MOUSE POPLITEAL LYMPH NODE ASSAY FOR ASSESSMENT OF ALLERGIC AND AUTOIMMUNITY-INDUCING POTENTIALS OF LOW-MOLECULAR-WEIGHT DRUGS

Published on May 10, 1999in Journal of Toxicological Sciences1.737
· DOI :10.2131/JTS.24.95
Kanade Shinkai26
Estimated H-index: 26
,
Kenkichi Shinkai4
Estimated H-index: 4
+ 9 AuthorsEiji Maki5
Estimated H-index: 5
Sources
Abstract
In the present collaborative study, popliteal lymph node (PLN) responses to penicillin G (an allergenic chemical), D-penicillamine (an autoimmunity-inducing chemical), and barbital (a negative reference chemical) were investigated in three different mouse strains by ten pharmaceutical companies. Two inbred mouse strains (BALB/c and A/J) and one outbred strain (ICR) were subcutaneously injected with saline solutions containing penicillin G (1.25, 2.5 and 5 mg/mouse), D-penicillamine (0.5, 1 and 2 mg/mouse), or barbital (2 mg/mouse) into one hind footpad and saline only was injected into the contralateral footpad. PLN cellularity indices were determined on day 7. In the three strains tested, the penicillin G and D-penicillamine injections resulted in approximately dose-dependent responses. In contrast, barbital failed to generate a significant PLN reaction. In the typical data from one of the participating laboratories, the PLN responses of A/J, BALB/c, and ICR to penicillin G were high, intermediate and low, respectively, while their PLN responses to D-penicillamine were all high. Some variation in PLN cellularity indices was observed among the participating laboratories, but reproducibility of the popliteal lymph node assay (PLNA) evaluation was partly confirmed. Although the appropriate selection of mouse strains and drug dosage levels has to be considered, these results suggest that the PLNA may be an appropriate screening system for prediction of the allergic or autoimmunity-inducing potentials of low-molecular-weight drugs.
📖 Papers frequently viewed together
2 Citations
17 Citations
References32
Newest
#1Helga Gleichmann (NKI-AVL: Netherlands Cancer Institute)H-Index: 4
#2Steven T. Pals (UvA: University of Amsterdam)H-Index: 74
Last. Thaddäus Radaszkiewicz (University of Vienna)H-Index: 21
view all 3 authors...
We have postulated that binding of the hydrophobic anticonvulsant drug diphenylhydantoin (DPH) to lymphoid cells might induce graft-versus-host (GVH)-like cell reactions by T lymphocytes and thus trigger autoimmunization and lymphoma development observed in patients treated with DPH. This hypothesis was studied in mice by means of the popliteal lymph node (PLN) assay. DPH, injected s.c. into the footpads of mice, induced a significant T cell-dependent PLN enlargement. The B cell-derived populati...
33 CitationsSource
#1Tetsuo AidaH-Index: 6
#2Tsutomu KimuraH-Index: 2
Last. Kenkichi ShinkaiH-Index: 4
view all 4 authors...
In the present study, the correlation between mouse PLNA and those obtained from GP-PCA and from GP-ASA reactions fro sodium 2, 4, 6-trinitrobenzenesulfonate dihydrate (TNBS), penicillin G and cephalothin was investigated. Next, variou drugs were tested using the mouse PLNA to study whether PLN reactivity could be related to the potential of the compounds to induce allergic and autoimmune disorders in humans. The parameter of the PLNA was determined by the PLN cellularity index in BALB/c and A/J...
13 CitationsSource
#1N. TsutsuiH-Index: 2
#1Naohisa TsutsuiH-Index: 4
Last. Eiji MakiH-Index: 5
view all 4 authors...
2 Citations
#1Kanade ShinkaiH-Index: 26
#1Kenkichi ShinkaiH-Index: 4
Last. Eiji MakiH-Index: 5
view all 12 authors...
1 Citations
#1Hiroyuki HattoriH-Index: 6
#2Fumie YamaguchiH-Index: 3
Last. Mamoru NomuraH-Index: 8
view all 5 authors...
Allergic reactions are among the common adverse effects in humans. However, it is widely assumed that there are practically no reliable animal models for preclinical tests of low-molecular weight drugs that are available to predict such reactions. This study was designed to compare the detecting ability of test methods for antigenic potential of eight β-lactam antibiotics with which allergic outcome has been reported in humans. The tests included active systemic anaphylaxis (ASA), delayed type s...
10 CitationsSource
#1Elisabetta Padovan (MPG: Max Planck Society)H-Index: 6
#2Tanja BauerH-Index: 2
Last. Hans Ulrich Weltzien (MPG: Max Planck Society)H-Index: 33
view all 5 authors...
Although hapten immune responses have been intensively studied in the mouse, very little is known about hapten determinants involved in human allergic reactions. Penicillins, as chemically reactive compounds of low molecular weight, constitute typical examples of hapten allergens for humans. Penicillins become immunogenic only after covalent binding to carrier proteins and in this form frequently induced IgE-mediated allergic reactions in patients subjected to antibiotic treatment. However, our ...
134 CitationsSource
#1Carsten Goebel (HHU: University of Düsseldorf)H-Index: 15
#2P GriemH-Index: 2
Last. Ernst GleichmannH-Index: 32
view all 5 authors...
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. ...
15 Citations
5 Citations
Optimal experimental methods for antigenicity studies in guinea pigs were investigated on : (1) the effects of different immunizing methods using complete or incomplete Freund's adjuvants (CFA or IFA), and various injection sites, the number of immunizations, the immunizing doses, and the immunizing periods, (2) the relationship between the severity of active systemic anaphylaxis (ASA) reactions and passive cutaneous anaphylaxis (PCA) titers, (3) positive control for oral administration, and (4)...
13 CitationsSource
#1Krzysztof Krzystyniak (Université du Québec)H-Index: 5
#2Ewa Kozlowska (University of Warsaw)H-Index: 9
Last. Krystyna Izdebska-Szymona (University of Warsaw)H-Index: 1
view all 7 authors...
Abstract A popliteal lymph node (PLN) test was further validated for predictive screening of autoimmunity-inducing drugs. Autoimmune-like T-cell activation of streptozotocin (STZ) was compared with the effect of Freund's complete adjuvant (FCA), injected locally into the foot pad of BALB/c mice. Early cell activation in enlarged PLN was monitored by flow cytometry. Injection of both STZ and FCA markedly increased the absolute PLN cell number as well as specific T-helper (CD4 + ), T-suppressor/cy...
7 CitationsSource
Cited By9
Newest
#1Janos Szebeni (Semmelweis University)H-Index: 51
#2Gert Storm (UU: Utrecht University)H-Index: 108
Abstract Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. admin...
61 CitationsSource
#1Rudolf Urbanics (Semmelweis University)H-Index: 13
#2Péter Bedőcs (USU: Uniformed Services University of the Health Sciences)H-Index: 5
Last. Janos Szebeni (Semmelweis University)H-Index: 51
view all 3 authors...
20 CitationsSource
#1Jessica Whritenour (Pfizer)H-Index: 7
#2Susan Cole (Pfizer)H-Index: 16
Last. Thomas T. Kawabata (Pfizer)H-Index: 18
view all 5 authors...
AbstractAnimal models that can be used to predict the allergenic potential of drug candidates have not been adequately optimized, validated, or characterized. While initial validation data from an inter-laboratory study of the mouse lymph node proliferation assay (LNPA) appeared promising, no additional investigations in this model have been reported. The objectives of this study were to use positive and negative control drugs to further optimize and validate the LNPA utilizing a non-radioactive...
6 CitationsSource
#1Erica Salguero (National University of Colombia)H-Index: 1
#2David F. Plaza (National University of Colombia)H-Index: 9
Last. Gabriela Delgado (National University of Colombia)H-Index: 11
view all 5 authors...
Immunotoxicology can lead to determining the adverse effects of different compounds on the immune system. Sometimes, many drugs (especially antibiotics) induce immune alterations, mainly auto-immunity. This study was aimed at determining vancomycin's immunotoxic effect by comparing the original molecule to two of the most used copies. Thirty-two mice from two murine strains (Swiss and CFW) were treated with three antibiotic formulations for studying its effect on splenic lymphoid and peripheral ...
3 CitationsSource
The popliteal lymph node assay (PLNA) derives from the hypothesis that some supposedly immunemediated 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, fail...
23 CitationsSource
#1Gregory A MooreH-Index: 1
#2Olle NygrenH-Index: 1
5 Citations
#1Bradford W. Gutting (Pfizer)H-Index: 4
#2Lawrence W. Updyke (Pfizer)H-Index: 4
Last. David E. Amacher (Pfizer)H-Index: 21
view all 3 authors...
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 (P...
10 CitationsSource
#1Akiko SudaH-Index: 2
#2Yoshinobu IwakiH-Index: 6
Last. Masaaki KimuraH-Index: 10
view all 3 authors...
The mouse popliteal lymph node assay(PLNA)has been proposed as an immunotoxicological test to predict allergenic chemicals. However, PLN response is also observed in association with non-specific activation induced by some irritants. We, therefore, examined the kinetics of the PLN cellularity indices of primary and secondary responses. Flow cytometric analysis was used to measure the proportions of T and B cells in PLN. Male ICR mice were subcutaneously injected with TNBS(an allergenic compound)...
9 CitationsSource
#1Genevieve Choquet-Kastylevsky (French Institute of Health and Medical Research)H-Index: 10
#2R. Tedone (French Institute of Health and Medical Research)H-Index: 8
Last. Jacques Descotes (French Institute of Health and Medical Research)H-Index: 30
view all 6 authors...
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 histocompatib...
10 CitationsSource