Heart-Specific Immune Responses in an Animal Model of AutoimmuneRelated Myocarditis Mitigated by an Immunoproteasome Inhibitor and Genetic Ablation

• Published in: Circulation (New York, N.Y.)
• Main Authors: Bockstahler, Mariella, Fischer, Andrea, Goetzke, Carl Christoph, Neumaier, Hannah Louise, Sauter, Martina, Kespohl, Meike, Müller, Anna-Maria, Meckes, Christin, Salbach, Christian, Schenk, Mirjam, Heuser, Arnd, Landmesser, Ulf, Weiner, January, Meder, Benjamin, Lehmann, Lorenz, Kratzer, Adelheid, Klingel, Karin, Katus, Hugo A, Kaya, Ziya, Beling, Antje
• Format: Journal Article
• Language: English
• Published: United States 12.03.2020
• Subjects: immune checkpoint inhibitor; immunoproteasome; autoimmunity
• ISSN: 1524-4539

Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1, control the threshold of self-antigen responses directed against cardiac troponin I (TnI). Here, we aimed at identifying how the immunoproteasome, the main proteolytic machinery in immune cells harboring three distinct protease activities in the LMP2, LMP7 and MECL1 subunit, affects TnI-directed autoimmune pathology of the heart. TnI-directed autoimmune myocarditis (TnI-AM), a CD4 T cell-mediated disease, was induced in mice lacking all three immunoproteasome subunits, triple-ip , or lacking either the LMP2 or LMP7 gene, by immunization with a cardiac TnI peptide. Alternatively, prior to induction of TnI-AM or after establishment of AM, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in both experimental TnI-AM and in two cases of ICI-related myocarditis. All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower pro-inflammatory and chemotactic cytokines, less IL-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7 mice involved a changed balance between effector and regulatory CD4 T cells in the spleen, with CD4 T cells from LMP7 mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 and TLR7/8-engaged CD14 monocytes with ONX 0914, diminished pro-inflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4 T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing both the induction and progression of TnI-AM, when self-reactive CD4 T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulinG deposition, IL-17 production in heart tissue and TnI-directed humoral autoimmune responses, was also present in two cases of ICI-related myocarditis, thus demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including cases with ICI-related heart-specific autoimmunity.