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

Aged Amino Acid Sequence Animals Autoimmune Diseases / chemically induced Cysteine Endopeptidases / deficiency Disease Models, Animal Female Gene Deletion Humans Immune Checkpoint Inhibitors / adverse effects Immunity / drug effects Male Mice Mice, Knockout Myocarditis / chemically induced Proteasome Endopeptidase Complex / deficiency
autoimmunity cardio-oncology models myocarditis proteasome

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
09 06 2020
Historique:
pubmed: 13 3 2020
medline: 24 8 2021
entrez: 13 3 2020
Statut: ppublish

Résumé

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. TnI-directed autoimmune myocarditis (TnI-AM), a CD4 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 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.

Sections du résumé

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
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
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.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.119.043171 PMID: 32160764
pubmed: 32160764
doi: 10.1161/CIRCULATIONAHA.119.043171
doi:

Substances chimiques

Immune Checkpoint Inhibitors 0
LMP-2 protein 144416-78-4
Cysteine Endopeptidases EC 3.4.22.-
LMP7 protein EC 3.4.25.1
Proteasome Endopeptidase Complex EC 3.4.25.1
Psmb10 protein, mouse EC 3.4.25.1

Types de publication

Case Reports Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1885-1902

Auteurs

Mariella 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.).

Andrea 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.).

Carl Christoph 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.
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Germany (C.C.G., M.K., U.L., A.K., A.B.).

Hannah Louise 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.

Martina Sauter (M)

Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Germany (M.S., K.K.).

Meike 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.
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Germany (C.C.G., M.K., U.L., A.K., A.B.).

Anna-Maria 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.).

Christin 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.).

Christian 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.).

Mirjam Schenk (M)

Institute of Pathology, University of Bern, Switzerland (M.S.).

Arnd Heuser (A)

Core Unit Pathophysiology (A.H.), Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.

Ulf 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.
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Germany (C.C.G., M.K., U.L., A.K., A.B.).

January Weiner (J)

Core Unit Bioinformatics (J.W.), Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.

Benjamin 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.).
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Heidelberg/Mannheim, Heidelberg, Germany (B.M., L.L., H.A.K., Z.K.).

Lorenz 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.).
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Heidelberg/Mannheim, Heidelberg, Germany (B.M., L.L., H.A.K., Z.K.).
Cardio-Oncology Unit, University Hospital of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany (L.L.).

Adelheid 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.
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Germany (C.C.G., M.K., U.L., A.K., A.B.).

Karin Klingel (K)

Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Germany (M.S., K.K.).

Hugo A 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.).
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Heidelberg/Mannheim, Heidelberg, Germany (B.M., L.L., H.A.K., Z.K.).

Ziya 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.).
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Heidelberg/Mannheim, Heidelberg, Germany (B.M., L.L., H.A.K., Z.K.).

Antje 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.
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner side Berlin, Germany (C.C.G., M.K., U.L., A.K., A.B.).

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questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Heart-Specific Immune Responses in an Animal...
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questionsmedicales.fr › Eucaryotes › Animaux › Heart-Specific Immune Responses in an Animal...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Heart-Specific Immune Responses in an Animal...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Endopeptidases › Cysteine endopeptidases › Heart-Specific Immune Responses in an Animal...
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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Heart-Specific Immune Responses in an Animal...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Heart-Specific Immune Responses in an Animal...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Cardiomyopathies › Myocardite › Heart-Specific Immune Responses in an Animal...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Proteasome endopeptidase complex › Heart-Specific Immune Responses in an Animal...