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Abacavir-reactive memory T cells are present in drug naïve individuals.

Lucas A, Lucas M, Strhyn A, Keane NM, McKinnon E, Pavlos R, Moran EM, Meyer-Pannwitt V, Gaudieri S, D'Orsogna L, Kalams S, Ostrov DA, Buus S, Peters B, Mallal S, Phillips E - PLoS ONE (2015)

Bottom Line: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug.Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors.Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.

ABSTRACT

Background: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.

Methods: To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.

Results: Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

Conclusions: We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

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Abacavir responsive CD8+ T cells can be expanded from unsorted, memory and naïve phenotype T cells from abacavir-unexposed HLA-B*57:01 positive donors.CD8+/IFN-γ frequencies are compared across T-cell populations which had been cultured ± abacavir, and then re-stimulated with APCs treated with abacavir (yes) or untreated (no), respectively. A: CD8+/IFN-γ frequencies in unsorted PBMC from HLA-B*57:01 negative (n = 3) and positive donors (n = 8). CD8+/IFN-γ frequencies in HLA-B*57:01 positive donors according to memory and naïve phenotype in B: sorted CD4+ and CD8+ T cells (n = 8) and C: sorted CD8+ T cells only (4 samples, n = 3 donors). Each donor is represented by the same symbol in the different figures; group median CD8+ /IFN-γ+ T-cell frequencies are indicated by a horizontal line. Pairwise differences in observed frequencies according to abacavir stimulation are assessed by a donor-stratified Wilcoxon test.
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pone.0117160.g005: Abacavir responsive CD8+ T cells can be expanded from unsorted, memory and naïve phenotype T cells from abacavir-unexposed HLA-B*57:01 positive donors.CD8+/IFN-γ frequencies are compared across T-cell populations which had been cultured ± abacavir, and then re-stimulated with APCs treated with abacavir (yes) or untreated (no), respectively. A: CD8+/IFN-γ frequencies in unsorted PBMC from HLA-B*57:01 negative (n = 3) and positive donors (n = 8). CD8+/IFN-γ frequencies in HLA-B*57:01 positive donors according to memory and naïve phenotype in B: sorted CD4+ and CD8+ T cells (n = 8) and C: sorted CD8+ T cells only (4 samples, n = 3 donors). Each donor is represented by the same symbol in the different figures; group median CD8+ /IFN-γ+ T-cell frequencies are indicated by a horizontal line. Pairwise differences in observed frequencies according to abacavir stimulation are assessed by a donor-stratified Wilcoxon test.

Mentions: Short-term abacavir responsive T-cell lines were generated from all eight unsorted PBMC samples tested. Similar to previous reports [2,23], we could detect abacavir reactive CD8+/IFN-γ+ T-cells in 100% of eight HLA-B*57:01 positive donors (2.21% [1.26–3.12] versus 0.35% [0.23–0.69]; median [IQR] p = 0.005; Fig. 5A) and in 0% of three HLA-B*57:01 negative donors (0.16% [0.08–0.23] versus 0.10 [0.05–0.11]; median [IQR], not significant.


Abacavir-reactive memory T cells are present in drug naïve individuals.

Lucas A, Lucas M, Strhyn A, Keane NM, McKinnon E, Pavlos R, Moran EM, Meyer-Pannwitt V, Gaudieri S, D'Orsogna L, Kalams S, Ostrov DA, Buus S, Peters B, Mallal S, Phillips E - PLoS ONE (2015)

Abacavir responsive CD8+ T cells can be expanded from unsorted, memory and naïve phenotype T cells from abacavir-unexposed HLA-B*57:01 positive donors.CD8+/IFN-γ frequencies are compared across T-cell populations which had been cultured ± abacavir, and then re-stimulated with APCs treated with abacavir (yes) or untreated (no), respectively. A: CD8+/IFN-γ frequencies in unsorted PBMC from HLA-B*57:01 negative (n = 3) and positive donors (n = 8). CD8+/IFN-γ frequencies in HLA-B*57:01 positive donors according to memory and naïve phenotype in B: sorted CD4+ and CD8+ T cells (n = 8) and C: sorted CD8+ T cells only (4 samples, n = 3 donors). Each donor is represented by the same symbol in the different figures; group median CD8+ /IFN-γ+ T-cell frequencies are indicated by a horizontal line. Pairwise differences in observed frequencies according to abacavir stimulation are assessed by a donor-stratified Wilcoxon test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4326126&req=5

pone.0117160.g005: Abacavir responsive CD8+ T cells can be expanded from unsorted, memory and naïve phenotype T cells from abacavir-unexposed HLA-B*57:01 positive donors.CD8+/IFN-γ frequencies are compared across T-cell populations which had been cultured ± abacavir, and then re-stimulated with APCs treated with abacavir (yes) or untreated (no), respectively. A: CD8+/IFN-γ frequencies in unsorted PBMC from HLA-B*57:01 negative (n = 3) and positive donors (n = 8). CD8+/IFN-γ frequencies in HLA-B*57:01 positive donors according to memory and naïve phenotype in B: sorted CD4+ and CD8+ T cells (n = 8) and C: sorted CD8+ T cells only (4 samples, n = 3 donors). Each donor is represented by the same symbol in the different figures; group median CD8+ /IFN-γ+ T-cell frequencies are indicated by a horizontal line. Pairwise differences in observed frequencies according to abacavir stimulation are assessed by a donor-stratified Wilcoxon test.
Mentions: Short-term abacavir responsive T-cell lines were generated from all eight unsorted PBMC samples tested. Similar to previous reports [2,23], we could detect abacavir reactive CD8+/IFN-γ+ T-cells in 100% of eight HLA-B*57:01 positive donors (2.21% [1.26–3.12] versus 0.35% [0.23–0.69]; median [IQR] p = 0.005; Fig. 5A) and in 0% of three HLA-B*57:01 negative donors (0.16% [0.08–0.23] versus 0.10 [0.05–0.11]; median [IQR], not significant.

Bottom Line: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug.Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors.Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.

ABSTRACT

Background: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.

Methods: To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.

Results: Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

Conclusions: We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

Show MeSH
Related in: MedlinePlus