PMID- 37030592 OWN - NLM STAT- MEDLINE DCOM- 20230807 LR - 20230928 IS - 1097-6825 (Electronic) IS - 0091-6749 (Print) IS - 0091-6749 (Linking) VI - 152 IP - 2 DP - 2023 Aug TI - Development of mouse models with restricted HLA-B *57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury. PG - 486-499.e7 LID - S0091-6749(23)00429-3 [pii] LID - 10.1016/j.jaci.2023.03.029 [doi] AB - BACKGROUND: Flucloxacillin (FLX)-induced liver injury is immune-mediated and highly associated to HLA-B *57:01 expression. Host factors leading to drug-induced liver injury are not yet well understood. OBJECTIVE: Characterize in vivo immune mechanisms determining the development of CD8(+) T cells reactive to FLX in animals expressing the risk human leukocyte antigen (HLA) allotype. METHODS: HLA-B *57:01 transgenic mice (Tg) or Tg strains with H2-K(b)D(b) knockout (Tg/KO) or H2-K(b)D(b)/PD-1 double knockout (Tg/DKO) were treated with drug and/or anti-CD4 antibody. Drug-induced liver injury was evaluated on the basis of liver enzyme and histologic changes at day 10 of treatment. FLX-reactive CD8(+) T cells were characterized in vitro by release of effector molecules on drug restimulation, gene expression, and flow cytometry analysis, and functionality tested for hepatic cytotoxicity. RESULTS: CD8(+) T-cell responses to FLX in Tg were dependent on both HLA and mouse major histocompatibility complex I presentation and in vivo priming. Eliminating H2-K(b)D(b) in Tg/KO to allow exclusive presentation of FLX by HLA resulted in a less robust drug-specific CD8(+)T-cell response unless CD4(+) cells, including regulatory T cells, were depleted. Treatment of Tg/KO with anti-CD4 antibody and FLX led to subclinical liver inflammation associated with an increase in PD1(+)CD8(+) T cells in the lymphoid organs and liver. Impaired PD-1 expression in Tg/DKO led to liver histopathologic and transcriptional alterations but without hepatic enzyme elevations. Moreover, effector lymphocytes accumulated in the liver and showed FLX-dependent hepatic cytotoxicity in vitro when tolerogenic liver cells were depleted. CONCLUSIONS: In our in vivo models, FLX primes CD8(+) T cells to recognize drug presented by HLA-B *57:01 and murine major histocompatibility complex I. HLA-B *57:01-dependent CD8(+) T-cell reaction to FLX is limited by the presence of CD4(+) cells, presumably regulatory T cells, and PD-1 expression. Tolerogenic hepatic cells limit clinical disease through PD-L1 or additional unexplored mechanisms. CI - Published by Elsevier Inc. FAU - Ananthula, Suryatheja AU - Ananthula S AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Krishnaveni Sivakumar, Kirthiram AU - Krishnaveni Sivakumar K AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Cardone, Marco AU - Cardone M AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Su, Shan AU - Su S AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Roderiquez, Gregory AU - Roderiquez G AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Abuzeineh, Hanan AU - Abuzeineh H AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Kleiner, David E AU - Kleiner DE AD - Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Md. FAU - Norcross, Michael A AU - Norcross MA AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. FAU - Puig, Montserrat AU - Puig M AD - Laboratory of Immunology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Md. Electronic address: Montserrat.puig@fda.hhs.gov. LA - eng GR - FD999999/ImFDA/Intramural FDA HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Research Support, U.S. Gov't, P.H.S. DEP - 20230407 PL - United States TA - J Allergy Clin Immunol JT - The Journal of allergy and clinical immunology JID - 1275002 RN - 0 (HLA-B57 antigen) RN - 43B2M34G2V (Floxacillin) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (HLA Antigens) SB - IM MH - Mice MH - Humans MH - Animals MH - *CD8-Positive T-Lymphocytes MH - Floxacillin/adverse effects/metabolism MH - Programmed Cell Death 1 Receptor/genetics/metabolism MH - Histocompatibility Antigens Class I MH - Mice, Transgenic MH - HLA Antigens/genetics MH - Disease Models, Animal MH - *Chemical and Drug Induced Liver Injury/genetics/metabolism PMC - PMC10524621 MID - NIHMS1898899 OTO - NOTNLM OT - Flucloxacillin OT - HLA-B *57:01 transgenic mice OT - drug-induced liver injury OT - tolerance COIS- Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. EDAT- 2023/04/09 06:00 MHDA- 2023/08/07 06:41 PMCR- 2023/09/27 CRDT- 2023/04/08 19:30 PHST- 2022/11/04 00:00 [received] PHST- 2023/03/23 00:00 [revised] PHST- 2023/03/27 00:00 [accepted] PHST- 2023/08/07 06:41 [medline] PHST- 2023/04/09 06:00 [pubmed] PHST- 2023/04/08 19:30 [entrez] PHST- 2023/09/27 00:00 [pmc-release] AID - S0091-6749(23)00429-3 [pii] AID - 10.1016/j.jaci.2023.03.029 [doi] PST - ppublish SO - J Allergy Clin Immunol. 2023 Aug;152(2):486-499.e7. doi: 10.1016/j.jaci.2023.03.029. Epub 2023 Apr 7.