New approaches for predicting T cell–mediated drug reactions: A role for inducible and potentially preventable autoimmunity

Abstract

Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacological target (Type A ADR) or an unintended target (Type B ADR). Immunologically mediated Type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), can be severe and result in a diverse set of clinical manifestations that include fever and rash as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell–mediated ADRs are strikingly similar to those displayed by autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for developing immunologically mediated Type B ADRs. Since methods to predict type 1 diabetes using genetic and immunological biomarkers have been developed to a high level of accuracy (predicting 100% of individuals likely to progress), new research strategies based on these methods may also improve the ability to predict drug hypersensitivity.

Occurrence of Dermatomyositis Immediately after Mastectomy Subsequent to Severe Chemotherapeutic Drug Eruption

“…Drug hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, another type of dug eruption, has also been reported to be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and autoantibody productions, suggesting that autoimmune responses occur after severe drug eruptions ( 10 , 11 ). In these cases of severe drug eruption, herpes viruses are activated after the eruption ( 28 ). Virus infection is generally associated with autoimmune diseases ( 28 ) and has also been proposed as a cause of the production of myositis-specific antibodies ( 29 ).…”

Advances and highlights in mechanisms of allergic disease in 2015

“…Several features of T cell-mediated adverse drug reactions (ADRs) are strikingly similar to those displayed by patients with autoimmune diseases. 52 In a recent review White et al 53 discussed the role of host genetics, microbes, and drugs in the development of immunemediated adverse drug reactions (IM-ADRs). They focused on…”

Predicting CD4 T-cell epitopes based on antigen cleavage, MHCII presentation, and TCR recognition

“…Here, we focus on predicting T-cell epitopes within an input antigen sequence, restricted to a given human MHCII (Human Leukocyte Antigen, HLA) and to specific TCR sequences. Knowledge of immunodominant epitopes is helpful in designing vaccines [ 4 ], improving cancer immunotherapy [ 5 ], studies of autoimmune diseases [ 6 , 7 ], and engineering of protein replacement therapies [ 8 ]. Unfortunately, most current in vitro and in vivo experimental methods for predicting immunogenicity in pre-clinical settings are resource intensive and relatively slow [ 5 , 9 , 10 ].…”