An intravenous exposure mouse model for prediction of potential drug‐sensitization using reporter antigens popliteal lymph node assay

Abstract

Immune-mediated drug hypersensitivity is a particularly concerning health-safety issue among clinicians given its unpredictability and potentially life-threatening effects, especially with exposure to intravenous drugs. Therefore, the development of intravenous drug-exposure models for drug-hazard assessments has garnered increasing interest in recent years. In this study, we used reporter antigens popliteal lymph node assay to investigate the potential value of intravenous exposure to a selected variety of allergenic compounds, including ovalbumin (OVA), concanavalin A (ConA) and diclofenac. The trinitrophenyl (TNP)-specific antibody-forming cells were used to assess the systemic immune responses to a bystander antigen. Mice were subsequently sensitized by TNP-OVA, and then intravenous exposure to one of the selective compounds. As expected, all positive compounds induced significant popliteal lymph node (PLN) proliferation compared with the control. OVA significantly increased Cluster of Differentiation 4 receptors (CD⁴)⁺ interleukin-4 (IL-4)⁺ T-helper 2 (Th2) cells and, consequently, increased the ratios of IL-4/interferon-γ (IFN-γ) antibody-forming cells (AFCs) in PLNs, while bringing about a dose-dependent increase in immunoglobulin G1 (IgG1) AFCs; these findings indicate that a Th2 hypersensitivity response was induced. A Th2 response was also observed in diclofenac sodium-treated groups, and for ConA, a more mixed Th1/Th2 immune response appeared to be induced. In addition, there was no marked reaction with the negative compound. Together, it seems likely that the intravenous exposure model may be useful for drug-induced systemic hypersensitivity assessments.

Lessons learned from the porcine CARPA model: constant and variable responses to different nanomedicines and administration protocols

“…These include the mouse popliteal lymph node assay (PLNA) (20)(21)(22), the mouse ear-swelling test (23)(24)(25), the guinea pig (GP) maximization test (GPMT), the GP occluded patch test (Buehler's test) (26,27) and the murine local lymph node assay (MLLA) (26). In fact, the standard guinea pig assays were shown to be useless in predicting systemic hypersensitivity (28).…”

Evaluation of the Potential Sensitization of Chlorogenic Acid: A Meta-Analysis

“…In this work, two studies were included in meta-analysis of PLNA parameters; one proved a positive reaction by using an intravenous mouse model [14, 35], while another showed a negative result by subcutaneous administration. The inconsistent results of PLN cellularity and IgG1 AFCs were pooled by meta-analysis and the pooled results showed that CGA might significantly increase PLN cellularity and induce IgG1 AFCs formation.…”

“…With the wide application in China, the safety issues of TCMIs are becoming increasingly critical in recent years. One research indicated that TCMIs accounted for 66.7% of adverse reactions in traditional Chinese medicines [14]. Furthermore, it is estimated that 90% of these adverse reactions, especially the systemic safety of sensitization, are related to TCMIs containing CGA [15].…”

Structure–Activity Differences of Chlorogenic Acid and Its Isomers on Sensitization via Intravenous Exposure

“…Based on the RA-PLNA, a particularly useful tool for the systemic sensitizing potential assessment, 29 our previous studies have demonstrated that an intravenous exposure mouse model, which was validated by 3 positive and 1 negative compounds, appears to be a potentially useful tool for drug-induced hypersensitivity screening via intravenous exposure. 21 In this study, by using the mouse model, the potential sensitization of CGA and its isomers via intravenous exposure were further determined. Our results showed that, CGA and its isomers (except CA and QA) may significantly enhance the weight indexes and cell numbers in PLN compared with the control.…”

“…Therefore, by using an intravenous mouse model that we have developed in our previous study, 21 the primary issue addressed in this study was to explore the sensitization potential of CGA. Furthermore, we hypothesize that CGA or its isomers, including caffeic acid (CA), quinic acid (QA), crypto-chlorogenic acid (crypto-CGA), iso-chlorogenic acid A (iso-CGA A), and iso-chlorogenic acid B ([iso-CGA B] for structures see Figure 1), have a structure-activity relationship in immunostimulation.…”