Suitability of the Popliteal Lymph Node Assay as a Predictive Immunotoxicological Test
- PDF / 286,676 Bytes
- 4 Pages / 504 x 720.24 pts Page_size
- 54 Downloads / 173 Views
Information Journal, Vol. 31, pp. 1337-1340. 1997 Printed in the USA. All rights reserved.
Drug
Copyright 0 1997 Drug Information Association Inc.
SUITABILITY OF THE POPLITEAL LYMPH NODE ASSAY AS A PREDICTIVE IMMUNOTOXICOLOGICAL TEST RUUDALBERS,PHD, WILLEMSEINEN,PHD, AND RAYMONDRETERS, PHD Research Institute of Toxicology, Immunotoxicology Section, Utrecht University, Utrecht, the Netherlands
This paper reviews the suitability of the popliteal lymph node (PLN)assay as a preclinical screening test to predict the potential of systemically administered pharmaceuticals to induce allergic or autoimmune responses. The basic assay provides a rapid, simple, and objective method to grade the immunostimulating capacity of compounds. Secondary PLN assays in sensitized animals can demonstrate specific immunological memory for the compound, whereas addition of defined reporter antigens allows identification of the type of response stimulated, and facilitates studies into the underlying mechanism. Key Words: PLN assay; Immunotoxicology; Autoimmunity; Allergy; Test model
INTRODUCTION IT HAS BEEN WELL established that certain drugs and chemicals can induce allergic or autoimmune reaction in susceptible persons. Although several test systems exist to predict the capacity of pharmaceuticals to induce contact dermatitis or respiratory allergy, no validated models are available to indicate potential to induce allergic or autoimmune reactions after systemic exposure to pharmaceuticals. These effects are, therefore, easily missed during safety evaluation and are sometimes first discovered upon human exposure. As a result, several drugs have recently been withdrawn from the market, at considerable cost to the manufacturing com-
Presented at the DIA Workshop “Immunotoxicity of Pharmaceuticals: Current Knowledge, Testing Strategies, B s k Evaluation and. Consequences for Human Health,” October 2 4 1996, Montreux, Switzerland. Reprint address: Ruud Albers, Research Institute of Toxicology. Immunotoxicology Section, Utrecht University, Po Box 80.176, NL-3508 TD, Utrecht, the Netherlands. E-mail: [email protected]
panies. Currently, the direct popliteal lymph node assay in rodents is the most promising candidate test system to determine this potential in an early preclinical phase of drug development. Because the assay measures initiating events rather than unpredictable endpoints, it indicates both allergenic and autoimmunogenic potential without distinguishing between these. Recently, several modifications have been made to the basic direct PLN assay, and these have largely increased its flexibility and potential use.
THE DIRECT (PRIMARY) PLN ASSAY In the direct PLN assay, test compounds are subcutaneously (s.c.) injected without adjuvant into one hindpaw of a naive mouse or rat (Figure 1). Compounds with immunostimulating properties induce local immune responses in the draining PLN. Dosing has largely been empirical (typically 0.05 to 2 mg per mouse and 1-10 mg per rat), and dose-response relations were evident for all
133
Data Loading...
