An in vivo tiered approach to test immunosensitization by low molecular weight compounds.

Published on Jan 1, 2010in Methods of Molecular Biology
· DOI :10.1007/978-1-60761-401-2_3
Irene S. Ludwig12
Estimated H-index: 12
(UU: Utrecht University),
Lydia M. Kwast5
Estimated H-index: 5
(UU: Utrecht University)
+ 1 AuthorsRaymond Pieters36
Estimated H-index: 36
(UU: Utrecht University)
Sources
Abstract
: New chemical entities are tested in general toxicity assays during development before entering clinical trials. However, immunosensitization of these entities is not tested on a standard basis. There are no in vitro or in vivo standardized methods available for testing immunosensitization or immunostimulation. In this chapter, we describe a tiered strategy oral exposure model for assessing immunosensitization or immunostimulation capacity of low molecular weight compounds. The strategy starts from a set of data that may provide information on bioactivation, conjugation (hapten-protein conjugate formation), cytotoxicity and signs of inflammation in any of the animals in a 28 day-toxicity study. In case of concern, a reporter antigen-popliteal lymph node assay (RA-PLNA) and, subsequently, an oral exposure experiment with the reporter antigen can be performed. Based on the presence of RA-specific immune responses an indication for immunosensitization can be found.
References5
Newest
#1Raymond Pieters (UU: Utrecht University)H-Index: 36
Abstract Despite the important health and economic impact of autoimmunogenicity or allergenicity by pharmaceuticals models to detect such adverse effects are not available yet. The most important reason for this is the related complex interplay of multiple factors, for which reason these adverse effects are also referred to as idiosyncratic in nature. Moreover, clinical effects are quite diverse, and involve both organ-specific and systemic effects, including a diversity of skin diseases. Becaus...
15 CitationsSource
#1Stefan Nierkens (UU: Utrecht University)H-Index: 29
#2Marloes Aalbers (UU: Utrecht University)H-Index: 3
Last. Raymond Pieters (UU: Utrecht University)H-Index: 36
view all 6 authors...
The capability of certain drugs to cause immune-mediated drug hypersensitivity reactions in susceptible individuals has initiated a search for pre-clinical screening tools to identify immunosensitizing drugs. Since most drugs are taken orally, hazard assessment of their immunosensitizing potential should include oral exposure models. In this study, the predictive value of the reporter antigen (RA) approach was investigated in combination with oral or intraperitoneal (ip) exposure to a selection ...
16 CitationsSource
#1Stefan NierkensH-Index: 29
#2Pauline van HeldenH-Index: 1
Last. Raymond PietersH-Index: 36
view all 8 authors...
CD154 is transiently expressed by activated T cells and interacts with CD40 on B cells, dendritic cells, macrophages, and monocytes. This costimulatory receptor-ligand couple seems decisive in Ag-driven immune responses but may be differentially involved in type 1 vs type 2 responses. We studied the importance of CD40-CD154 in both responses using the reporter Ag popliteal lymph node assay in which selectively acting drugs generate clearly polarized type 1 (streptozotocin) or type 2 (D-penicilla...
28 CitationsSource
#1Ruud Albers (UU: Utrecht University)H-Index: 8
#2A. Broeders (UU: Utrecht University)H-Index: 2
Last. Raymond Pieters (UU: Utrecht University)H-Index: 36
view all 5 authors...
Abstract Various drugs and other chemicals can induce T-cell-dependent B-cell activation which may lead to allergic or autoimmune-like diseases. Because the nature of the relevant (neo-) antigens is generally not known and probably depends on the chemical, we have explored the potential use of reporter antigens to determine T-cell-dependent B-cell activation by chemicals. TNP-Ficoll and TNP-OVA were used for this purpose because they are recognized by the same TNP-specific B cells, but these cel...
58 CitationsSource
#1Peter Schielen (UU: Utrecht University)H-Index: 5
#2W. Van Rodijnen (UU: Utrecht University)H-Index: 2
Last. Willem Seinen (UU: Utrecht University)H-Index: 60
view all 5 authors...
Abstract We describe here a new type of solid support for the ELISPOT assay, the PVDF membrane. In parallel tests, spot yields on this membrane were superior to those obtained with the frequently used nitrocellulose (NC) membrane, coated with the same rat anti-IgM and anti-IgG antibodies, incubated with the same rat spleen cell suspensions, and developed with the same combination of AP-labeled conjugates and substrate. We therefore used the PVDF membrane, coated with anti-rat IgM and IgG antibod...
30 CitationsSource
Cited By1
Newest
#1Qiang You (UM: University of Montana)H-Index: 1
#2Linling Cheng (UM: University of Montana)H-Index: 1
Last. Cynthia Ju (UM: University of Montana)H-Index: 13
view all 6 authors...
AbstractEvidence suggests that bio-activation of drugs to generate chemically reactive metabolites (RM) that act as haptens to form immunogenic protein conjugates may be an important cause of immune-mediated drug hypersensitivity reactions (IDHR). Although many drugs that form RMs raise concerns about producing IDHR, standard non-clinical testing methods are rarely able to identify compounds with the potential to produce IDHR in humans. The objective of this study was to develop a predictive ass...
3 CitationsSource