Abacavir Induced T Cell Reactivity from Drug Naïve Individuals Shares Features of Allo-Immune Responses

Abstract

Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele (‘altered self-allele’) and create the potential for robust T cell responses.

Multiple Drug Hypersensitivity

“…This massive, drug-induced proliferation in a 6- to 7-day culture is reminiscent of proliferations observed in mixed leukocyte reactions. This would be consistent with the allo-immune hypothesis of DHR which postulates that severe DHR are due to p-i stimulations resulting in allo-like immune stimulations [32,45]. It hypothesizes that drug binding to HLA modifies the HLA-peptide complex and makes it look like an allo-HLA structure, which then elicits a strong, polyclonal T-cell stimulation.…”

“…These linkages can be explained by an off-target activity of a particular drug to a certain HLA protein [32]. For example, carbamazepine binds with a rather high affinity to HLA-B*15:02, oxypurinol binds to HLA-B*58:01, and abacavir binds to HLA-B*57:01 [28,29,30,31].…”

“…It hypothesizes that drug binding to HLA modifies the HLA-peptide complex and makes it look like an allo-HLA structure, which then elicits a strong, polyclonal T-cell stimulation. This has been documented in the abacavir model, where the peptide-abacavir-HLA-B*57:01 complex acquires the conformation of the {peptide-HLA-B*58:01} complex [32]. If one applies this concept to severe DHR in general, MDH may start with a massive, graft-versus-host disease-like immune stimulation, which in the case of MDH somehow persists for years (elevated PD-1/CD38+ T cells).…”

Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors

“…In addition and/or instead of usual peptides, altered peptides are selected for binding to {abacavir-HLA-B*57:01} [28,29,30]; (ii) moreover, the abacavir binding makes the {abacavir-HLA-B*57:01} complex look like a foreign (allo) HLA-protein. The {abacavir-peptHLA} complex is transported to the cell surface, where it elicits an auto- and predominantly an allo-like immune reaction [40]. The stimulation by an abacavir-induced TCC occurs independently of extracellular or intracellular abacavir loading on HLA-B*57:01.…”

“…The stimulation by an abacavir-induced TCC occurs independently of extracellular or intracellular abacavir loading on HLA-B*57:01. This argues for a poly-specificity of the reactive T cells [35] - not so much the particular peptide but the whole configuration of the {abacavir-peptHLA} complex seems to elicit T cell reactivity [35,40]. …”