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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 ELISpot responses.A. Mean abacavir ELISpot responses for HLA B*57:01 positive or negative individuals, that were either abacavir naïve or treatment experienced. B Abacavir ELISpot responses in patch test confirmed abacavir HSR patients plotted relative to time from first exposure to abacavir (25-562 SFU/106 PBMC, n = 12). Positivity of abacavir ELISpot responses was defined using a cut-off response of ≥ 10 SFU/106 PBMC above background, and differences in proportions of positive responses were assessed using a Fishers exact test.
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pone.0117160.g002: Abacavir ELISpot responses.A. Mean abacavir ELISpot responses for HLA B*57:01 positive or negative individuals, that were either abacavir naïve or treatment experienced. B Abacavir ELISpot responses in patch test confirmed abacavir HSR patients plotted relative to time from first exposure to abacavir (25-562 SFU/106 PBMC, n = 12). Positivity of abacavir ELISpot responses was defined using a cut-off response of ≥ 10 SFU/106 PBMC above background, and differences in proportions of positive responses were assessed using a Fishers exact test.

Mentions: Non-covalent binding of abacavir to HLA-B*57:01 results in the presentation of self-peptides that would not otherwise be presented [12,13] suggesting that drug associated neo-antigen exposure should have rapid onset and offset. Supporting this, symptoms of acute abacavir HSR correlate with plasma level and disappear within 24–48 hours of drug withdrawal. To assess whether this transient exposure to abacavir leads to establishment of long-term memory, we measured overnight IFN-γ ELISpot assay responses of 12 patients with patch test confirmed abacavir HSR (Part A in S2 Table). We compared these responses to those from HLA-B*57:01 positive abacavir naive patients, HLA-B*57:01 negative tolerant or abacavir naïve patients (Parts B & C in S2 Table). The HLA-B*57:01 positive abacavir HSR patients show significantly higher responses when compared to each control group (Fig. 2A). In particular 12/12 elicited positive responses in contrast to the controls (0/3 HLA-B*57:01 positive drug naïve controls, p = 0.002; 1/15 HLA-B*57:01 negative abacavir tolerant control, p<0.0001; 0/9 HLA-B*57:01 negative drug naïve controls, p<0.0001; Fisher exact test). Moreover, the magnitude of ELISpot responses measured at multiple time-points in the same individual indicates the maintenance of a durable CD8+ T-cell response (Fig. 2B).


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 ELISpot responses.A. Mean abacavir ELISpot responses for HLA B*57:01 positive or negative individuals, that were either abacavir naïve or treatment experienced. B Abacavir ELISpot responses in patch test confirmed abacavir HSR patients plotted relative to time from first exposure to abacavir (25-562 SFU/106 PBMC, n = 12). Positivity of abacavir ELISpot responses was defined using a cut-off response of ≥ 10 SFU/106 PBMC above background, and differences in proportions of positive responses were assessed using a Fishers exact test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0117160.g002: Abacavir ELISpot responses.A. Mean abacavir ELISpot responses for HLA B*57:01 positive or negative individuals, that were either abacavir naïve or treatment experienced. B Abacavir ELISpot responses in patch test confirmed abacavir HSR patients plotted relative to time from first exposure to abacavir (25-562 SFU/106 PBMC, n = 12). Positivity of abacavir ELISpot responses was defined using a cut-off response of ≥ 10 SFU/106 PBMC above background, and differences in proportions of positive responses were assessed using a Fishers exact test.
Mentions: Non-covalent binding of abacavir to HLA-B*57:01 results in the presentation of self-peptides that would not otherwise be presented [12,13] suggesting that drug associated neo-antigen exposure should have rapid onset and offset. Supporting this, symptoms of acute abacavir HSR correlate with plasma level and disappear within 24–48 hours of drug withdrawal. To assess whether this transient exposure to abacavir leads to establishment of long-term memory, we measured overnight IFN-γ ELISpot assay responses of 12 patients with patch test confirmed abacavir HSR (Part A in S2 Table). We compared these responses to those from HLA-B*57:01 positive abacavir naive patients, HLA-B*57:01 negative tolerant or abacavir naïve patients (Parts B & C in S2 Table). The HLA-B*57:01 positive abacavir HSR patients show significantly higher responses when compared to each control group (Fig. 2A). In particular 12/12 elicited positive responses in contrast to the controls (0/3 HLA-B*57:01 positive drug naïve controls, p = 0.002; 1/15 HLA-B*57:01 negative abacavir tolerant control, p<0.0001; 0/9 HLA-B*57:01 negative drug naïve controls, p<0.0001; Fisher exact test). Moreover, the magnitude of ELISpot responses measured at multiple time-points in the same individual indicates the maintenance of a durable CD8+ T-cell response (Fig. 2B).

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