abacavir and Virus-Diseases

Various types of transgenic mice carrying either class I or II human leukocyte antigen (HLA) molecules are readily available, and reports describing their use in a variety of studies have been published for more than 30 years. Examples of their use include the discovery of HLA-specific antigens against viral infection as well as the reproduction of HLA-mediated autoimmune diseases for the development of therapeutic strategies. Recently, HLA transgenic mice have been used to reproduce HLA-mediated idiosyncratic drug toxicity (IDT), a rare and unpredictable adverse drug reaction that can result in death. For example, abacavir-induced IDT has successfully been reproduced in HLA-B*57:01 transgenic mice. Several reports using HLA transgenic mice for IDT have proven the utility of this concept for the evaluation of IDT using various HLA allele combinations and drugs. It has become apparent that such models may be a valuable tool to investigate the mechanisms underlying HLA-mediated IDT. This review summarizes the latest findings in the area of HLA transgenic mouse models and discusses the current challenges that must be overcome to maximize the potential of this unique animal model.

Topics: Alleles; Animals; Antiviral Agents; Dideoxynucleosides; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; HLA Antigens; Humans; Mice; Mice, Transgenic; Virus Diseases

Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.

Topics: Allopurinol; B-Lymphocytes; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Loci; HLA Antigens; Humans; Models, Immunological; Pharmacogenetics; Stevens-Johnson Syndrome; T-Lymphocytes; Virus Diseases

Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacologic 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 syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis, 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 patients with 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 immunologically mediated type B ADRs. Because methods to predict type 1 diabetes by using genetic and immunologic biomarkers have been developed to a high level of accuracy (predicting 100% of subjects likely to progress), new research strategies based on these methods might also improve the ability to predict drug hypersensitivity.

Topics: Autoimmunity; Carbamazepine; Diabetes Mellitus, Type 1; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; HLA Antigens; Humans; Models, Molecular; Pharmacogenetics; Prognosis; Receptors, Antigen, T-Cell; Stevens-Johnson Syndrome; T-Lymphocytes; Virus Diseases

Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein.

Topics: Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression; Haptens; HLA Antigens; Humans; Immunoglobulin E; National Institute of Allergy and Infectious Diseases (U.S.); Practice Guidelines as Topic; Receptors, Antigen, T-Cell; Stevens-Johnson Syndrome; Terminology as Topic; Translational Research, Biomedical; United States; Virus Diseases