Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Pathological changes in various organs in HLA-B*57:01 transgenic mice with abacavir-induced skin eruption

  • Akira Kazaoka (Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University) ;
  • Kazuyoshi Kumagai (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd) ;
  • Junya Matsushita (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd) ;
  • Tetsuo Aida (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd) ;
  • Saki Kuwahara (Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University) ;
  • Shigeki Aoki (Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University) ;
  • Kousei Ito (Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University)
  • Received : 2023.09.23
  • Accepted : 2023.11.30
  • Published : 2024.04.15
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Abstract

Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with cutaneous eruption following drug administration will help understand disease onset and progression, aiding the development of prevention strategies and interventions. Therefore, we aimed to understand the effects of abacavir (ABC) on various organs in patients with ABC-induced eruptions by evaluating its effects in a mouse model. We found pathological changes in various organs of HLA-B*57:01 transgenic mice (B*57:01-Tg) following oral administration of ABC (20 mg/body/day). B*57:01-Tg exhibited a significant body weight decrease from day 1 of ABC administration, and reddening of the auricle was observed from day 5, and approximately 2/3 mice died by day 7. Histopathological examination revealed severe thymic atrophy after day 3, infiltration of inflammatory cells, predominantly lymphocytes with neutrophils, not only in the skin but also in the liver, kidney, and lung after day 5, and an increased number of lymphocytes with enlarged nuclei and granulocytic hematopoiesis were observed in the spleen after day 5. Blood chemistry revealed that albumin/globulin ratio was below 1.0 on day 5, reflecting a systemic inflammatory response, and the aspartate aminotransferase concentration rose to 193 ± 93.0 U/L on day 7, suggesting that cell damage may have occurred in various organs including liver accompanying inflammatory cell infiltration. These examinations of a mouse model of ABC-induced skin eruption show that disorders in various organs other than the skin should be considered and provide insights into the unexpected early systemic responses dependent on HLA-B*57:01.

Keywords

Acknowledgement

The authors thank Mx. Yoko Sasaki, animal technician, for directing animal care and use at the Laboratory of Biopharmaceutics at Chiba University. The authors also thank Kumi Honda (Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan) for performing the blood chemistry analysis. We acknowledge Editage (www. edita ge. com) for English language editing.

References

  1. Darlenski R, Kazandjieva J, Tsankov N (2015) Systemic drug reactions with skin involvement: Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS. Clin Dermatol 33:538-541. https://doi.org/10.1016/j.clindermatol.2015.05.005
  2. Sanabria-Cabrera J, Medina-Caliz I, Stankeviciute S, Rodriguez-Nicolas A, Almarza-Torres M, Lucena MI, Andrade RJ (2019) Drug-induced liver injury associated with severe cutaneous hypersensitivity reactions: a complex entity in need of a multidisciplinary approach. Curr Pharm Des 25:3855-3871. https://doi.org/10.2174/1381612825666191107161912
  3. Clay PG (2002) The abacavir hypersensitivity reaction: a review. Clin Ther 24:1502-1514. https://doi.org/10.1016/s0149-2918(02)80057-1
  4. Hewitt RG (2002) Abacavir hypersensitivity reaction. Clin Infect Dis 34:1137-1142. https://doi.org/10.1086/339751
  5. Herring SJ, Krieger AC (2006) Acute respiratory manifestations of the abacavir hypersensitivity reaction. AIDS (London, England) 20:301-302. https://doi.org/10.1097/01.aids.0000199833.87606.95
  6. Yoon JH, Kim M, Jin SJ, Kim SK, Lee SH, Cheon J, Gy Y, Kim MK, Ha J, Song YG (2012) The first case of abacavir hypersensitivity associated with the HLA-B*57:01-positive allele in Korea. Infect Chemother 44:399-402. https://doi.org/10.3947/ic.2012.44.5.399
  7. Kubo M, Moriura T, Matsuda H (1990) Pharmacological study on Aconiti Tuber. I. Effect of water extract from Aconiti Tuber on adjuvant-induced arthritis. Yakugaku zasshi J Pharm Soc Japan 110:16-26. https://doi.org/10.1248/yakushi1947.110.1_16
  8. Kawase A, Tateishi S, Kazaoka A (2018) Profiling of hepatic metabolizing enzymes and nuclear receptors in rats with adjuvant arthritis by targeted proteomics. Biopharm Drug Dispos 39:308-314. https://doi.org/10.1002/bdd.2147
  9. Kawase A, Yoshida I, Tsunokuni Y, Iwaki M (2007) Decreased PXR and CAR inhibit transporter and CYP mRNA levels in the liver and intestine of mice with collagen-induced arthritis. Xenobiotica 37:366-374. https://doi.org/10.1080/00498250701230534
  10. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jagel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A, Team P-S (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358:568-579. https://doi.org/10.1056/NEJMoa0706135
  11. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD (2002) Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet (London, England) 359:1121-1122. https://doi.org/10.1016/s0140-6736(02)08158-8
  12. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. The Lancet 359:727-732. https://doi.org/10.1016/s0140-6736(02)07873-x
  13. Cardone M, Garcia K, Tilahun ME, Boyd LF, Gebreyohannes S, Yano M, Roderiquez G, Akue AD, Juengst L, Mattson E, Ananthula S, Natarajan K, Puig M, Margulies DH, Norcross MA (2018) A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity. J Clin Investig 128:2819-2832. https://doi.org/10.1172/JCI99321
  14. Susukida T, Aoki S, Kogo K, Fujimori S, Song B, Liu C, Sekine S, Ito K (2018) Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice. Arch Toxicol 92:1177-1188. https://doi.org/10.1007/s00204-017-2112-9
  15. Susukida T, Kuwahara S, Song B, Kazaoka A, Aoki S, Ito K (2021) Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity. Commun Biol 4:1137. https://doi.org/10.1038/s42003-021-02657-2
  16. Gao Y, Kuwahara S, Kazaoka A, Ito K, Aoki S (2022) TARC/CCL17 expression is associated with CD8(+) T cell recruitment in abacavir-induced skin hypersensitivity in HLA-transgenic mice. Biol Pharm Bull 45:1347-1353. https://doi.org/10.1248/bpb.b22-00313
  17. Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol 129:705-733. https://doi.org/10.1007/s00418-008-0435-6
  18. Zhang J, Lei Z, Xu C, Zhao J, Kang X (2021) Current perspectives on severe drug Eruption. Clin Rev Allergy Immunol 61:282-298. https://doi.org/10.1007/s12016-021-08859-0
  19. Redwood AJ, Pavlos RK, White KD, Phillips EJ (2018) HLAs: key regulators of T-cell-mediated drug hypersensitivity. HLA 91:3-16. https://doi.org/10.1111/tan.13183
  20. Murphy JE, Robert C, Kupper TS (2000) Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J Investig Dermatol 114:602-608. https://doi.org/10.1046/j.1523-1747.2000.00917.x
  21. Natsuaki Y, Egawa G, Nakamizo S, Ono S, Hanakawa S, Okada T, Kusuba N, Otsuka A, Kitoh A, Honda T, Nakajima S, Tsuchiya S, Sugimoto Y, Ishii KJ, Tsutsui H, Yagita H, Iwakura Y, Kubo M, Ng L, Hashimoto T, Fuentes J, Guttman-Yassky E, Miyachi Y, Kabashima K (2014) Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin. Nat Immunol 15:1064-1069. https://doi.org/10.1038/ni.2992
  22. Esser PR, Huber M, Martin SF (2023) Endoplasmic reticulum stress and the inflammatory response in allergic contact dermatitis. Eur J Immunol 53:e2249984. https://doi.org/10.1002/eji.202249984
  23. Martin AM, Almeida CA, Cameron P, Purcell AW, Nolan D, James I, McCluskey J, Phillips E, Landay A, Mallal S (2007) Immune responses to abacavir in antigen-presenting cells from hypersensitive patients. AIDS (London, England) 21:1233-1244. https://doi.org/10.1097/QAD.0b013e3280119579
  24. Terrab L, Wipf P (2020) Hsp70 and the unfolded protein response as a challenging drug target and an inspiration for probe molecule development. ACS Med Chem Lett 11:232-236. https://doi.org/10.1021/acsmedchemlett.9b00583
  25. Shirayanagi T, Aoki S, Fujimori S, Watanabe K, Aida T, Hirasawa M, Kumagai K, Hoshino T, Ito K (2020) Detection of abacavir-induced structural alterations in human leukocyte antigen-B*57: 01 using phage display. Biol Pharm Bull 43:1007-1015. https://doi.org/10.1248/bpb.b20-00102
  26. Atallah E, Freixo C, Alvarez-Alvarez I, Cubero FJ, Gerbes AL, Kullak-Ublick GA, Aithal GP (2021) Biomarkers of idiosyncratic drug-induced liver injury (DILI)-a systematic review. Expert Opin Drug Metab Toxicol 17:1327-1343. https://doi.org/10.1080/17425255.2021.1999410
  27. Luster AD, Unkeless JC, Ravetch JV (1985) Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 315:672-676. https://doi.org/10.1038/315672a0
  28. Osabe M, Tajika T, Tohkin M (2018) Allopurinol suppresses expression of the regulatory T-cell migration factors TARC/CCL17 and MDC/CCL22 in HaCaT keratinocytes via restriction of nuclear factor-kappaB activation. J Appl Toxicol 38:274-283. https://doi.org/10.1002/jat.3522
  29. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG (2012) Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76:16-32. https://doi.org/10.1128/mmbr.05015-11
  30. Janardhanan M, Amberkar VM, Vidyasagar S, Kumari KM, Holla SN (2014) Hypersensitivity reaction associated with abacavir therapy in an Indian HIV patient-a case report. J Clin Diagn Res JCDR 8:100. https://doi.org/10.7860/jcdr/2014/10063.4820
  31. Koech MK, Ali SM, Karoney MJ, Kigen G (2022) Severe abacavir hypersensitivity reaction in a patient with human immunodeficiency virus infection: a case report. J Med Case Rep 16:407. https://doi.org/10.1186/s13256-022-03647-6
  32. Frissen PH, de Vries J, Weigel HM, Brinkman K (2001) Severe anaphylactic shock after rechallenge with abacavir without preceding hypersensitivity. AIDS (London, England) 15:289. https://doi.org/10.1097/00002030-200101260-00027