![]() ![]() Through this mechanism, abacavir binds specifically to HLA-B*57:01 and alters the peptide-binding groove, which results in the selection of altered self-peptides that bind abacavir–HLA-B*57:01 complexes. Finally, immune reactivity by an altered peptide repertoire was described recently as an alternative mechanism for abacavir hypersensitivity syndrome, which is associated with the HLA-B*57:01 allele ( 11– 13). Consequently, the classic Ag-processing pathway normally required for T cell stimulation of proteins is bypassed. It is a typical “off-target” activity of a drug, whereby the peculiar consequences of the p-i concept are caused by this off-target activity being directed to the immune receptors, leading to immune stimulation. Therefore, the immune receptor, rather than the Ag itself, is modified by a noncovalently bound drug. The second mechanism, known as the “pharmacological interaction with immune receptors” (p-i) concept, suggests that a drug may directly and reversibly bind to TCR and/or HLA protein and not the antigenic peptide ( 9, 10). Therefore, it first must bind covalently to an endogenous protein to form an antigenic hapten-carrier complex, which, after processing to an immunogenic hapten-modified peptide, can elicit a T cell response. The hapten concept postulates that a small chemical compound cannot be immunogenic on its own because of its small size. There are three main concepts to explain how T cells can be stimulated by a drug. Furthermore, the positive-predictive value of HLA-B*58:01 is estimated to be only 2.7%, implying that other risk factors are also important ( 8). Nonetheless, 45% of patients of European ancestry with ALP-induced SJS/TEN did not have HLA-B*58:01, suggesting that this allele is not an absolute risk factor ( 3). Therefore, recent recommendations suggest that HLA-B*58:01 screening should be considered before prescribing ALP to those from high-risk ancestry, such as Han Chinese or Thai ( 6, 7). In all of these populations, the frequency of the HLA-B*58:01 allele is high (6.5–10%) ( 5). All Han Chinese and Thai individuals with ALP-induced SCAR had HLA-B*58:01, and most of the Korean patients also had this allele ( 2, 4, 5). Recent studies ( 2, 3) showed that ALP-induced SCAR is strongly associated with the HLA-B*58:01 allele. Although the overall incidence of SCAR is very low, ALP remains a major cause of SCAR and is the most common cause of SJS/TEN in Europe and Israel ( 1). Rarely, a severe cutaneous adverse reaction (SCAR) to ALP can develop and manifest clinically as Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) or drug rash with eosinophilia and systemic symptoms. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.Īllopurinol (ALP) is a commonly prescribed drug to treat gout a hypersensitivity reaction occurs in ∼2% of patients. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vβ repertoires. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. Although most OXP-specific T cells from HLA-B*58:01 + donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This direct activation occurred regardless of HLA-B*58:01 status. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the “pharmacological interaction with immune receptors” (p-i) concept. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01 + and HLA-B*58:01 − donors and assessed their reactivity. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell–reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. However, it can occur in the absence of this allele with identical clinical manifestations. ![]() Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. ![]()
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