evidence of the potential predictive value of the PLN assay.

Animals↗
PubMed1997

Drug-induced autoimmunity: experience of the French pharmacovigilance system.

Spontaneous reporting of suspected adverse drug reactions to a pharmacovigilance structure is a reasonable tool to detect new associations between drugs and a given toxic effect. An analysis of the French national database of pharmacovigilance was undertaken to evaluate how such a system is relevant to survey and/or detect drug-associated autoimmune disorders. Only 0.2% of reports were coded with terms suggestive of systemic autoimmune diseases. Drugs most frequently found were cardiovascular drugs, antiepileptic drugs and slow-acting anti-inflammatory drugs. Most of reports involved drugs previously recognized as a possible cause of autoimmune disorders. Minocycline or HMG-CoA reductase inhibitors were suggested to be involved in several reports and represented possible new cases of drug-associated autoimmune disorders. In conclusion, drugs are infrequently reported as a cause of systemic autoimmune disorders compared to other adverse drug reactions and may not represent a critical health problem for drug regulatory agencies to deal with.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

The popliteal lymph node assay in 1996.

The popliteal lymph node (PLN) assay is based on the assumption that a mechanism similar to a graft-versus-host (GvH) reaction is involved in 'GvH-like' drug-induced side-effects, including generalized lymphadenopathy, serum sickness-like disease, scleroderma-like reaction and the lupus syndrome. An increased PLN weight 7-10 days after injection of the test article into the footpad is generally held as a positive response. Most, if not all compounds reported to induce pseudo-GvH side-effects in man (namely positive model compounds) have been shown to induce positive PLN responses in mice and/or rats. Reproducible results have been obtained in several laboratories, in some instances blindly. However, positive responses have also been obtained with the negative model compounds acetone and imipramine. Flow cytometry analysis and conventional histology failed to help differentiate between a true GvH response and a primary irritative effect. In order to confirm the potential value of the PLN assay to predict the risk for drug-induced GvH-like reactions, mechanistic studies are urgently needed.

Animals↗
PubMed1997

Autoantibodies in conventional toxicity testing.

A number of drugs and chemicals can induce autoimmune disorders. The use of autoantibody assays in toxicology has been evaluated as a tool to predict and explain autoimmune reactions. Autoantibodies are divided between organ-specific and ubiquitous autoantibodies and several mechanisms have been proposed for their pathogenesis. Assay methods depend on the autoantibody investigated and the specificity of the assay required. There is only a partial correlation between the presence of autoantibodies in humans or animals and the risk of developing an autoimmune disease. Responses in animals vary according to genetic influence and extrapolation to humans is difficult. Therefore, autoantibody assays were not considered absolutely predictive of the potential of a new drug to trigger autoimmune diseases. However assays such as the Coombs test for hemolytic anemia or anti-thyroid antibody assay for thyroiditis, can be useful for explaining the possible mechanisms of autoimmune reactions which occur during toxicology studies.

Animals↗