T cell-mediated hypersensitivity reactions to drugs

Abstract

The immunological mechanisms driving delayed hypersensitivity reactions (HSRs) to drugs mediated by drug-reactive T lymphocytes are exemplified by several key examples and their human leukocyte antigen (HLA) associations: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02, allo-purinol and HLA-B*58:01, and both amoxicillin-clavulanate and nevirapine with multiple class I and II alleles. For HLA-restricted drug HSRs, specific class I and/or II HLA alleles are necessary but not sufficient for tissue specificity and the clinical syndrome. Several models have been proposed to explain the immunopathogenesis of severe T cell-mediated drug HSRs, and our increased understanding of the risk factors and mechanisms involved in the development of these reactions will further the development of sensitive and specific strategies for preclinical screening that will lead to safer and more cost-effective drug design.

Keywords: Stevens-Johnson syndrome; altered peptide; human leukocyte antigen; major histocompatibility complex; pharmacogenomics; toxic epidermal necrolysis.

Figure 1

Timeline of class I and II HLA associations with key examples of drug hypersensitivity reactions (HSRs). The discovery of the association of abacavir hypersensitivity and HLA-B^*57:01 was the breakthrough observation that first linked drug hypersensitivity to class I–restricted, T cell–driven mechanisms (7, 8). Since then, associations between class I HLA alleles and severe immunologically mediated drugs reactions have dominated. The early examples of carbamazepine and HLA-B^*15:02 in SJS/TEN (Stevens-Johnson syndrome/toxic epidermal necrolysis) in Asians and allopurinol and HLA-B^*58:01 and SCAR (severe cutaneous adverse reactions) have also provided key insights into HSR pathogenesis (, , –11). In some examples, such as amoxicillin-clavulanate drug-induced liver disease in Northern Europeans, class I/II pairings appear important, whereas others, such as nevirapine hypersensitivity with hepatotoxocity phenotype, appear restricted primarily to class II HLA (, , –18, 31, 32).

Figure 2

(a) Established models of T cell–mediated drug hypersensitivity. (i) In the hapten/prohapten model, drugs form covalent bonds with endogenous proteins/peptides. The drug-modified peptides are then processed by antigen-presenting cells (APC) and presented on the major histocompatibility complex (MHC), resulting in a T cell response. (ii) In the P-I model, the drug in its native form is able to bind directly to immune receptors such as the T cell receptor (TCR) via noncovalent bonds without a peptide. Dashed lines represent noncovalent bonds. (iii) In the altered peptide repertoire model, the drug forms noncovalent bonds within the binding pocket(s) of the MHC to alter the chemistry of the binding cleft and repertoire of self-peptides that can bind to the HLA molecule in question. Some of these newly presented self-peptides have not been previously tolerized, and their presentation results in a T cell response. Adapted from Reference with permission. (b) The heterologous immunity model of drug hypersensitivity. In this model, tissue-specific memory T cells reside at specific sites following a viral infection. These memory T cell subsets may cross-react with (i) drugs binding noncovalently to the TCR and/or the MHC in a P-I manner to activate the T cell directly without the involvement of peptide, (ii) endogenous peptides presented in an “altered peptide repertoire” fashion, (iii) a change to the conformation of the binding pocket with partial peptide binding with or without a direct effect from the drug, or (iv) haptenated endogenous peptides that bind to the TCR. Dashed lines represent noncovalent bonds.

Figure 3

(a) Crystal structure of the abacavir-peptide-MHC complex reveals intermolecular contacts within the antigen-binding cleft of HLA-B^*57:01. Diagram of HLA-B^*57:01 in gray. The synthetic peptide HSITYLLPV is shown in cyan carbons. Abacavir is shown as orange for carbon, blue for nitrogen, and red for oxygen. The residues that distinguish the abacavir-sensitive allele HLAB^* 57:01 from abacavir-insensitive HLA-B^*57:03 are shown in magenta for carbon, blue for nitrogen, and red for oxygen. Abacavir forms hydrogen-bond interactions (black dashes) with both the peptide and HLAB^*57:01 (32). (b) Model of abacavir-peptide-MHC complex interacting with the T cell receptor. HLA-B^*57:01 is depicted in gray. The peptide HSITYLLPV is shown in cyan carbons. Abacavir is shown as spheres: orange for carbon, blue for nitrogen. The T cell receptor is shown in pink.