Human Leukocyte Antigen Class I-Restricted Activation of CD8+ T Cells Provides the Immunogenetic Basis of a Systemic Drug Hypersensitivity

Abstract

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.

Human Leukocyte Antigen (HLA)-B*57:01-Restricted Activation of Drug-Specific T cells Provides the Immunological Basis for Flucloxacillin-Induced Liver Injury

“…Flucloxacillin-responsive CD8þ clones expressing a range of different Vb receptors were successfully isolated from the four HLA-B*57:01 ELIspot-positive patients. Contrary to the findings of Chessman et al, 6 showing that abacavir-activated T cells were exclusively CD8þ, we were also successful in isolating flucloxacillin-responsive CD4þ clones, albeit in low numbers. Activation of clones with flucloxacillin was concentration-dependent and provoked the secretion of IFN-c and cytolytic molecules (granzyme B, FasL, and perforin).…”

“…17 Importantly, abacavir-specific T-cell responses are not detectable using antigen-presenting cells expressing HLA-B*58:01. 6 Flucloxacillin-responsive clones were stimulated to proliferate with flucloxacillin-pulsed autologous antigen-presenting cells and antigen-presenting cells from the three donors expressing HLA-B*57:01. Furthermore, several clones were stimulated by flucloxacillin-derived antigens presented on antigen-presenting cells expressing HLA-B*58:01.…”

“…Importantly, HLA-B*57:01 and B*58:01 are part of the same HLA-B17 serotype; they differ in structure by only five amino acids and have a significant overlap in their antigenic peptide repertoire. 6 Given that the HLA-B*57:01 allele is in the strongest linkage disequilibrium with DRB1*07:01 in worldwide populations, 24 it is not surprising that all patients positive for B*57:01 were also carriers of DRB1*07:01. We are actively pursuing whether flucloxacillin-responsive CD4þ T cells are DRB1*07:01-restricted.…”

“…Dose ranges have been shown to be optimal for the activation of T cells. 6,[13][14][15] Cell phenotyping was performed by flow cytometry on a BD FACSCanto II using CD4, CD8, CDR1, CCR2, CCR3, CCR4, CCR5, CCR8, CCR9, CCR10, CXCR3, CXCR6, and CLA antibodies (BD Biosciences) and the IOtest Beta Mark TCR Vb repertoire kit.…”

“…For abacavir and carbamazepine, it has been possible to relate the genetic association to the mechanism of disease by characterizing drug-specific CD8þ T-cell responses in volunteers expressing HLA-B*57:01 and B*15:02, respectively. 6,7 The role of T cells in drug reactions targeting the liver is less well defined. In 1997, Maria and Victorino 8 described lymphocyte proliferative responses to drugs in over 50% of patients with drug-induced liver injury (DILI).…”