Developing a T cell:Dendritic cell co-culture system to predict idiosyncratic drug induced hypersensitivity reactions

Abstract

Abstract Idiosyncratic drug induced hypersensitivy reactions (IDHR)s pose a significant safety risk to patients. Indeed, IDHRs have been associated with severe, life-threatening conditions such as Stevens Johnson syndrome, Toxic epidermal necrolysis, and hepatotoxicity. Though drug-induced immune system activation is often implicated in IDHRs, the mechanisms by which this occurs are poorly understood and likely involve formation of drug metabolites or haptens. Furthermore, pre-clinical models often fail to detect the potential of drugs to cause these reactions. Thus, there is a need to create models that can 1) examine how drugs or drug byproducts activate the immune system and 2) predict the potential of drugs to induce IDHRs before they are evaluated in clinical trials. To that end, we have examined the in vitro activation of T cells by autologous monocyte derived dendritic cells (DC)s in the presence of drugs that are associated with IDHR. In concert with previous findings, IDHR associated drugs induce T cell proliferation. Additionally, T cells stimulated by IDHR associated drugs upregulate cell surface markers of activation including CD71, CD69, CD45RO, CD25, and MHC-II. Importantly, we have begun to explore how drug metabolites formed either during T cell:DC co-culture or during culture with hepatocytes influence DC presentation and T cell activation.