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OR20 THE MECHANISTIC DIFFERENCES IN HLA-ASSOCIATED DRUG HYPERSENSITIVITY. HeikeKunze-Schumacher, Huyton Trevor, Rainer Blasczyk, Christina Bade-Doeding. Hannover Medical School,Hannover, Germany.

Severe drug hypersensitivity reactions that resemble acute GvHD are linked to certain specific HLA alleles.The most common hypersensitivity reactions occur after the treatment of HLA-B⁄57:01+ HIV patients withAbacavir and HLA-A⁄31:01+ or B⁄15:02+ epileptic patients with Carbamazepine. In these instances the drugmolecule is able to occupy part of the HLA molecules peptide binding groove and modify the selected peptiderepertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal ofmedication.

HLA-A⁄31:01 and B⁄15:02 are significantly different within their respective peptide binding groovestherefore understanding the mechanistic differences in the interaction between Carbamazepine or its metab-olites and these alleles is critical in developing effective and safe medications.

The mode of peptide loading for A⁄31:01 and B⁄15:02 was first evaluated by analyzing their interactionwith the peptide loading complex. Our result show that while A⁄31:01 is able to bypass the conventional pep-tide loading pathway B⁄15:02 is not. Soluble HLA molecules were then expressed in LCL721.221 cells(A⁄31:01 and B⁄15:02) or LCL 721.220 (A⁄31:01) cells and their bound peptides sequenced by massspectrometry.

In the absence of the chaperone tapasin, that helps in the exchange of low affinity for high affinity pep-tides, a complete different set of peptides with different binding affinities could be obtained from A⁄31:01.Interestingly, all the peptides isolated were highly specific at their C-terminal anchor but demonstrated a highpromiscuity in their N-terminal AAs. For B⁄15:02, that can only aquire peptides in the presence of the chap-erone tapasin, all peptides were found to be of high affinity and showed distinct features and anchors.

The evaluation of the HLA-A⁄31:01 and B⁄15:02 specific self-peptidome is the first step towards under-standing their association to drug hypersensitivity.

Abstracts / Human Immunology 75 (2014) 1–49 17