Assessment of Hypersensitivity

Adverse drug reactions (ADRs) are considered the sixth leading cause of death in the United States and cost between 30 and 130 billion annually (White et al., 1999). Hypersensitivity reactions are thought to be responsible for about 6-10% of ADRs (Thong and Tan, 2011). Manifestations of drug hypersensitivity include contact hypersensitivity, respiratory hypersensitivity, systemic hypersensitivity, and autoimmunity. Pseudoallergy is also included in the category 

Several in vivo methods exist and are used as tools to determine the potential for contact, and potentially respiratory, hypersensitivity (e.g., the local lymph node (LENA) (Kimber et al., 2002) and popliteal lymph node (PLNA) (Pieters, 2001) assays) and the mouse drug allergy model, which is a modification of the LENA, demonstrates promise as a screening tool in that a number of drugs which cause idiosyncratic hypersensitivity reactions in humans were positive in this assay (Whritenour et al., 2014 Zhu et al., 2014). However, there are no fully predictive animal models of drug allergy in humans. 

Mast Cell Degranulation Mast cells play a role in Type 1 hypersensitivity reactions, but they can also be stimulated by pharmaceuticals in an IgE-independent manner due to direct interactions with mast cell membranes or surface receptors (de Week, 1984). The reaction in vivo typically occurs at maximum drug concentration, or very soon after an IV infusion, and tends to diminish with subsequent exposures to the drug. Pseudoallergy is a rare event, and routine screening 

This assay can be used to characterize findings in preclinical studies using mast cells from the preclinical species and compared with results using human mast cells to determine translatability and relative risk. 

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