Delayed drug hypersensitivity: models of T-cell stimulation

Br J Clin Pharmacol. 2011 May;71(5):701-7. doi: 10.1111/j.1365-2125.2010.03764.x.

Abstract

Drug-induced hypersensitivity reactions can cause a variety of serious diseases by involving drug-specific T-cells. Many of these reactions have been explained by the hapten concept, which postulates that small chemical compounds need to bind covalently to proteins to be recognized by the immune system. Due to their chemical reactivity, haptens stimulate the innate immunity by binding covalently to endogenous proteins and form so called hapten-carrier complexes, which are antigenic and induce T-cell responses. In recent years, a new concept has been developed since drug-induced hypersensitivity reactions were also observed with chemically unreactive drugs. This concept implies direct and reversible interactions of the drug between T-cell receptors (TCR) and major histocompatability complex (MHC) molecules. Therefore it was termed pharmacological interactions with immune receptors (p-i concept). Early observations on drug reacting T-cell clones (TCC) let believe that drugs bind first to the T-cell receptor since HLA molecules could be exchanged without affecting the drug reactivity. However, MHC molecules were always required for full activation of TCC. According to its strong HLA-B*5701 association, recent data on abacavir suggest that a drug could first bind to the peptide binding groove of the MHC molecule. The thereby modified HLA molecule can then be recognized by specific T-cells. Consequently, two types of reactions based on the p-i mechanism may occur: on the one hand, drugs might preferentially bind directly to the TCR, whereas in defined cases with strong HLA association, drugs might bind directly to the MHC molecule.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Hypersensitivity / genetics
  • Drug Hypersensitivity / immunology*
  • Genetic Predisposition to Disease
  • Haptens / immunology
  • Humans
  • Hypersensitivity, Delayed / genetics
  • Hypersensitivity, Delayed / immunology*
  • Lymphocyte Activation / immunology*
  • Major Histocompatibility Complex / immunology
  • T-Lymphocytes / immunology*

Substances

  • Haptens