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

The MHC, disease and selection

“…Others include HLA-B*15:02 and Stevens-Johnson syndrome, induced by carbamazepine in Han Chinese [60]. The favoured hypothesis to account for these reactions invokes covalent modification of a protein such that a haptenated peptide is presented on an HLA molecule to CD8 T cells [61].…”

Human leukocyte antigen (HLA) and pharmacogenetics: screening for HLA-B*57:01 among human immunodeficiency virus–positive patients from southern Alberta

“…Direct and indirect HLA-involved mechanisms are suggested to be behind this strong association. Recently, we and others have demonstrated that in the case of abacavir hypersensitivity, drug presentation is major histocompatibility complex class I (more specifically, HLA-B*57:01) restricted, and there is a clonal expansion of CD8 cytotoxic T cells that induces a multifunctional response [15,16]. These studies clearly suggest the direct functional involvement of HLA molecules in the pathogenesis of the ADR.…”

“…However, this result is highly unlikely because all subsequent association reports [19] and functional studies from our laboratory and other research groups indicated that systemic reactions to abacavir are cytotoxic CD8 T cell mediated and are uniquely restricted to antigen recognition by HLA-B*57:01 [15,16]. Chessman et al, however, have demonstrated that recognition of abacavir requires other factors such as transporter associated with antigen presentation and tapasin [15]. It is possible that diminished function of any of these other factors may abrogate AHS in HLA-B*57:01 ϩ individuals.…”

“…Many virus-specific T cells have exhibited cross-reactivity with both of these major histocompatibility complexes [22]. However, Chessman et al have demonstrated that abacavir-specific CD8 T cells raised in vitro from an HLA-B*57:01 ϩ donor, when restimulated with human lymphoblastoid cell lines expressing HLA-B*58:01 in the presence and absence of abacavir, did not exhibit an abacavir-specific response from CD8 T cells [15].…”

Chemical-protein interactome and its application in off-target identification

“…A docking score matrix comprising 162 drug molecules across 845 proteins was constructed, and the patient-specific offtargets of abacavir-induced hypersensitivity was mined, which was supported by a third party in vitro assay (Chessman et al, 2008). A similar strategy was applied to identify off-targets of anti-Alzheimer drugs (Yang et al, 2010a) using a 401 human protein set.…”