A transgenic mouse model for HLA-B*57: 01-linked abacavir drug tolerance and reactivity

被引:52
作者
Cardone, Marco [1 ]
Garcia, Karla [1 ]
Tilahun, Mulualem E. [2 ,4 ]
Boyd, Lisa F. [2 ]
Gebreyohannes, Sintayehu [1 ]
Yano, Masahide [1 ]
Roderiquez, Gregory [1 ]
Akue, Adovi D. [3 ]
Juengst, Leslie [1 ]
Mattson, Elliot [1 ]
Ananthula, Suryatheja [1 ]
Natarajan, Kannan [2 ]
Puig, Montserrat [1 ]
Margulies, David H. [2 ]
Norcross, Michael A. [1 ]
机构
[1] US FDA, Lab Immunol, DBRR 3, OBP,OPQ,CDER, Silver Spring, MD 20993 USA
[2] NIAID, Lab Immune Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA
[3] US FDA, DBPAP, OVRR, CBER, Silver Spring, MD 20993 USA
[4] NIH, Off AIDS Res, DPCPSI, OD, Bldg 10, Bethesda, MD 20892 USA
关键词
REGULATORY T-CELLS; HYPERSENSITIVITY REACTIONS; IMMUNE-RESPONSES; DENDRITIC CELLS; LIVER-INJURY; ACTIVATION; SELF; CD4(+); DEATH; MOLECULES;
D O I
10.1172/JCI99321
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01' patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8(+) T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8(+) T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4(+) T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8(+) T cells with an effector-like and skin-homing phenotype along with CD8(+) T infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8(+) T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8(+) T cells dependent on both HLA genetic risk and immunoregulatory host factors.
引用
收藏
页码:2819 / 2832
页数:14
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