ORCID Profile
0000-0002-6438-9225
Current Organisation
Murdoch University
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Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1111/AJT.15470
Abstract: Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ in iduals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ in iduals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-γ production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed.
Publisher: Research Square Platform LLC
Date: 20-05-2022
DOI: 10.21203/RS.3.RS-1613398/V1
Abstract: Immune checkpoint therapy (ICT) causes durable tumor responses in a subgroup of patients. Profiling T cell receptor beta (TCRβ) repertoire structure in ICT responders and non-responders provides mechanistic insight into what constitutes an effective anti-tumor response, and could result in the development of predictive biomarkers of response to identify and stratify patients for ICT. To examine how the TCRβ repertoire dynamics contribute to ICT response, we utilized an established murine model that excludes variation in host genetics, environmental factors and tumor mutation burden, limiting variation between animals to naturally erse TCRβ repertoires. Oligoclonal expansion of TCRβ clonotypes that corresponded with a low TCRβ ersity was observed in responding tumors prior to ICT. We modeled TCRβ cluster dynamics during ICT and found that select clonotypes expanded slower in responders compared to non- responders. Clonally expanded CD8+ tumor infiltrating T cells in non-responders exhibited a T cell exhaustion phenotype. We conclude that an early burst of clonal expansion followed by a contraction during ICT is associated with response.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2022
DOI: 10.1038/S42003-022-03058-9
Abstract: Pre-existing pathogen-specific memory T cell responses can contribute to multiple adverse outcomes including autoimmunity and drug hypersensitivity. How the specificity of the T cell receptor (TCR) is subverted or seconded in many of these diseases remains unclear. Here, we apply abacavir hypersensitivity (AHS) as a model to address this question because the disease is linked to memory T cell responses and the HLA risk allele, HLA-B*57:01, and the initiating insult, abacavir, are known. To investigate the role of pathogen-specific TCR specificity in mediating AHS we performed a genome-wide screen for HLA-B*57:01 restricted T cell responses to Epstein-Barr virus (EBV), one of the most prevalent human pathogens. T cell epitope mapping revealed HLA-B*57:01 restricted responses to 17 EBV open reading frames and identified an epitope encoded by EBNA3C. Using these data, we cloned the dominant TCR for EBNA3C and a previously defined epitope within EBNA3B. TCR specificity to each epitope was confirmed, however, cloned TCRs did not cross-react with abacavir plus self-peptide. Nevertheless, abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule. These results provide an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mark Watson.