Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko

Disclosures

Personalized Medicine. 2010;7(5):495-516. 

In This Article

Mechanistic Models for T-cell-mediated Hypersensitivity

The activation of drug-specific T cells requires the generation of MHC–peptide complexes that are recognized as nonself or 'altered-self'. Two main pathways have been proposed for the generation of immunogenic MHC–peptide complexes in drug hypersensitivity and appear to be utilized by different drugs.[22] The first is the hapten/prohapten concept and involves the covalent binding of the drug (considered the hapten), or a metabolite thereof (the drug is considered a prohapten), to a cellular peptide or protein leading to MHC presentation of haptenated self peptides.[22,105] Alternatively, haptenation of the complete MHC–peptide complex can occur. The hapten/prohapten concept is seen in DTH to drugs such as sulfamethoxazole, a prohapten, which must first be metabolized to nitroso-sulfamethoxazole and penicillins.[2,92,106,107]

The second mechanism of T-cell activation involves a noncovalent interaction of the drug with the MHC–peptide complex and TCR in a labile fashion. This mechanism has been coined the 'p-i concept' standing for the 'direct pharmacological interaction of drugs with immune receptors'.[108] Activation of T cells in this manner is independent of antigen processing and contingent on maintained drug presence owing to the labile nature of the interaction. Examples of drugs that elicit T-cell responses in this fashion are sulfamethoxazole, in its nonreactive form, and lidocaine.[109,110]

It is our hypothesis that the associations reviewed here are the result of drug presentation being specific to the associated HLA alleles due to the unique structure of their peptide-binding grooves. This unique structure enables the binding of a haptenated peptide, the drug or a metabolite thereof, which is not supported by other alleles.

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