Table 1.

Preclinical models for immune checkpoint inhibitor associated myocarditis studies.

Immune Checkpoint Inhibition	Myocarditis induction	Susceptible Mice Strain	Advantages	Limitations	Reference
Anti-PD-1 mAb & Anti-PD-L1 mAb	CVB3 infection	C3H/He (4-9 weeks)	- Use of clinically relevant virus	- High mortality - High biosafety standard required - Not relevant induction to clinical ICI-myocarditis	Nagai et al. Cardiovasc Res. 2007 (133)
Anti-PD-1 mAb & Anti-PD-L1 mAb PD-1-/- mice	T.cruzi infection	C57BL/6 (6-8weeks)	- Use of clinically relevant pathogen	- Pathogen strain-dependent variability - Long-term model	Silva et al. Infect Immun. 2011 (134)
PD-L1/2-/- mice	Crossed to cMy-mOVA mice and OT-I T cell transfer	C57BL/6 (8-12 weeks)	- Biosafe - Suitable to study T cell mediated cytotoxicity against cardiomyocytes	- Reactivity against non-cardiac antigen - In vitro T cell activation - Genetic not mAb induced model	Lichtman et al. Circulation. 2007 (135)
Pdcd-1-/- mice	Crossed to MRL mice (prone to autoimmune disease)	C57BL/6	- Biosafe - Suitable to study side effects of anti-PD-1/PD-L1 therapy	- Multiorgan involvement - High mortality - Genetic not mAb induced model	Okazaki et al. Int Immunol. 2010 (136)
Pdcd-1-/- mice	Crossed to CTLA4+/- mice	C57BL/6	- Biosafe - Suitable to study side effects of anti-CTLA-4 therapy	- High mortality - Genetic not mAb induced model	Moslehi and Allison et al. Cancer Discov. 2021 (137)
Anti-PD-1 mAb	Anti-PD-1 mAb alone	A/J (8-12 weeks)	- Biosafe - Clinically relevant model to study ICI-myocarditis	- Relatively low incidence - Reliance on A/J mice	Cihakova et al. Cell Rep. 2022 (138)

cMy, cardiac myosin; CVB3, Coxsackievirus B3; mOVA, membrane-anchored ovalbumin; PD-1, programmed death-1; PD-L1, programmed death ligand-1; Pdcd1, programmed cell death protein 1; T.cruzi, Trypanosoma cruzi.