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Published on: November 1, 2015
Pathological changes in various organs in HLA-B*57:01 transgenic mice with abacavir-induced skin eruption
Akira Kazaoka1, Kazuyoshi Kumagai2, Junya Matsushita2
1Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-City, Chiba 260-8675 Japan.
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.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s43188-023-00220-1.
Insights
Abacavir (ABC) causes severe systemic reactions and organ damage in HLA-B*57:01 mice, highlighting the need to monitor organs beyond the skin in patients with ABC-induced eruptions.
Area of Science:
- Pharmacology
- Immunology
- Toxicology
Background:
- Cutaneous adverse drug reactions can lead to severe extracutaneous organ damage and mortality.
- Understanding organ-specific changes during drug-induced eruptions is crucial for prevention and intervention.
Purpose of the Study:
- To investigate the systemic effects of abacavir (ABC) on various organs in a mouse model of ABC-induced eruptions.
- To evaluate the role of HLA-B*57:01 in ABC-induced toxicity.
Main Methods:
- Oral administration of abacavir (ABC) to HLA-B*57:01 transgenic mice (B*57:01-Tg).
- Monitoring of body weight, clinical signs, survival rates, and histopathological changes.
- Blood chemistry analysis to assess systemic inflammation and organ damage.
Main Results:
- Significant body weight decrease and mortality observed in B*57:01-Tg mice treated with ABC.
- Histopathology revealed thymic atrophy, inflammatory cell infiltration in skin, liver, kidney, and lung, and splenic abnormalities.
- Blood chemistry indicated a systemic inflammatory response and elevated liver enzymes, suggesting organ damage.
Conclusions:
- Abacavir (ABC) induces significant systemic toxicity and multi-organ damage in the HLA-B*57:01 mouse model.
- These findings underscore the importance of considering extracutaneous organ involvement in patients experiencing ABC-induced skin eruptions.
- The study provides insights into the early systemic responses mediated by HLA-B*57:01.
