Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation
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...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
June 9, 2020
|
| In: |
Circulation
Year: 2020, Jahrgang: 141, Heft: 23, Pages: 1885-1902 |
| ISSN: | 1524-4539 |
| DOI: | 10.1161/CIRCULATIONAHA.119.043171 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCULATIONAHA.119.043171
|
| Verfasserangaben: | Mariella Bockstahler, Andrea Fischer, Carl Christoph Goetzke, Hannah Louise Neumaier, Martina Sauter, Meike Kespohl, Anna-Maria Mueller, Christin Meckes, Christian Salbach, Mirjam Schenk, Arnd Heuser, Ulf Landmesser, January Weiner, Benjamin Meder, Lorenz Lehmann, Adelheid Kratzer, Karin Klingel, Hugo A. Katus, Ziya Kaya, Antje Beling |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1734636912 | ||
| 003 | DE-627 | ||
| 005 | 20230427033721.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 201005s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCULATIONAHA.119.043171 |2 doi | |
| 035 | |a (DE-627)1734636912 | ||
| 035 | |a (DE-599)KXP1734636912 | ||
| 035 | |a (OCoLC)1341368368 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Bockstahler, Mariella |e VerfasserIn |0 (DE-588)1076880533 |0 (DE-627)835424448 |0 (DE-576)44616593X |4 aut | |
| 245 | 1 | 0 | |a Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation |c Mariella Bockstahler, Andrea Fischer, Carl Christoph Goetzke, Hannah Louise Neumaier, Martina Sauter, Meike Kespohl, Anna-Maria Mueller, Christin Meckes, Christian Salbach, Mirjam Schenk, Arnd Heuser, Ulf Landmesser, January Weiner, Benjamin Meder, Lorenz Lehmann, Adelheid Kratzer, Karin Klingel, Hugo A. Katus, Ziya Kaya, Antje Beling |
| 264 | 1 | |c June 9, 2020 | |
| 300 | |a 18 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 05.10.2020 | ||
| 520 | |a 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. | ||
| 650 | 4 | |a autoimmunity | |
| 650 | 4 | |a cardiac troponin-i | |
| 650 | 4 | |a cardio-oncology | |
| 650 | 4 | |a deficiency | |
| 650 | 4 | |a dexamethasone | |
| 650 | 4 | |a dilated cardiomyopathy | |
| 650 | 4 | |a failure | |
| 650 | 4 | |a induction | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a models | |
| 650 | 4 | |a myocarditis | |
| 650 | 4 | |a pd-1 | |
| 650 | 4 | |a proteasome | |
| 650 | 4 | |a selective inhibitor | |
| 650 | 4 | |a tumor-necrosis-factor | |
| 700 | 1 | |a Fischer, Andrea |d 1972- |e VerfasserIn |0 (DE-588)121638863 |0 (DE-627)705594645 |0 (DE-576)292810776 |4 aut | |
| 700 | 1 | |a Goetzke, Carl Christoph |e VerfasserIn |4 aut | |
| 700 | 1 | |a Neumaier, Hannah Louise |e VerfasserIn |4 aut | |
| 700 | 1 | |a Sauter, Martina |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kespohl, Meike |e VerfasserIn |4 aut | |
| 700 | 1 | |a Müller, Anna-Maria |e VerfasserIn |0 (DE-588)1074026713 |0 (DE-627)830176012 |0 (DE-576)435538136 |4 aut | |
| 700 | 1 | |a Meckes, Christin |d 1995- |e VerfasserIn |0 (DE-588)1218996900 |0 (DE-627)1734641967 |4 aut | |
| 700 | 1 | |a Salbach, Christian |e VerfasserIn |0 (DE-588)1200157389 |0 (DE-627)168241230X |4 aut | |
| 700 | 1 | |a Schenk, Mirjam |e VerfasserIn |4 aut | |
| 700 | 1 | |a Heuser, Arnd |e VerfasserIn |4 aut | |
| 700 | 1 | |a Landmesser, Ulf |e VerfasserIn |4 aut | |
| 700 | 1 | |a Weiner, January |e VerfasserIn |4 aut | |
| 700 | 1 | |a Meder, Benjamin |e VerfasserIn |0 (DE-588)135821630 |0 (DE-627)571676316 |0 (DE-576)300664745 |4 aut | |
| 700 | 1 | |a Lehmann, Lorenz |d 1980- |e VerfasserIn |0 (DE-588)131855212 |0 (DE-627)515807184 |0 (DE-576)298796104 |4 aut | |
| 700 | 1 | |a Kratzer, Adelheid |e VerfasserIn |4 aut | |
| 700 | 1 | |a Klingel, Karin |e VerfasserIn |4 aut | |
| 700 | 1 | |a Katus, Hugo |d 1951- |e VerfasserIn |0 (DE-588)108916618 |0 (DE-627)577155040 |0 (DE-576)289625076 |4 aut | |
| 700 | 1 | |a Kaya, Ziya |d 1971- |e VerfasserIn |0 (DE-588)120790319 |0 (DE-627)704990016 |0 (DE-576)292386672 |4 aut | |
| 700 | 1 | |a Beling, Antje |e VerfasserIn |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation |d Philadelphia, Pa. : Lippincott, Williams & Wilkins, 1950 |g 141(2020), 23, Seite 1885-1902 |h Online-Ressource |w (DE-627)265784670 |w (DE-600)1466401-X |w (DE-576)074891189 |x 1524-4539 |7 nnas |a Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation |
| 773 | 1 | 8 | |g volume:141 |g year:2020 |g number:23 |g pages:1885-1902 |g extent:18 |a Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation |
| 856 | 4 | 0 | |u https://doi.org/10.1161/CIRCULATIONAHA.119.043171 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20201005 | ||
| 993 | |a Article | ||
| 994 | |a 2020 | ||
| 998 | |g 120790319 |a Kaya, Ziya |m 120790319:Kaya, Ziya |d 910000 |d 910100 |e 910000PK120790319 |e 910100PK120790319 |k 0/910000/ |k 1/910000/910100/ |p 19 | ||
| 998 | |g 108916618 |a Katus, Hugo |m 108916618:Katus, Hugo |d 910000 |d 910100 |e 910000PK108916618 |e 910100PK108916618 |k 0/910000/ |k 1/910000/910100/ |p 18 | ||
| 998 | |g 131855212 |a Lehmann, Lorenz |m 131855212:Lehmann, Lorenz |d 910000 |d 910100 |e 910000PL131855212 |e 910100PL131855212 |k 0/910000/ |k 1/910000/910100/ |p 15 | ||
| 998 | |g 135821630 |a Meder, Benjamin |m 135821630:Meder, Benjamin |d 910000 |d 910100 |e 910000PM135821630 |e 910100PM135821630 |k 0/910000/ |k 1/910000/910100/ |p 14 | ||
| 998 | |g 1200157389 |a Salbach, Christian |m 1200157389:Salbach, Christian |d 910000 |d 910100 |e 910000PS1200157389 |e 910100PS1200157389 |k 0/910000/ |k 1/910000/910100/ |p 9 | ||
| 998 | |g 1218996900 |a Meckes, Christin |m 1218996900:Meckes, Christin |d 50000 |e 50000PM1218996900 |k 0/50000/ |p 8 | ||
| 998 | |g 1074026713 |a Müller, Anna-Maria |m 1074026713:Müller, Anna-Maria |d 50000 |e 50000PM1074026713 |k 0/50000/ |p 7 | ||
| 998 | |g 121638863 |a Fischer, Andrea |m 121638863:Fischer, Andrea |p 2 | ||
| 998 | |g 1076880533 |a Bockstahler, Mariella |m 1076880533:Bockstahler, Mariella |d 910000 |d 910100 |e 910000PB1076880533 |e 910100PB1076880533 |k 0/910000/ |k 1/910000/910100/ |p 1 |x j | ||
| 999 | |a KXP-PPN1734636912 |e 3767110423 | ||
| BIB | |a Y | ||
| SER | |a newspaper | ||
| JSO | |a {"type":{"media":"Online-Ressource","bibl":"article-newspaper"},"id":{"eki":["1734636912"],"doi":["10.1161/CIRCULATIONAHA.119.043171"]},"physDesc":[{"extent":"18 S."}],"relHost":[{"language":["eng"],"recId":"265784670","disp":"Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablationCirculation","type":{"media":"Online-Ressource","bibl":"newspaper"},"pubHistory":["1.1950 -"],"title":[{"title":"Circulation","subtitle":"an official journal of the American Heart Association","title_sort":"Circulation"}],"corporate":[{"role":"isb","display":"American Heart Association"}],"origin":[{"dateIssuedDisp":"1950-","publisher":"Lippincott, Williams & Wilkins ; Ovid","publisherPlace":"Philadelphia, Pa. ; [Erscheinungsort nicht ermittelbar]","dateIssuedKey":"1950"}],"note":["Gesehen am 10.10.2025"],"physDesc":[{"extent":"Online-Ressource"}],"part":{"volume":"141","text":"141(2020), 23, Seite 1885-1902","pages":"1885-1902","year":"2020","issue":"23","extent":"18"},"id":{"eki":["265784670"],"zdb":["1466401-X"],"issn":["1524-4539"]}}],"note":["Gesehen am 05.10.2020"],"recId":"1734636912","origin":[{"dateIssuedKey":"2020","dateIssuedDisp":"June 9, 2020"}],"name":{"displayForm":["Mariella Bockstahler, Andrea Fischer, Carl Christoph Goetzke, Hannah Louise Neumaier, Martina Sauter, Meike Kespohl, Anna-Maria Mueller, Christin Meckes, Christian Salbach, Mirjam Schenk, Arnd Heuser, Ulf Landmesser, January Weiner, Benjamin Meder, Lorenz Lehmann, Adelheid Kratzer, Karin Klingel, Hugo A. Katus, Ziya Kaya, Antje Beling"]},"person":[{"family":"Bockstahler","display":"Bockstahler, Mariella","given":"Mariella","role":"aut"},{"family":"Fischer","given":"Andrea","display":"Fischer, Andrea","role":"aut"},{"role":"aut","family":"Goetzke","given":"Carl Christoph","display":"Goetzke, Carl Christoph"},{"display":"Neumaier, Hannah Louise","given":"Hannah Louise","family":"Neumaier","role":"aut"},{"display":"Sauter, Martina","given":"Martina","family":"Sauter","role":"aut"},{"role":"aut","given":"Meike","display":"Kespohl, Meike","family":"Kespohl"},{"family":"Müller","given":"Anna-Maria","display":"Müller, Anna-Maria","role":"aut"},{"family":"Meckes","given":"Christin","display":"Meckes, Christin","role":"aut"},{"display":"Salbach, Christian","given":"Christian","family":"Salbach","role":"aut"},{"family":"Schenk","given":"Mirjam","display":"Schenk, Mirjam","role":"aut"},{"role":"aut","display":"Heuser, Arnd","given":"Arnd","family":"Heuser"},{"role":"aut","given":"Ulf","display":"Landmesser, Ulf","family":"Landmesser"},{"display":"Weiner, January","given":"January","family":"Weiner","role":"aut"},{"role":"aut","family":"Meder","display":"Meder, Benjamin","given":"Benjamin"},{"family":"Lehmann","display":"Lehmann, Lorenz","given":"Lorenz","role":"aut"},{"role":"aut","family":"Kratzer","display":"Kratzer, Adelheid","given":"Adelheid"},{"family":"Klingel","given":"Karin","display":"Klingel, Karin","role":"aut"},{"role":"aut","family":"Katus","display":"Katus, Hugo","given":"Hugo"},{"family":"Kaya","display":"Kaya, Ziya","given":"Ziya","role":"aut"},{"display":"Beling, Antje","given":"Antje","family":"Beling","role":"aut"}],"language":["eng"],"title":[{"title":"Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation","title_sort":"Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation"}]} | ||
| SRT | |a BOCKSTAHLEHEARTSPECI9202 | ||