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The immunopathogenesis of drug hypersensitivity

Rive, Craig (2016) The immunopathogenesis of drug hypersensitivity. PhD thesis, Murdoch University.

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Abstract

Introduction: Immunologically mediated-adverse drug reactions threaten the viability of drugs and the health of patients (1, 2). The mechanistic basis for abacavir hypersensitivity is understood and preventable through HLA-B*57:01 screening. The immunopathogenesis of most immunologically mediated-adverse drug reaction remain unsolved, representing an opportunity to improve drug safety.

Methods: Using a repository of clinically phenotyped and HLA typed human Donors and Controls, this work aimed to shed light on the immunopathogenesis of nevirapine and carbamazepine severe cutaneous adverse reactions. Cellular and molecular, techniques were employed including ex-vivo/in-vitro immunophenotyping, detection, stimulation and expansion of drug-specific responses, and characterisation of the specific T-cell receptor using droplet digital PCR. Virtual and Bioinformatics approaches were used to define potential interactions between nevirapine and class-I HLA

Results and discussion: In carbamazepine associated Steven-Johnson’s Syndrome / toxic epidermal necrolysis, increased expression of granulysin was seen ex-vivo in CD8+ T cells exposed to carbamazepine. To explore the hypothesis that this is related to a cross-reactive memory cytotoxic T-cell response, we examined responses to human simplex virus 1 / 2 responses in HLA-B*15:02 carbamazepine associated Steven-Johnson’s Syndrome / toxic epidermal necrolysis patients and identified a shared epitope. Common T-cell receptor clonotypes were identified using droplet digital PCR in HLA-B*15:02 carbamazepine associated Steven-Johnson’s Syndrome / toxic epidermal necrolysis patients. Nevirapine severe cutaneous adverse reactions are associated with multiple class-I HLA alleles across differing ethnicities. The hypothesis that this relates to shared peptide-binding specificities between these alleles was confirmed using bioinformatics, statistical, and virtual approaches. This showed the strongest association across European, Asian and African-American ethnicities to be with two HLA class C alleles HLA-C*04:01 and C*05:01 defined by a unique F-binding pocket.

Conclusion: Continuing work should build on the results presented and the unique techniques used, to further understand the underlying immunopathogenesis and the mechanistic basis for these adverse reactions, leading to the development of screening strategies to improve drug and patient safety.

Publication Type: Thesis (PhD)
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Supervisor: Phillips, Elizabeth and Chopra, Abha
URI: http://researchrepository.murdoch.edu.au/id/eprint/34536
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