Evaluation of allergenic potential of low-molecular compounds by mouse popliteal lymph node assay.

Abstract

In the present study, the correlation between mouse PLNA results and those obtained from GP-PCA and from GP-ASA reactions for sodium 2,4,6-trinitrobenzenesulfonate dihydrate (TNBS), penicillin G and cephalothin was investigated. Next, various 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 mice treated with a single subcutaneous injection of compounds. Hartley guinea pigs were immunized subcutaneously with the compounds without adjuvant, and then the GP-PCA and GP-ASA reactions were assessed. The examinations using mice and guinea pigs showed that mouse PLN responses to TNBS, penicillin G and cephalothin correlated with the allergenicity responses obtained in the GP-PCA reaction to three compounds. In the mouse PLNA, ten drugs considered to be well-known inducers of allergic side-effects in humans (i.e., penicillin G, cephalothin, ampicillin, carbenicillin, cefazolin, cefotaxime, streptomycin, 4-aminoantipyrine, chlorhexidine and sulfamethoxazole) caused increases in PLN cellularity indices as well. These results indicate that the PLNA may be useful as a short-term and simple test system for detecting low-molecular drugs exhibiting allergenicity potential.

Development and partial validation of a mouse model for predicting drug hypersensitivity reactions

“…The popliteal lymph node assay (PLNA), first published in 1981, is the most thoroughly investigated model for predicting drugs that are associated with autoimmune and hypersensitivity responses in the clinical setting (Aida et al, 1998;Gleichmann, 1981;Pieters, 2001;Ravel & Descotes, 2005;Shinkai et al, 1999). The model itself has been modified to include several approaches (indirect and adoptive transfer PLNA) (Pieters, 2001;Ravel & Descotes, 2005).…”

Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin

“…STZ, a nitrosourea derivative approved for the treatment of carcinoid and pancreatic islet cell tumors, is known to induce type I diabetes in both animals (Like and Rossini 1976;Cheta 1998) and man (Schulz et al 1990). STZ was repeatedly shown to induce markedly positive PLN responses (Klinkhammer et al 1988;Verdier et al 1990;Krzystyniak et al 1992a, b;Brouland et al 1994;Patriarca et al 1994;Vial et al 1997;Aida et al 1998) and is therefore considered a prototypic reference compound in the PLN assay.…”

“…STZ was repeatedly shown to cause strongly positive PLN responses in rats and mice (Klinkhammer et al 1988;Verdier et al 1990;Krzystyniak et al 1992a, b;Brouland et al 1994;Patriarca et al 1994;Vial et al 1997;Aida et al 1998). As mentioned above, a pseudoGvH reaction is presumably involved.…”

“…To date, over 100 chemicals, of which the majority are pharmaceuticals, have been tested in mice or rats using the PLN assay (Kammu¨ller et al 1989;Verdier et al 1990;Descotes et al 1997;Vial et al 1997;Aida et al 1998;Pieters 2001).…”

Investigating the TNP‐OVA and direct popliteal lymph node assays for the detection of immunostimulation by drugs associated with anaphylaxis in humans

“…9 Furthermore, recent studies have also demonstrated that penicillin G and cephalothin, two LMWCs that are associated with drug-induced anaphylaxis in humans, produce positive reactions in the direct PLNA. 13,14 Despite these promising results, the direct PLNA is limited by the fact that PLN weight and PLN cellularity are relatively insensitive endpoints that do not provide information regarding the potential mechanisms causing PLN enlargement and are not designed to detect IgE synthesis. 10 Recently, in an attempt to address these limitations, the direct PLNA was modified by including a reporter antigen, TNP-OVA (trinitrophenyl-ovalbumin), in the injection mixture.…”