Immuno-dermatology

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Characterization of Immune Responses in Nevirapine-induced Stevens-johnson Syndrome/toxic Epidermal Necrolysis

Wednesday, June 14
6:15 PM - 7:45 PM

Nevirapine is used globally in the combination treatment of HIV. Its current use in first-line therapy is limited by immune-mediated adverse drug reactions (IM-ADRs) that significantly impact patient outcome and healthcare cost. Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN) is the severest nevirapine-induced IM-ADR. SJS/TEN is a HLA class I restricted, CD8+ T-cell dependent hypersensitivity syndrome, which presents as a severe blistering skin rash that can result in extensive epidermal necrosis. We have recently identified HLA-C*04:01 as a significant class I risk allele in South African HIV+ patients with nevirapine SJS/TEN. The feasibility of preventive HLA screening for nevirapine is hampered by the fact that only a small percentage of those carrying a risk allele develop an IM-ADR. To understand why hypersensitivity occurs in only a small proportion of those carrying an HLA-risk allele, we have immunophenotyped the nevirapine-specific pathogenic CD8+ T cells based on their cytokine outputs, cell surface and activation markers (CD137+/CD69+) using ELISpot assays, intracellular cytokine staining and flow cytometry following ex-vivo stimulation with nevirapine. To identify the TCR specificities of the T-cell repertoire in patients with HLA-C*04:01+ nevirapine SJS/TEN, single cell TCR sequencing for paired TCR alpha and beta genes and phenotypic markers will be performed to compare T cell populations in the presence and absence of drug. Candidate TCRs will be confirmed with a Jurkat TCR reporter assay. It is expected that these approaches will lead to a sensitive predictive assay to identify the dominant cross-reactive TCRs in HLA-C*04:01+ patients who are destined to develop nevirapine SJS/TEN.

Katherine C. Konvinse

MD/PhD Student
Vanderbilt University School of Medicine

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    Katie D. White

    Vanderbilt University Medical Center

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      Rebecca Pavlos

      The Institute for Immunology & Infectious Diseases, Murdoch University

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        Alec Redwood

        The Institute for Immunology & Infectious Diseases, Murdoch University

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          Simon Mallal

          Vanderbilt University Medical Center

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            Elizabeth J. Phillips

            Vanderbilt University Medical Center

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