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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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Days to onset of hypersensitivity symptoms in patch test confirmed cases of abacavir HSR (range <2–19 days, median 8 days; n = 23).
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pone.0117160.g001: Days to onset of hypersensitivity symptoms in patch test confirmed cases of abacavir HSR (range <2–19 days, median 8 days; n = 23).

Mentions: Abacavir patch testing is a specific and highly sensitive research tool used to identify HLA-B*57:01 positive patients who have experienced immunologically-mediated abacavir HSR [3,11,22]. This test was utilized in the randomized, controlled and double-blinded PREDICT-1 study where none of the 1956 individuals enrolled had symptoms of hypersensitivity and became patch test positive in the arm that underwent real-time HLA-B*57:01 screening. In the unscreened arm of the study there were 23 subjects with a clinical diagnosis of abacavir HSR who became patch test positive and all 23 carried HLA-B*57:01. Here we show further that these patch test positive patients all had onset of symptoms within 19 days, with 26% having onset within 36 hours to five days following first drug exposure (Fig. 1, S1 Table). Abacavir HSR symptom onset as early as 36 hours following first exposure suggests that cross-reactive memory CD8+ T-cell responses are responsible at least in some individuals. The study had a double-blind design and an independent expert panel adjudicated the patch test photographs to eliminate the possibility of bias.


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)

Days to onset of hypersensitivity symptoms in patch test confirmed cases of abacavir HSR (range <2–19 days, median 8 days; n = 23).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0117160.g001: Days to onset of hypersensitivity symptoms in patch test confirmed cases of abacavir HSR (range <2–19 days, median 8 days; n = 23).
Mentions: Abacavir patch testing is a specific and highly sensitive research tool used to identify HLA-B*57:01 positive patients who have experienced immunologically-mediated abacavir HSR [3,11,22]. This test was utilized in the randomized, controlled and double-blinded PREDICT-1 study where none of the 1956 individuals enrolled had symptoms of hypersensitivity and became patch test positive in the arm that underwent real-time HLA-B*57:01 screening. In the unscreened arm of the study there were 23 subjects with a clinical diagnosis of abacavir HSR who became patch test positive and all 23 carried HLA-B*57:01. Here we show further that these patch test positive patients all had onset of symptoms within 19 days, with 26% having onset within 36 hours to five days following first drug exposure (Fig. 1, S1 Table). Abacavir HSR symptom onset as early as 36 hours following first exposure suggests that cross-reactive memory CD8+ T-cell responses are responsible at least in some individuals. The study had a double-blind design and an independent expert panel adjudicated the patch test photographs to eliminate the possibility of bias.

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