Journal article
Heart-Specific Immune Responses in an Animal Model of Autoimmune-Related Myocarditis Mitigated by an Immunoproteasome Inhibitor and Genetic Ablation.
- Bockstahler M Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Fischer A Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Goetzke CC Institute of Biochemistry (C.C.G., H.L.N., M.K., A.B.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Germany.
- Neumaier HL Institute of Biochemistry (C.C.G., H.L.N., M.K., A.B.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Germany.
- Sauter M Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Germany (M.S., K.K.).
- Kespohl M Institute of Biochemistry (C.C.G., H.L.N., M.K., A.B.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Germany.
- Müller AM Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Meckes C Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Salbach C Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Schenk M Institute of Pathology, University of Bern, Switzerland (M.S.).
- Heuser A Core Unit Pathophysiology (A.H.), Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
- Landmesser U Medizinische Klinik für Kardiologie Campus Benjamin Franklin (U.L., A.K.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Germany.
- Weiner J Core Unit Bioinformatics (J.W.), Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
- Meder B Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Lehmann L Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Kratzer A Medizinische Klinik für Kardiologie Campus Benjamin Franklin (U.L., A.K.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Germany.
- Klingel K Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Germany (M.S., K.K.).
- Katus HA Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Kaya Z Medizinische Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany (M.B., A.F., A.-M.M., C.M., C.S., B.M., L.L., H.A.K., Z.K.).
- Beling A Institute of Biochemistry (C.C.G., H.L.N., M.K., A.B.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Germany.
- 2020-03-13
Published in:
- Circulation. - 2020
English
BACKGROUND
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 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) subunit, affects TnI-directed autoimmune pathology of the heart.
METHODS
TnI-directed autoimmune myocarditis (TnI-AM), a CD4+ T-cell-mediated disease, was induced in mice lacking all 3 immunoproteasome subunits (triple-ip-/-) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis.
RESULTS
All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-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 (Toll-like receptor 2)-engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)-engaged CD14+ monocytes with ONX 0914, diminished proinflammatory 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 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, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, demonstrating the activation of heart-specific autoimmune reactions by ICI therapy.
CONCLUSIONS
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 patients with ICI-related heart-specific autoimmunity.
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 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) subunit, affects TnI-directed autoimmune pathology of the heart.
METHODS
TnI-directed autoimmune myocarditis (TnI-AM), a CD4+ T-cell-mediated disease, was induced in mice lacking all 3 immunoproteasome subunits (triple-ip-/-) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis.
RESULTS
All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-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 (Toll-like receptor 2)-engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)-engaged CD14+ monocytes with ONX 0914, diminished proinflammatory 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 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, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, demonstrating the activation of heart-specific autoimmune reactions by ICI therapy.
CONCLUSIONS
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 patients with ICI-related heart-specific autoimmunity.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1161/CIRCULATIONAHA.119.043171
- PMID 32160764
- Persistent URL
- https://sonar.ch/global/documents/279095
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