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Jacques Descotes - One of the best experts on this subject based on the ideXlab platform.

  • Popliteal Lymph Node assay: facts and perspectives.
    Journal of applied toxicology : JAT, 2005
    Co-Authors: Guillaume Ravel, Jacques Descotes
    Abstract:

    The Popliteal Lymph Node assay (PLNA) derives from the hypothesis that some supposedly immune-mediated adverse effects induced by certain pharmaceuticals involve a mechanism resembling a graft-versus-host reaction. The injection of many but not all of these compounds into the footpad of mice or rats produces an increase in the weight and/or cellularity of the Popliteal Lymph Node in the treated limb (direct PLNA). Some of the compounds known to cause these adverse effects in humans, however, failed to induce a positive PLNA response, leading to refinements of the technique to include pretreatment with enzyme inducers, depletion of CD4(+) T cells or additional endpoints such as histological examination, Lymphocyte subset analysis and cytokine fingerprinting. Alternative approaches have been used to improve further the predictability of the assay. In the secondary PLNA, the test compound is injected twice in order to illicit a greater secondary response, thus suggesting a memory-specific T cell response. In the adoptive PLNA, Popliteal Lymph Node cells from treated mice are injected into the footpad of naive mice; a marked response to a subsequent footpad challenge demonstrates the involvement of T cells. Finally, the reporter antigens TNP-Ficoll and TNP-ovalbumin are used to differentiate compounds that induce responses involving neo-antigen help or co-stimulatory signals (modified PLNA). The PLNA is increasingly considered as a tool for detection of the potential to induce both sensitization and autoimmune reactions. A major current limitation is validation. A small inter-laboratory validation study of the direct PLNA found consistent results. No such study has been performed using an alternative protocol. Other issues include selection of the optimal protocol for an improved prediction of sensitization vs autoimmunity, and the elimination of false-positive responses due to primary irritation. Finally, a better understanding of underlying mechanisms is essential to determine the most relevant endpoints. The confusion resulting from use of the PLNA to predict autoimmune-like reactions as well as sensitization should be clarified. Interestingly, most drugs that were positive in the direct PLNA are also known to cause drug hypersensitivity syndrome in treated patients. This observation is expected to open new avenues of research.

  • Cytokine release does not improve the sensitivity and specificity of the direct Popliteal Lymph Node assay.
    Toxicology, 2004
    Co-Authors: Guillaume Ravel, Marielle Christ, Françoise Horand, Jacques Descotes
    Abstract:

    The Popliteal Lymph Node assay (PLNA) is being considered as a tool to predict the potential of drugs for inducing systemic autoimmune and hypersensitivity reactions. Despite the use of different technical approaches and the evaluation of over 130 compounds, the sensitivity and specificity of the PLNA are still debatable due to many false positive and negative responses. In this study, cytokine production was assessed as a possible endpoint to improve the direct (primary) PLNA. Diclofenac, imipramine, hydralazine, glafenin and minocycline were tested using the classical procedure. TH1 cytokines (IL-2 and IFN-gamma), TH2 cytokines (IL-4 and IL-5) and pro-inflammatory cytokines (IL-6, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), IL-12p70 and IL-10) were measured in the serum and in suspensions of Popliteal Lymph Node cells of female Balb/c mice by flow cytometry 7 days after drug administration. Only diclofenac and imipramine induced a cellularity index above 5 (considered as a positive response). Of the five tested drugs, only diclofenac induced a slight increase in TH1 cytokines, but there were no effects on TH2 cytokine production whatever the drug tested. Diclofenac increased the production of pro-inflammatory cytokines, whereas the production of MCP-1 was increased by minocycline and decreased by imipramine. No changes in serum cytokine levels were evident. These results suggest that measuring cytokine release is unlikely to improve the sensitivity and specificity of the direct PLNA.

  • Popliteal Lymph Node responses to acetone and ethanol differ from those induced by streptozotocin
    Archives of Toxicology, 2004
    Co-Authors: Genevieve Choquetkastylevsky, Jacques Descotes
    Abstract:

    The Popliteal Lymph Node (PLN) assay was proposed to detect the potential of immunotoxicants for inducing systemic autoimmune-like reactions, but also xenobiotics that are sensitizing or exert immunostimulatory properties. Results on over 100 chemicals, mostly pharmaceuticals, are available with the PLN assay and show many correlations between rodent data and the clinical experience. A major issue is that the mechanisms involved have not been fully elucidated. In order to provide mechanistic clues to improve the predictability of the PLN assay, the effects of streptozotocin (STZ) were compared to those of ethanol and acetone in normal C57Bl/6 mice as well as mice depleted in CD4+ or CD8+ T-cells by treatment with specific monoclonal antibodies. STZ, ethanol and acetone gave similar positive responses in normal mice. Neither CD4+ nor CD8+ T-cell depletion influenced the PLN responses to ethanol or acetone, whereas CD8+ in contrast to CD4+ T-cell depletion abolished the response to STZ. There was an increase in the production of IL-6 and IFN-γ mRNAs measured by RT-PCR in STZ-, but not in ethanol- or acetone-treated normal mice. The production of TNFα, IL-1α, IL-1β, IL-2R and IL-12 mRNAs was increased whatever the treatment, but increases were 2- to 3-fold greater after STZ than ethanol or acetone. These results suggest that PLN responses to primary irritants such as ethanol and acetone essentially reflect non-specific inflammation, whereas PLN responses to an autoimmunogenic compound such as STZ involve CD8+ T Lymphocytes and the production of IFN-γ and IL-6. These findings may prove useful to improve the predictability of the PLN assay.

  • Tritiated thymidine incorporation does not enhance sensitivity of the Popliteal Lymph Node assay.
    Toxicology, 2003
    Co-Authors: C. Ruat, Guillaume Ravel, L. Faure, Genevieve Choquet-kastylevsky, Jacques Descotes
    Abstract:

    Abstract The Popliteal Lymph Node (PLN) assay has been proposed as a tool to predict drugs and chemicals with the potential to induce systemic autoimmune reactions in man. In this assay, weight and cellularity indices typically are the measured endpoints. The present study was conducted to test whether incorporation of tritiated thymidine could improve sensitivity of the PLN assay. Male and female Balb/c mice were injected with 20 μCi of [ 3 H]-methyl-thymidine intravenously 7 days after receiving 0.5, 1 or 2 mg of diphenylhydantoin, streptozotocin, sulfamethoxazole, ofloxacin, phenobarbital, or metformin intradermally. Results obtained with incorporation of tritiated thymidine were compared to weight indices. No consistent or marked differences in these endpoints were noted whatever the compound used. This study shows that incorporation of tritiated thymidine does not improve sensitivity of the PLN assay.

  • Positive responses to imipramine in the Popliteal Lymph Node assay are due to primary irritation.
    Human & experimental toxicology, 2001
    Co-Authors: Genevieve Choquet-kastylevsky, R. Tedone, Jacques Descotes
    Abstract:

    The Popliteal Lymph Node (PLN) assay has long been proposed as a tool to detect immunotoxicants with the potential to induce systemic autoimmunity. A major problem hampering the further validation of this assay is the need to rule out irritants that cause false-positive PLN responses. The anti-depressant, imipramine, has not been reported to induce systemic autoimmune reactions in treated patients, but has been repeatedly found positive in the PLN assay, suggesting that this is a false-positive response. To test this hypothesis, the effects of imipramine were compared to those of 50% ethanol in C57Bl/6 mice. Footpad edema was evidenced in the few days after injection of both ethanol and imipramine. T-cell depletion using monoclonal antibodies against either CD4+ or CD8+T-Lymphocytes prior to the PLN assay did not influence the responses to either ethanol or imipramine. Cytokine (TNF, IL-1, IL-1, IL-2R, IL-6, IL-12 and IFN-) fingerprinting of the PLNs after injection of ethanol and imipramine evidenced the...

Caroline Patriarca - One of the best experts on this subject based on the ideXlab platform.

  • The Popliteal Lymph Node assay in 1996.
    Toxicology, 1997
    Co-Authors: Jacques Descotes, Caroline Patriarca, Thierry Vial, François Verdier
    Abstract:

    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.

  • Morphology of Popliteal Lymph Node responses in brown‐norway rats
    Journal of toxicology and environmental health, 1994
    Co-Authors: Jean-philippe Brouland, François Verdier, Caroline Patriarca, Thierry Vial, Jacques Descotes
    Abstract:

    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 CvH‐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.

  • morphology of Popliteal Lymph Node responses in brown norway rats
    Journal of Toxicology and Environmental Health, 1994
    Co-Authors: Jean-philippe Brouland, François Verdier, Caroline Patriarca, Thierry Vial, Jacques Descotes
    Abstract:

    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 CvH‐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.

  • Comparison of Popliteal Lymph Node Responses in Various Strains of Rats
    Human & experimental toxicology, 1994
    Co-Authors: Caroline Patriarca, F. Verdier, Jean-philippe Brouland, Thierry Vial, Jacques Descotes
    Abstract:

    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.

  • Popliteal Lymph Node response to procainamide and isoniazid. Role of β-naphthoflavone, phenobarbitone and S9-mix pretreatment
    Toxicology letters, 1993
    Co-Authors: Caroline Patriarca, F. Verdier, Jean-philippe Brouland, Jacques Descotes
    Abstract:

    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.

David E Amacher - One of the best experts on this subject based on the ideXlab platform.

  • diclofenac activates t cells in the direct Popliteal Lymph Node assay and selectively induces igg1 and ige against co injected tnp ova
    Toxicology Letters, 2002
    Co-Authors: Bradford W Gutting, Lawrence W Updyke, David E Amacher
    Abstract:

    Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently associated with immune-mediated hypersensitivity reactions. The NSAID diclofenac is associated with several distinct allergic and autoimmune-like reactions including anaphylaxis, idiosyncratic hepatotoxicity and autoimmune hemolytic anemia. The aim of this study was to examine the immunostimulating potential of diclofenac in the direct Popliteal Lymph Node assay (PLNA) and reporter antigen PLNA. In BALB/c mice, diclofenac caused dose-dependent increases in PLN weight and PLN cellularity in the direct PLNA; 0.25 mg was non-immunostimulating whereas 0.50–1.00 mg caused a significant PLN reaction. In the direct PLNA, diclofenac also increased the percent of T cells in the PLN with activated phenotypes (CD44 high CD62L low and CD44 high CD62L high ). Finally, the magnitude of the diclofenac-induced direct PLN reaction was significantly reduced when the assay was conducted in T-cell-deficient mice. When co-injected with the reporter antigen TNP–Ficoll (trinitrophenyl Ficoll), 0.50 mg diclofenac caused significant increases in PLN weight, PLN cellularity, and induced IgM and IgG 1 anti-TNP antibody forming cells (AFCs) in the PLN. In a final set of studies, a TNP–OVA PLNA was conducted using diclofenac, phenobarbital (negative control) and streptozotocin (positive control). As expected, phenobarbital (1.00 mg) failed to cause an increase in PLN cellularity or induce AFCs in the PLN. Streptozotocin (1.00 mg) caused significant increases in PLN cellularity, IgM AFCs, and selectively induced IgG 2a and IgG 2b AFCs against TNP–OVA. Likewise, diclofenac caused dose-dependent increases (0.25–1.00 mg) in PLN cellularity and IgM AFCs. However, in contrast to streptozotocin, diclofenac caused a selective dose-dependent increase in both IgG 1 and IgE AFCs. Finally, an increase in the intracellular level of IL-4, but not INFγ, was detected in CD4 + PLN cells following the injection of diclofenac mixed with TNP–OVA. Collectively, these data suggest that diclofenac: (i) induces a T-cell-dependent direct PLN reaction that; (ii) provides non-cognate help for IgG AFC production when co-injected with TNP–Ficoll, possibly through the formation of neo-antigens; and (iii) possesses intrinsic adjuvant activity that selectively induces IL-4 mediated production of IgG 1 and IgE against co-injected TNP–OVA.

  • investigating the tnp ova and direct Popliteal Lymph Node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans
    Journal of Applied Toxicology, 2002
    Co-Authors: Bradford W Gutting, Lawrence W Updyke, David E Amacher
    Abstract:

    Using current animal models, it is not possible to identify low-molecular-weight compounds (LMWCs) that are likely to be associated with anaphylaxis. It is generally accepted that the ultimate effector mechanism involves drug-induced IgE antibody. The objective of the present study was to determine if diclofenac, zomepirac and glafenine, which are associated with anaphylaxis in humans, have immunostimulating potential in the murine TNP-OVA (trinitrophenyl-ovalbumin) Popliteal Lymph Node assay (PLNA), and more specifically to determine if the immunostimulation caused by these LMWCs results in IgE antibody production. These LMWCs were chosen because both zomepirac and glafenine were removed from the market due to high association with anaphylaxis, and diclofenac, which remains on the market, is frequently associated with anaphylaxis. In addition to conducting a TNP-OVA PLNA, the immunostimulating potential of these compounds was examined in the direct PLNA. When co-administered with TNP-OVA, all three LMWCs caused dose-dependent (0.25, 0.50, 1.00 and 1.25 mg) increases in Popliteal Lymph Node (PLN) weight and cellularity that were observed beginning with the 0.25-mg dose. In addition, beginning with the 0.25-mg dose, all three compounds caused dose-dependent increases in TNP-OVA specific IgM and IgG(1) antibody-forming cells (AFCs). Diclofenac induced an isotype switch and caused a dose-dependent increase in the number of IgE AFCs with no detectable IgG(2a) AFCs and minimal high-dose-only IgG(2b) AFCs. Zomepirac induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50 mg only, and glafenine induced IgE, IgG(2a) and IgG(2b) AFCs following the injection of 0.50-1.00 mg. In the direct PLNA, diclofenac caused dose-dependent increases in PLN weight and cellularity that were observed beginning with dose of 0.50 mg, whereas zomepirac failed to increase any PLN parameter and glafenine only increased the PLN weight. These results suggest that diclofenac, zomepirac and glafenine are immunostimulating LMWCs in the TNP-OVA PLNA with the potential to induce IgE antibody against a co-administered hapten-conjugate. Furthermore, these results suggest that the TNP-OVA PLNA offered significant advantages over the direct PLNA. Although it is not realistic to suggest that a single assay, based on a low number of test compounds, can identify all LMWCs with the potential to cause anaphylaxis in humans, these observations do demonstrate the potential utility of the PLNAs in examining LMWC-induced immunomodulation and support further development and investigation of the assays.

Raymond Pieters - One of the best experts on this subject based on the ideXlab platform.

  • the reporter antigen Popliteal Lymph Node assay
    Current protocols in immunology, 2006
    Co-Authors: Stefan Nierkens, Raymond Pieters
    Abstract:

    Many chemicals, including drugs and environmental pollutants, may have the intrinsic capacity to stimulate or dysregulate immune responses. These responses may create considerable problems for exposed subjects in terms of development of autoimmunity or hypersensitivity reactions. The Popliteal Lymph Node assay (PLNA) provides a suitable tool to assess the immunostimulating potential of chemicals and might be a potential candidate as a screening tool in immunotoxicological hazard identification. The use of so-called reporter antigens (RA) in this assay additionally enables differentiation between immunosensitizing (sensitizers), immunostimulating (irritants), and innocent chemicals. In the RA-PLNA, the compound of interest is injected into the hind footpad together with a nonsensitizing dose of the RA. After 6 to 8 days, RA-specific responses are monitored in the draining PLN by measuring RA-specific antibody formation, cytokine secretion, and shifts in immune cell numbers. Hence, this simple and straightforward assay provides immunologically relevant information about the immunomodulating properties of a chemical. Keywords: Popliteal Lymph Node assay; immunostimulation; sensitization; hypersensitivity; allergy; autoimmunity; predictive screening assay

  • Current Protocols in Toxicology - The reporter antigen Popliteal Lymph Node assay.
    Current Protocols in Toxicology, 2006
    Co-Authors: Stefan Nierkens, Raymond Pieters
    Abstract:

    Many chemicals, including drugs and environmental pollutants, may have the intrinsic capacity to stimulate or dysregulate immune responses. These responses may create considerable problems for exposed subjects in terms of development of autoimmunity or hypersensitivity reactions. The Popliteal Lymph Node assay (PLNA) provides a suitable tool to assess the immunostimulating potential of chemicals and might be a potential candidate as a screening tool in immunotoxicological hazard identification. The use of so-called reporter antigens (RA) in this assay additionally enables differentiation between immunosensitizing (sensitizers), immunostimulating (irritants), and innocent chemicals. In the RA-PLNA, the compound of interest is injected into the hind footpad together with a nonsensitizing dose of the RA. After 6 to 8 days, RA-specific responses are monitored in the draining PLN by measuring RA-specific antibody formation, cytokine secretion, and shifts in immune cell numbers. Hence, this simple and straightforward assay provides immunologically relevant information about the immunomodulating properties of a chemical. Keywords: Popliteal Lymph Node assay; immunostimulation; sensitization; hypersensitivity; allergy; autoimmunity; predictive screening assay

  • The reporter antigen Popliteal Lymph Node assay.
    Current protocols in toxicology, 2006
    Co-Authors: Stefan Nierkens, Raymond Pieters
    Abstract:

    Many chemicals, including drugs and environmental pollutants, may have the intrinsic capacity to stimulate or dysregulate immune responses. These responses may create considerable problems for exposed subjects in terms of development of autoimmunity or hypersensitivity reactions. The Popliteal Lymph Node assay (PLNA) provides a suitable tool to assess the immunostimulating potential of chemicals and might be a potential candidate as a screening tool in immunotoxicological hazard identification. The use of so-called reporter antigens (RA) in this assay additionally enables differentiation between immunosensitizing (sensitizers), immunostimulating (irritants), and innocent chemicals. In the RA-PLNA, the compound of interest is injected into the hind footpad together with a nonsensitizing dose of the RA. After 6 to 8 days, RA-specific responses are monitored in the draining PLN by measuring RA-specific antibody formation, cytokine secretion, and shifts in immune cell numbers. Hence, this simple and straightforward assay provides immunologically relevant information about the immunomodulating properties of a chemical.

  • drug induced type 1 and type 2 immune responses are characterized by distinct profiles of cell kinetics cytokine production and expression of co stimulatory molecules in the Popliteal Lymph Node assay
    Journal of Immunotoxicology, 2005
    Co-Authors: Stefan Nierkens, Rob Bleumink, Marloes Aalbers, Louis Boon, Raymond Pieters
    Abstract:

    Some drugs have the undesired side effect of systemically stimulating the immune system, which may eventually lead to the development of drug-induced allergy or autoimmunity. Unfortunately, validated predictive screening tools to assess the immune stimulatory potential of compounds are presently unavailable. The Popliteal Lymph Node assay (PLNA) with reporter antigens (RA) seems a valuable candidate for this purpose. The aims of the present study were 1) to provide additional mechanistic information on the very early induction phase of drug-induced type 1 (TH1-associated) and type 2 (TH2-associated) immune reactions in the PLNA and 2) to explore the use of these mechanism-based parameters to predict the immune stimulating potential of drugs. Streptozotocin (STZ), a chemotherapeutic drug, and D-Penicillamine (D-Pen, anti-rheumatic drug) were used as model compounds as they respectively induce clearly differentiated type 1 and type 2 immune responses in the PLNA. Type 1 responses were characterized by the p...

  • The Popliteal Lymph Node assay: a tool for predicting drug allergies
    Toxicology, 2001
    Co-Authors: Raymond Pieters
    Abstract:

    A considerable number of drugs is able to induce systemic hypersensitivity in man. Systemic hypersensitivity can be drug- or autoantigen-specific, but in either case a complex of immunological processes and predisposing factors are involved and it is rarely if ever noticed in standard toxicity testing. The Popliteal Lymph Node assay (PLNA) is regarded a suitable test to screen for the immunostimulating ability of a chemical, which may indicate its immunosensitizing potential. The most simple, primary PLNA measures Popliteal Lymph Node hyperplasia after subcutaneous injection of a chemical into the footpad of the hindpaw of a mouse or rat. In order to assess the involvement of T cells, and hence immunosensitizating potential of a chemical, anamnestic immune reactions to a chemical or its metabolite can be measured in previously exposed (and sensitized) animals or in naive animals that received an adoptive transfer of syngeneic T cells from previously exposed animals. In the recently introduced modified PLNA, defined reporter antigens TNP-OVA (T cell-dependent antigen) and TNP-Ficoll (T cell-independent antigen) are used to distinguish between sensitizing and non-sensitizing (IgG1-response or not to TNP-Ficoll, respectively) and between mere inflammatory and complete innocent (no IgG1-response to TNP-Ficoll and an IgG1-response or not to TNP-OVA, respectively) drugs. Results with about 130 compounds (drugs and environmental pollutants) with the various types of the PLNA show a good correlation with documented immunostimulating (both autoimmunogenic and allergic) potential and no false negative chemicals were detected if metabolism was considered. The PLNA awaits further validation before this test can be recommended as a tool for prediction of drug allergy.

Nanne Bloksma - One of the best experts on this subject based on the ideXlab platform.

  • The Popliteal Lymph Node assay in mice: screening of drugs and other chemicals for immunotoxic hazard.
    Inflammation Research, 1996
    Co-Authors: Carsten Goebel, Nanne Bloksma, P. Griem, B Sachs, Ernst Gleichmann
    Abstract:

    The Popliteal Lymph Node assay (PLNA) in mice represents a predictive test for assessing the sensitizing (allergenic and autoimmunogenic) potential of drugs and low molecular weight chemicals. Measuring activation of the draining Lymph Node of the hind paw, the PLNA facilitates the detection and analysis of immunotoxic effects in a rapid and reproducible manner. An attractive feature of the PLNA is that it can be performed in combination with the routine toxicity testing required for new drugs. Thus, it is possible to investigate whether animals exposed by the oral, intravenous, or inhalative route have been sensitized to the test compound or a reactive metabolite of the test compound generated in vivo. PLNAs may be appropriate supplements to routine toxicity screening of chemicals, thereby enhancing chemical safety.

  • predictive immunotoxicological test systems suitability of the Popliteal Lymph Node assay in mice and rats
    Critical Reviews in Toxicology, 1995
    Co-Authors: Nanne Bloksma, Ernst Gleichmann, Hans-christian Schuppe, Malgorzata Kubickamuranyi, Helga Gleichmann
    Abstract:

    This article reviews results obtained with Popliteal Lymph Node assays (PLNAs) in rodents and discusses their ability to detect and analyze immunotoxic effects of drugs and other low molecular weight (LMW) chemicals. In its basic form, the PLNA measures activation of the draining Lymph Node of the hind paw (i.e., the PLN) after injection of a test chemical into the hind foot pad. The assay appears to be appropriate to recognize sensitizing, that is, allergenic and autoimmunogenic, chemicals, as well as nonsensitizing immunostimulatory chemicals. With modifications, PLNAs can detect immunosuppressive chemicals and distinguish sensitizing from nonsensitizing chemicals. Furthermore, modified PLNAs enable detection of known as well as unknown sensitizing metabolites, and may assist in the identification of the self-molecules that act as carriers for chemical sensitization or as targets of chemical-induced autoimmune disease. Experience with PLNAs shows that they are rapid, reproducible, and objective tests for recognition of sensitizing or otherwise immunomodulating chemicals. Because current protocols of toxicity testing are insensitive in predicting a chemical's potential to result in immunomodulation, PLNAs, when further validated, may provide welcome supplements to routine toxicity screening of chemicals, thus enhancing chemical safety.

  • Popliteal Lymph Node enlargement and antibody production in the mouse induced by drugs affecting monoamine levels in the brain.
    International journal of immunopharmacology, 1991
    Co-Authors: C. Thomas, Willem Seinen, W. Lippe, Nanne Bloksma
    Abstract:

    Drugs that affect monoamine levels in the brain were screened for their potential to cause immunological changes in the Popliteal Lymph Node (PLN) of mice after injection into the hind paw. The tricyclic antidepressant (TCA) drugs, imipramine and amitriptyline, and the serotonin reuptake blocker, zimeldine, induced a prominent PLN weight gain in C57BL/6 mice. Ketanserin and ritanserin appeared less effective while nomifensine, serotonin and the antigen, sheep erythrocytes, lacked significant activity. In BALB/c mice all agents induced an increase of PLN cell number, the TCA drugs and zimeldine appeared superior in this respect. Increased IgM as well as IgG production on a per cell basis was only induced by the TCA drugs, zimeldine and, especially, sheep erythrocytes. Data indicate that induction of PLN responses is not a general property of agents affecting monoamine levels. Structural, i.e. antigenic, characteristics of the drugs rather than their pharmacological properties are probably at play.