Immunopharmacogenomics: Mechanisms of HLA‐Associated Drug Reactions

Abstract

The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T‐cell‐mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA‐B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug‐induced T‐cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T‐cell‐mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA‐associated drug reactions and the implications for future translation into clinical care.

In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals—A Systematic Review

“…However, if chemical-induced epitopes are formed inefficiently and if this is combined with the rarity of antigen-specific T cells, the detection of T cell activation may become virtually impossible. In addition, epitopes may form in an HLA allele-restricted manner, which is less well investigated for sensitizing chemicals that are not used as drugs [ 68 , 69 , 70 , 71 , 72 ].…”

“…Binding via p-i has often been reported in the context of HLA allele-associated drug hypersensitivities [ 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Arguably, the most prominent example is abacavir binding to the F-pocket of HLA-B*57:01, which conceals a carboxy-terminal tryptophan important for peptide anchoring.…”

Risk Assessment in Drug Hypersensitivity: Detecting Small Molecules Which Outsmart the Immune System

“…• p-i stimulations comprise DH which show an HLAassociation, since the binding of a drug to a certain HLAallele-which is the cause for this link-is non-covalent (24)(25)(26)(27)(28)(29). The list of such drugs is long (30); • The immunological (16) and clinical features of DRESS and SJS/TEN (with and without HLA association) are suggestive for p-i, and where investigated, a p-i mechanism was found (30,31).…”

Alergia a penicilina

“…11 El HLA juega un papel fundamental en la presentación de un autoantígeno a las células T para la inducción de inmunotolerancia. 12 Recientemente se ha buscado la asociación de genes implicados en la síntesis de IgE, así como su participación en la reacción alérgica a penicilina, los cuales se observan en el Cuadro 1. 13,14,15,16,17,18,19,20,21,22,23 Rev Alerg Mex.…”