Effect of PD-1 antibody on a mouse model for experimental autoimmune myocarditis

[Speaker] Kenjiro Tsuruoka:1
[Co-author] Shigeo Wakabayashi:2, Ninso Matsunaga:1, Hirofumi Morihara:2, Masaaki Ii:3, Yasuhito Fujisaka:1, Isao Goto:1, Michio Asahi:2
1:Division of Internal Medicine, Osaka Medical College Hospital, Japan, 2:Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Japan, 3:Division of Research Animal Laboratory and Translational Medicine Research and Development Center, Osaka Medical College, Japan

 Immune checkpoint inhibitors block the inhibitory signals from the ligands on cancer cells and prolong the activation of T lymphocytes, thereby inducing T cells to attack the cancer cells. On the other hand, there are reports of various immune related adverse events, and it is important to investigate its possible side effects for future clinical use. We examined the effects of programmed death-1 (PD-1) antibody on autoimmune diseases using a mouse model of autoimmune myocarditis.
 Autoimmune myocarditis was produced by administering twice (the 1st and 8th days) myocardial myosin fragment (aa 614-629) with adjuvant to 7-week-old Balb/c mice. PD-1 antibody or normal rat IgG was administered every second days into control or myosin fragment-injected mice. The hearts were removed 3 weeks after the start of the experiment, and their pathological features were examined by echocardiography, RT-PCR and immunohistochemistry. In myosin-fragment-injected mice, IL-1b, IL-6, and Collagen-1 genes were found to be markedly upregulated by RT-PCR analysis, and clear infiltration of inflammatory cells were observed in hematoxylin-eosin stained heart tissues. There were no significant differences in heart function assessed by echocardiography and heart weight/body weight ratio between control and myosin-fragment-injected mice. These data suggest that the outstanding inflammatory response occurs in myosin fragment-injected mice despite no apparent defects on cardiac function, and convince the successful production of autoimmune myocarditis. Interestingly, the expressions of IL-1b, IL-6, and Collagen-1 were alleviated by administration of PD-1 antibody in RT-PCR, although there was no apparent difference in immunohistochemistry.
 Based on this unexpected, rather beneficial effect of PD-1 antibody, we are trying to examine the various protocols (changing the timing of antibody administration, etc.) and to elucidate the possible mechanism of PD-1 antibody effect on autoimmune myocarditis.
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