Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

David A Ostrov; Barry J Grant; Yuri A Pompeu; John Sidney; Mikkel Harndahl; Scott Southwood; Carla Oseroff; Shun Lu; Jean Jakoncic; Cesar Augusto F de Oliveira; Lun Yang; Hu Mei; Leming Shi; Jeffrey Shabanowitz; A Michelle English; Amanda Wriston; Andrew Lucas; Elizabeth Phillips; Simon Mallal; Howard M Grey; Alessandro Sette; Donald F Hunt; Soren Buus; Bjoern Peters

doi:10.1073/pnas.1207934109

Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

David A Ostrov, Barry J Grant, Yuri A Pompeu, John Sidney, Mikkel Harndahl, Scott Southwood, Carla Oseroff, Shun Lu, Jean Jakoncic, Cesar Augusto F de Oliveira, Lun Yang, Hu Mei, Leming Shi, Jeffrey Shabanowitz, A Michelle English, Amanda Wriston, Andrew Lucas, Elizabeth Phillips, Simon Mallal, Howard M GreyAlessandro Sette, Donald F Hunt, Soren Buus, Bjoern Peters

LUKKET: Institut for Immunologi og Mikrobiologi

267 Citationer (Scopus)

Abstract

Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of the United States of America
Vol/bind	109
Udgave nummer	25
Sider (fra-til)	9959-9964
Antal sider	6
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1207934109
Status	Udgivet - 19 jun. 2012

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10.1073/pnas.1207934109

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Ostrov, D. A., Grant, B. J., Pompeu, Y. A., Sidney, J., Harndahl, M., Southwood, S., Oseroff, C., Lu, S., Jakoncic, J., de Oliveira, C. A. F., Yang, L., Mei, H., Shi, L., Shabanowitz, J., English, A. M., Wriston, A., Lucas, A., Phillips, E., Mallal, S., ... Peters, B. (2012). Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proceedings of the National Academy of the United States of America, 109(25), 9959-9964. https://doi.org/10.1073/pnas.1207934109

Ostrov, DA, Grant, BJ, Pompeu, YA, Sidney, J, Harndahl, M, Southwood, S, Oseroff, C, Lu, S, Jakoncic, J, de Oliveira, CAF, Yang, L, Mei, H, Shi, L, Shabanowitz, J, English, AM, Wriston, A, Lucas, A, Phillips, E, Mallal, S, Grey, HM, Sette, A, Hunt, DF, Buus, S & Peters, B 2012, 'Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire', Proceedings of the National Academy of the United States of America, bind 109, nr. 25, s. 9959-9964. https://doi.org/10.1073/pnas.1207934109

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abstract = "Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.",

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doi = "10.1073/pnas.1207934109",

language = "English",

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pages = "9959--9964",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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T1 - Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

AU - Ostrov, David A

AU - Grant, Barry J

AU - Pompeu, Yuri A

AU - Sidney, John

AU - Harndahl, Mikkel

AU - Southwood, Scott

AU - Oseroff, Carla

AU - Lu, Shun

AU - Jakoncic, Jean

AU - de Oliveira, Cesar Augusto F

AU - Yang, Lun

AU - Mei, Hu

AU - Shi, Leming

AU - Shabanowitz, Jeffrey

AU - English, A Michelle

AU - Wriston, Amanda

AU - Lucas, Andrew

AU - Phillips, Elizabeth

AU - Mallal, Simon

AU - Grey, Howard M

AU - Sette, Alessandro

AU - Hunt, Donald F

AU - Buus, Soren

AU - Peters, Bjoern

PY - 2012/6/19

Y1 - 2012/6/19

N2 - Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.

AB - Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.

KW - Amino Acid Sequence

KW - Crystallography, X-Ray

KW - Drug Hypersensitivity

KW - Enzyme-Linked Immunosorbent Assay

KW - Major Histocompatibility Complex

KW - Models, Molecular

KW - Peptides

U2 - 10.1073/pnas.1207934109

DO - 10.1073/pnas.1207934109

M3 - Journal article

C2 - 22645359

SN - 0027-8424

VL - 109

SP - 9959

EP - 9964

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 25

ER -

Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

Abstract

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