Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor
Background and purpose: Myocarditis induced by programmed death-1 (PD-1) inhibitors is in urgent need of animal models to explore therapeutic targets. The study aimed to figure out the best modeling method of this typical autoimmune myocarditis in mice. Methods: Thirty 6-week-old healthy male BALB/c...
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| Format: | Article |
| Language: | English |
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Editorial Office of China Oncology
2022-07-01
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| Series: | Zhongguo aizheng zazhi |
| Subjects: | |
| Online Access: | http://www.china-oncology.com/fileup/1007-3639/PDF/1660021584056-1566060562.pdf |
| _version_ | 1811209549363806208 |
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| author | CHEN Yifan, CHENG Leilei, SHEN Yihui, ZHANG Hui, WANG Xuejun, XU Yuchen, GE Junbo |
| author_facet | CHEN Yifan, CHENG Leilei, SHEN Yihui, ZHANG Hui, WANG Xuejun, XU Yuchen, GE Junbo |
| author_sort | CHEN Yifan, CHENG Leilei, SHEN Yihui, ZHANG Hui, WANG Xuejun, XU Yuchen, GE Junbo |
| collection | DOAJ |
| description | Background and purpose: Myocarditis induced by programmed death-1 (PD-1) inhibitors is in urgent need of animal models to explore therapeutic targets. The study aimed to figure out the best modeling method of this typical autoimmune myocarditis in mice. Methods: Thirty 6-week-old healthy male BALB/c mice were numbered and randomly divided into control group, autoimmune myocarditis group (TnⅠgroup) and immune checkpoint inhibitor (ICI)-related myocarditis group (TnⅠ+anti-PD-1 group), 10 in each group. Except for the control group, mice were subcutaneously injected with 0.1 mL complete Freund’s adjuvant containing 0.25 mg of mouse cardiac TnⅠ peptide on day 1 and day 7, respectively. From day 7, TnⅠ+anti-PD-1 group received intraperitoneal injection of PD-1 inhibitor at 5 mg/kg each time, once every 2 d, for a total of 5 times with a cumulative dose of 25 mg/kg. The general state, mortality, cardiac index, echocardiography, myocardial pathology and the levels of creatine kinase (CK) and CK isoenzyme (CK-MB) in serum were observed. Results: Compared with control group, the mass of mice in both TnⅠ and TnⅠ+anti-PD-1 groups decreased significantly on day 21 and day 56 (P<0.05, P<0.01), and there was a significant difference between these 2 groups (P<0.05). Both had significantly decreased food intake (compared with control group, P<0.05, P<0.01). The mortality rates were 0% and 10% on day 21, and 10% and 20% on day 56 in TnⅠ and TnⅠ+anti-PD-1 groups, respectively. On day 56, no significant increase in cardiac index could be observed in TnⅠ group (P>0.05), while a significant rise of cardiac index (P<0.05) with a decrease in left ventricular ejection fraction (EF) (P<0.001) were detected in TnⅠ+anti-PD-1 group. During the acute myocarditis stage, mild subepicardial inflammatory infiltration was found in TnⅠ group; Severe subepicardial inflammatory infiltration and myocardial cell necrosis were seen in TnⅠ+anti-PD-1 group. During the dilated cardiomyopathy stage, the infiltrated inflammatory cells in TnⅠ group decreased, mild boundaries unclear and cytoplasm vacuolization could be observed; TnⅠ+anti-PD-1 group also had decreased inflammatory infiltration while underwent more severe cell necrosis and vacuolization with nuclear atypia. On day 56, serum CK and CK-MB in TnⅠ+anti-PD-1 group rose significantly (P<0.001), which was more obvious compared with TnⅠ group (CK: P<0.01; CK-MB: P<0.05). Conclusion: A PD-1 inhibitor-induced myocarditis model with low mortality was established in mice, characterized by acute and chronic autoimmune myocardial inflammation, decreased ejection fraction and increased myocardial enzyme spectrum. A mouse cardiac TnⅠ peptide fragment was particularly designed and synthesized for modeling. |
| first_indexed | 2024-04-12T04:41:28Z |
| format | Article |
| id | doaj.art-a0e6fcbd5d544370b9459ce72608beee |
| institution | Directory Open Access Journal |
| issn | 1007-3639 |
| language | English |
| last_indexed | 2024-04-12T04:41:28Z |
| publishDate | 2022-07-01 |
| publisher | Editorial Office of China Oncology |
| record_format | Article |
| series | Zhongguo aizheng zazhi |
| spelling | doaj.art-a0e6fcbd5d544370b9459ce72608beee2022-12-22T03:47:37ZengEditorial Office of China OncologyZhongguo aizheng zazhi1007-36392022-07-0132760661310.19401/j.cnki.1007-3639.2022.07.004Establishment of a mouse myocarditis model induced by programmed death-1 inhibitorCHEN Yifan, CHENG Leilei, SHEN Yihui, ZHANG Hui, WANG Xuejun, XU Yuchen, GE Junbo01. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China;2. Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China;3. National Clinical Research Center for Interventional Medicine, Shanghai 200032, China;4. Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaBackground and purpose: Myocarditis induced by programmed death-1 (PD-1) inhibitors is in urgent need of animal models to explore therapeutic targets. The study aimed to figure out the best modeling method of this typical autoimmune myocarditis in mice. Methods: Thirty 6-week-old healthy male BALB/c mice were numbered and randomly divided into control group, autoimmune myocarditis group (TnⅠgroup) and immune checkpoint inhibitor (ICI)-related myocarditis group (TnⅠ+anti-PD-1 group), 10 in each group. Except for the control group, mice were subcutaneously injected with 0.1 mL complete Freund’s adjuvant containing 0.25 mg of mouse cardiac TnⅠ peptide on day 1 and day 7, respectively. From day 7, TnⅠ+anti-PD-1 group received intraperitoneal injection of PD-1 inhibitor at 5 mg/kg each time, once every 2 d, for a total of 5 times with a cumulative dose of 25 mg/kg. The general state, mortality, cardiac index, echocardiography, myocardial pathology and the levels of creatine kinase (CK) and CK isoenzyme (CK-MB) in serum were observed. Results: Compared with control group, the mass of mice in both TnⅠ and TnⅠ+anti-PD-1 groups decreased significantly on day 21 and day 56 (P<0.05, P<0.01), and there was a significant difference between these 2 groups (P<0.05). Both had significantly decreased food intake (compared with control group, P<0.05, P<0.01). The mortality rates were 0% and 10% on day 21, and 10% and 20% on day 56 in TnⅠ and TnⅠ+anti-PD-1 groups, respectively. On day 56, no significant increase in cardiac index could be observed in TnⅠ group (P>0.05), while a significant rise of cardiac index (P<0.05) with a decrease in left ventricular ejection fraction (EF) (P<0.001) were detected in TnⅠ+anti-PD-1 group. During the acute myocarditis stage, mild subepicardial inflammatory infiltration was found in TnⅠ group; Severe subepicardial inflammatory infiltration and myocardial cell necrosis were seen in TnⅠ+anti-PD-1 group. During the dilated cardiomyopathy stage, the infiltrated inflammatory cells in TnⅠ group decreased, mild boundaries unclear and cytoplasm vacuolization could be observed; TnⅠ+anti-PD-1 group also had decreased inflammatory infiltration while underwent more severe cell necrosis and vacuolization with nuclear atypia. On day 56, serum CK and CK-MB in TnⅠ+anti-PD-1 group rose significantly (P<0.001), which was more obvious compared with TnⅠ group (CK: P<0.01; CK-MB: P<0.05). Conclusion: A PD-1 inhibitor-induced myocarditis model with low mortality was established in mice, characterized by acute and chronic autoimmune myocardial inflammation, decreased ejection fraction and increased myocardial enzyme spectrum. A mouse cardiac TnⅠ peptide fragment was particularly designed and synthesized for modeling.http://www.china-oncology.com/fileup/1007-3639/PDF/1660021584056-1566060562.pdf|programmed death-1 inhibitor|immune checkpoint inhibitor-associated myocarditis|mouse|model |
| spellingShingle | CHEN Yifan, CHENG Leilei, SHEN Yihui, ZHANG Hui, WANG Xuejun, XU Yuchen, GE Junbo Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor Zhongguo aizheng zazhi |programmed death-1 inhibitor|immune checkpoint inhibitor-associated myocarditis|mouse|model |
| title | Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor |
| title_full | Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor |
| title_fullStr | Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor |
| title_full_unstemmed | Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor |
| title_short | Establishment of a mouse myocarditis model induced by programmed death-1 inhibitor |
| title_sort | establishment of a mouse myocarditis model induced by programmed death 1 inhibitor |
| topic | |programmed death-1 inhibitor|immune checkpoint inhibitor-associated myocarditis|mouse|model |
| url | http://www.china-oncology.com/fileup/1007-3639/PDF/1660021584056-1566060562.pdf |
| work_keys_str_mv | AT chenyifanchengleileishenyihuizhanghuiwangxuejunxuyuchengejunbo establishmentofamousemyocarditismodelinducedbyprogrammeddeath1inhibitor |