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2. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study

Author

Salles, Gilles, Duell, Johannes, González Barca, Eva, Tournilhac, Olivier, Jurczak, Wojciech, Liberati, Anna Marina, Nagy, Zsolt, Obr, Aleš, Gaidano, Gianluca, André, Marc, Kalakonda, Nagesh, Dreyling, Martin, Weirather, Johannes, Dirnberger-Hertweck, Maren, Ambarkhane, Sumeet, Fingerle-Rowson, Günter, and Maddocks, Kami

Published
2020
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3. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1–2a trial

Author

Raab, Marc S, Engelhardt, Monika, Blank, Antje, Goldschmidt, Hartmut, Agis, Hermine, Blau, Igor W, Einsele, Hermann, Ferstl, Barbara, Schub, Natalie, Röllig, Christoph, Weisel, Katja, Winderlich, Mark, Griese, Janine, Härtle, Stefan, Weirather, Johannes, Jarutat, Tiantom, Peschel, Christian, and Chatterjee, Manik

Published
2020
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4. Role of CD4+ T-cells for regulating splenic myelopoiesis and monocyte differentiation after experimental myocardial infarction.

Author

Gladow, Nadine, Hollmann, Claudia, Weirather, Johannes, Ding, Xin, Burkard, Matthias, Uehlein, Sabrina, Bharti, Richa, Förstner, Konrad, Kerkau, Thomas, Beyersdorf, Niklas, Frantz, Stefan, Ramos, Gustavo, and Hofmann, Ulrich

Subjects
MYOCARDIAL infarction, T cells, REGULATORY T cells, PROGENITOR cells, PARACRINE mechanisms
Abstract

Myocardial infarction (MI) induces the generation of proinflammatory Ly6Chigh monocytes in the spleen and the recruitment of these cells to the myocardium. CD4+ Foxp3+ CD25+ T-cells (Tregs) promote the healing process after myocardial infarction by engendering a pro-healing differentiation state in myocardial monocyte-derived macrophages. We aimed to study the effects of CD4+ T-cells on splenic myelopoiesis and monocyte differentiation. We instigated MI in mice and found that MI-induced splenic myelopoiesis is abrogated in CD4+ T-cell deficient animals. Conventional CD4+ T-cells promoted myelopoiesis in vitro by cell–cell-contact and paracrine mechanisms, including interferon-gamma (IFN-γ) signalling. Depletion of regulatory T-cells enhanced myelopoiesis in vivo, as evidenced by increases in progenitor cell numbers and proliferative activity in the spleen 5 days after MI. The frequency of CD4+ T-cells-producing factors that promote myelopoiesis increased within the spleen of Treg-depleted mice. Moreover, depletion of Tregs caused a proinflammatory bias in splenic Ly6Chigh monocytes, which showed predominantly upregulated expression of IFN-γ responsive genes after MI. Our results indicate that conventional CD4+ T-cells promote and Tregs attenuate splenic myelopoiesis and proinflammatory differentiation of monocytes. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Myocardial aging as a T-cell–mediated phenomenon

Author

Ramos, Gustavo Campos, van den Berg, Anne, Nunes-Silva, Vânia, Weirather, Johannes, Peters, Laura, Burkard, Matthias, Friedrich, Mike, Pinnecker, Jürgen, Abeßer, Marco, Heinze, Katrin G., Schuh, Kai, Beyersdorf, Niklas, Kerkau, Thomas, Demengeot, Jocelyne, Frantz, Stefan, and Hofmann, Ulrich

Published
2017

8. Prozesssimulation des Laserstrahlschmelzens mit der Smoothed-Particle-Hydrodynamics-Methode

Author

Zäh, Michael F. (Prof. Dr.), Zäh, Michael F. (Prof. Dr.);Adams, Nikolaus A. (Prof. Dr.), Weirather, Johannes, Zäh, Michael F. (Prof. Dr.), Zäh, Michael F. (Prof. Dr.);Adams, Nikolaus A. (Prof. Dr.), and Weirather, Johannes

Abstract

In dieser Arbeit wird ein numerisches Simulationsmodell für das additive Fertigungsverfahren Laserstrahlschmelzen vorgestellt. Das Modell basiert auf der Smoothed-Particle-Hydrodynamics-Methode (SPH) in einer für Mehrphasenströmungen geeigneten Formulierung. In die Modellierung gehen physikalische Phänomene wie die Wärmeleitung sowie der von an der Schmelzbadoberfläche verdampfenden Atomen verursachte Rückstoßdruck ein. Die Simulationsergebnisse werden experimentellen Daten gegenübergestellt., In this work, a numerical simulation model for the additive manufacturing process Laser Beam Melting is presented. The model is based on the Smoothed Particle Hydrodynamics (SPH) method in a formulation suitable for the computation of multiphase flows. Physical phenomena such as heat conduction and the recoil pressure caused by atoms evaporating at the melt pool surface are considered in the modeling. The simulation results are compared with experimental data.

Published
2023

9. Additive Fertigungsverfahren

Author

Zäh, Michael F., primary, Schilp, Johannes, additional, Weirather, Johannes, additional, Zeller, Christian, additional, Schmiegel, Benedikt, additional, Ott, Michael, additional, and Westhäuser, Sebastian, additional

Published
2018
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10. Poster: ABCL-022 Pharmacokinetics and Pharmacodynamics in First-MIND: A Phase Ib, Open-Label, Randomized Study of Tafasitamab ± Lenalidomide + R-CHOP in Patients With Newly Diagnosed Diffuse Large B-cell Lymphoma

Author

Belada, David, primary, Kopeckova, Katerina, additional, Burgues, Juan Miguel Bergua, additional, Stevens, Don, additional, Nowakowski, Grzegorz S., additional, Waldron-Lynch, Maeve, additional, Hadar, Nira, additional, Weirather, Johannes, additional, Lässig, Charlotte, additional, Blair, Derek, additional, and Dreyling, Martin, additional

Published
2022
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11. Pharmacokinetics (PK) and pharmacodynamics (PD) in First-MIND: A phase Ib, open-label, randomized study of tafasitamab (tafa) ± lenalidomide (LEN) in addition to R-CHOP in patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL).

Author

Belada, David, primary, Kopeckova, Katerina, additional, Bergua Burgues, Juan Miguel, additional, Stevens, Don A., additional, Nowakowski, Grzegorz S., additional, Waldron-Lynch, Maeve, additional, Hadar, Nira, additional, Weirather, Johannes, additional, Lässig, Charlotte, additional, Blair, Derek, additional, and Dreyling, Martin H., additional

Published
2022
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12. Contributors

Author

Altara, Raffaele, primary, Beaudoin, Jonathan, additional, Blankesteijn, W. Matthijs, additional, Brunner-La Rocca, Hans-Peter, additional, Buys, Emmanuel, additional, Carbone, Federico, additional, Cicero, Arrigo F.G., additional, Daskalopoulos, Evangelos P., additional, de Castro Brás, Lisandra E., additional, Deleon-Pennell, Kristine Y., additional, Eisel, Uli L.M., additional, Favari, Elda, additional, Frangogiannis, Nikolaos G., additional, Frantz, Stefan, additional, Frunza, Olga, additional, Hall, Michael E., additional, Hermans, Kevin C.M., additional, Heymans, Stephane, additional, Iyer, Rugmani Padmanabhan, additional, Kusters, Dennis H.M., additional, Lange, Richard A., additional, Lindsey, Merry L., additional, Ma, Yonggang, additional, Mann, Douglas L., additional, Montecucco, Fabrizio, additional, Planavila, Anna, additional, Reutelingsperger, Chris P.M., additional, Ronda, Nicoletta, additional, Scherrer-Crosbie, Marielle, additional, Schoemaker, Regien G., additional, Schroen, Blanche, additional, Schurgers, Leon J., additional, Tegtmeier, Jan, additional, Thoonen, Robrecht, additional, Toba, Hiroe, additional, van Bilsen, Marc, additional, van Delft, Lieke, additional, van Empel, Vanessa, additional, Vandenwijngaert, Sara, additional, Weirather, Johannes, additional, Yabluchanskiy, Andriy, additional, and Zimetti, Francesca, additional

Published
2015
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14. Tafasitamab combined with idelalisib or venetoclax in patients with CLL previously treated with a BTK inhibitor

Author

Staber, Philipp Bernhard, primary, Jurczak, Wojciech, additional, Greil, Richard, additional, Vucinic, Vladan, additional, Middeke, Jan Moritz, additional, Montillo, Marco, additional, Munir, Talha, additional, Neumeister, Peter, additional, Schetelig, Johannes, additional, Stilgenbauer, Stephan, additional, Striebel, Frank, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Brugger, Wolfram, additional, Kelemen, Peter, additional, Wendtner, Clemens-Martin, additional, and Woyach, Jennifer Ann, additional

Published
2021
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15. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma

Author

Duell, Johannes, primary, Maddocks, Kami J., additional, González-Barca, Eva, additional, Jurczak, Wojciech, additional, Liberati, Anna Marina, additional, De Vos, Sven, additional, Nagy, Zsolt, additional, Obr, Aleš, additional, Gaidano, Gianluca, additional, Abrisqueta, Pau, additional, Kalakonda, Nagesh, additional, André, Marc, additional, Dreyling, Martin, additional, Menne, Tobias, additional, Tournilhac, Olivier, additional, Augustin, Marinela, additional, Rosenwald, Andreas, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet, additional, and Salles, Gilles, additional

Published
2021
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16. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, Duell, Johannes, Maddocks, Kami J., González-Barca, Eva, Jurczak, Wojciech, Liberati, Anna Marina, De Vos, Sven, Nagy, Zsolt, Obr, Aleš, Gaidano, Gianluca, Abrisqueta, Pau, Kalakonda, Nagesh, André, Marc, Dreyling, Martin, Menne, Tobias, Tournilhac, Olivier, Augustin, Marinela, Rosenwald, Andreas, Dirnberger-Hertweck, Maren, Weirather, Johannes, Ambarkhane, Sumeet, Salles, Gilles, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, Duell, Johannes, Maddocks, Kami J., González-Barca, Eva, Jurczak, Wojciech, Liberati, Anna Marina, De Vos, Sven, Nagy, Zsolt, Obr, Aleš, Gaidano, Gianluca, Abrisqueta, Pau, Kalakonda, Nagesh, André, Marc, Dreyling, Martin, Menne, Tobias, Tournilhac, Olivier, Augustin, Marinela, Rosenwald, Andreas, Dirnberger-Hertweck, Maren, Weirather, Johannes, Ambarkhane, Sumeet, and Salles, Gilles

Abstract

Not available.

Published
2021

17. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.

Author

UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, Duell, Johannes, Maddocks, Kami J, González-Barca, Eva, Jurczak, Wojciech, Liberati, Anna Marina, De Vos, Sven, Nagy, Zsolt, Obr, Aleš, Gaidano, Gianluca, Abrisqueta, Pau, Kalakonda, Nagesh, André, Marc, Dreyling, Martin, Menne, Tobias, Tournilhac, Olivier, Augustin, Marinela, Rosenwald, Andreas, Dirnberger-Hertweck, Maren, Weirather, Johannes, Ambarkhane, Sumeet, Salles, Gilles, UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, Duell, Johannes, Maddocks, Kami J, González-Barca, Eva, Jurczak, Wojciech, Liberati, Anna Marina, De Vos, Sven, Nagy, Zsolt, Obr, Aleš, Gaidano, Gianluca, Abrisqueta, Pau, Kalakonda, Nagesh, André, Marc, Dreyling, Martin, Menne, Tobias, Tournilhac, Olivier, Augustin, Marinela, Rosenwald, Andreas, Dirnberger-Hertweck, Maren, Weirather, Johannes, Ambarkhane, Sumeet, and Salles, Gilles

Abstract

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study (NCT02399085) of autologous stem-cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had 1-3 prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression (PD). The primary endpoint was best objective response rate (ORR). After ≥35 months' follow-up (data cut-off: October 30, 2020), ORR was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). Median duration of response (DoR) was 43.9 months (95% CI: 26.1-not reached [NR]); median overall survival (OS) was 33.5 months (18.3-NR); and median progression-free survival was 11.6 months (6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most patient subgroups. This extended L-MIND follow-up confirms the long DoR, meaningful OS, and welldefined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in ASCT-ineligible patients with R/R DLBCL.

Published
2021

18. Long-Term Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Author

Maddocks, Kami J., Duell, Johannes, González-Barca, Eva, Jurczak, Wojciech, Liberati, Anna Marina, de Vos, Sven, Nagy, Zsolt, Obr, Aleš, Gaidano, Gianluca, Abrisqueta, Pau, André, Marc, Dreyling, Martin, Menne, Tobias F, Dirnberger-Hertweck, Maren, Weirather, Johannes, Ambarkhane, Sumeet, and Salles, Gilles

Published
2020
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19. Long-term analyses from L-MIND, a phase II study of tafasitamab (MOR208) combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).

Author

Düll, Johannes, primary, Maddocks, Kami J., additional, Gonzalez-Barca, Eva, additional, Jurczak, Wojciech, additional, Liberati, Anna Marina, additional, Obr, Aleš, additional, Gaidano, Gianluca, additional, Abrisqueta, Pau, additional, André, Marc, additional, Dreyling, Martin H., additional, Menne, Tobias, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet Vijay, additional, and Salles, Gilles A., additional

Published
2021
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20. Efficacy of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with High-Risk Relapsed or Refractory Diffuse Large B-Cell Lymphoma in the L-Mind Study

Author

González-Barca, Eva, primary, Duell, Johannes, additional, Cavallo, Federica, additional, Sancho, Juan-Manuel, additional, Nagy, Zsolt, additional, Abrisqueta, Pau, additional, Panizo, Carlos, additional, Augustin, Marinela, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet, additional, Maddocks, Kami J., additional, Kalakonda, Nagesh, additional, and Salles, Gilles, additional

Published
2020
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21. ABCL-170: Long-Term Outcomes from the Phase II L-MIND Study of Tafasitamab (MOR208) Plus Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Author

Salles, Gilles, primary, Duell, Johannes, additional, González-Barca, Eva, additional, Jurczak, Wojciech, additional, Marina Liberati, Anna, additional, de Vos, Sven, additional, Nagy, Zsolt, additional, Obr, Aleš, additional, Gaidano, Gianluca, additional, Abrisqueta, Pau, additional, Kalakonda, Nagesh, additional, André, Marc, additional, Dreyling, Martin, additional, Menne, Tobias, additional, Tournilhac, Olivier, additional, Augustin, Marinela, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet, additional, and Maddocks, Kami J, additional

Published
2020
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22. A Phase IIa, Open-Label, Multicenter Study of Single-Agent Tafasitamab (MOR208), an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma: Long-Term Follow-up, Final Analysis

Author

Jurczak, Wojciech, primary, Zinzani, Pier Luigi, additional, Hess, Georg, additional, Gaidano, Gianluca, additional, Provencio, Mariano, additional, Nagy, Zsolt, additional, Robak, Tadeusz, additional, Maddocks, Kami J., additional, Buske, Christian, additional, Ambarkhane, Sumeet, additional, Brugger, Wolfram, additional, Dirnberger-Hertweck, Maren, additional, Tillmanns, Sascha, additional, Weirather, Johannes, additional, and Blum, Kristie, additional

Published
2019
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23. Primary Analysis of Anti-CD19 Tafasitamab (MOR208) Treatment in Combination with Idelalisib or Venetoclax in R/R CLL Patients Who Failed Prior BTK Inhibitor Therapy (COSMOS Trial)

Author

Staber, Philipp Bernhard, primary, Jurczak, Wojciech, additional, Brugger, Wolfram, additional, Chanan-Khan, Asher A., additional, Greil, Richard, additional, Hellmann, Andrzej, additional, Dirnberger-Hertweck, Maren, additional, Kelemen, Peter, additional, Middeke, Jan Moritz, additional, Montillo, Marco, additional, Motta, Marina, additional, Munir, Talha, additional, Neumeister, Peter, additional, Niederweiser, Dietger, additional, Parikh, Sameer A., additional, Schetelig, Johannes, additional, Stilgenbauer, Stephan, additional, Vucinic, Vladan, additional, Weirather, Johannes, additional, Woyach, Jennifer, additional, and Wendtner, Clemens-Martin, additional

Published
2019
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24. Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Author

Duell, Johannes, primary, Maddocks, Kami J., additional, González-Barca, Eva, additional, Jurczak, Wojciech, additional, Liberati, Anna Marina, additional, de Vos, Sven, additional, Nagy, Zsolt, additional, Obr, Aleš, additional, Gaidano, Gianluca, additional, Abrisqueta, Pau, additional, André, Marc, additional, Dreyling, Martin, additional, Menne, Tobias F, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet, additional, and Salles, Gilles A., additional

Published
2019
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26. Update of the single-arm phase II L-MIND study of MOR208 + lenalidomide (LEN) in relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL): Response rates in patient subgroups with poor prognosis.

Author

Maddocks, Kami J., primary, Duell, Johannes, additional, González Barca, Eva, additional, Jurczak, Wojciech, additional, Liberati, Anna Marina, additional, Nagy, Zsolt, additional, Obr, Aleš, additional, Gaidano, Gianluca, additional, André, Marc, additional, Kalakonda, Nagesh, additional, Dreyling, Martin H., additional, Zinzani, Pier Luigi, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet Vijay, additional, and Salles, Gilles A., additional

Published
2019
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27. Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Author

Salles, Gilles Andre, primary, Duell, Johannes, additional, González-Barca, Eva, additional, Jurczak, Wojciech, additional, Liberati, Anna Marina, additional, Nagy, Zsolt, additional, Obr, Aleš, additional, Gaidano, Gianluca, additional, Andre, Marc, additional, Kalakonda, Nagesh, additional, Dreyling, Martin, additional, Zinzani, Pier Luigi, additional, Dirnberger-Hertweck, Maren, additional, Weirather, Johannes, additional, Ambarkhane, Sumeet, additional, and Maddocks, Kami J., additional

Published
2018
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28. Two-Cohort Phase II Study in R/R CLL (COSMOS): First Preliminary Safety and Efficacy Results of Anti-CD19 MOR208 Treatment in Combination with Venetoclax in Patients Who Discontinued Prior BTK Inhibitor Therapy

Author

Staber, Philipp Bernhard, primary, Chanan-Khan, Asher A., additional, Munir, Talha, additional, Niederweiser, Dietger, additional, Schetelig, Johannes, additional, Middeke, Jan Moritz, additional, Dirnberger-Hertweck, Maren, additional, Kelemen, Peter, additional, Weirather, Johannes, additional, Parikh, Sameer A., additional, Stilgenbauer, Stephan, additional, Wendtner, Clemens-Martin, additional, and Woyach, Jennifer A., additional

Published
2018
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29. L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.

Author

Maddocks, Kami J., primary, González Barca, Eva, additional, Jurczak, Wojciech, additional, Liberati, Anna Marina, additional, Duell, Johannes, additional, Nagy, Zsolt, additional, Papajík, Tomáš, additional, Andre, Marc, additional, Kalakonda, Nagesh, additional, Dreyling, Martin H., additional, Zinzani, Pier Luigi, additional, Ambarkhane, Sumeet Vijay, additional, Weirather, Johannes, additional, and Salles, Gilles A., additional

Published
2017
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30. Die Bedeutung von CD4+ T-Lymphozyten für die kardiale Wundheilung und Remodeling nach experimentellem Herzinfarkt im Mausmodell

Author

Weirather, Johannes

Subjects
T-Lymphozyt, Antigen CD4, Herzinfarkt, ddc:570, Wundheilung, Maus
Abstract

Cardiac healing after myocardial infarction (MI) represents the cardinal prerequisite for proper replacement of the irreversibly injured myocardium. In contrast to innate immunity, the functional role of adaptive immunity in postinfarction healing has not been systematically addressed. The present study focused on the influence of CD4+ T lymphocytes on wound healing and cardiac remodeling after experimental myocardial infarction in mice. Both conventional and Foxp3+ regulatory CD4+ T cells (Treg cells) became activated in heart draining lymph nodes after MI and accumulated in the infarcted myocardium. T cell activation was strictly antigen-dependant as T cell receptor-transgenic OT-II mice in which CD4+ T cells exhibit a highly limited T cell receptor repertoire did not expand in heart-draining lymph nodes post-MI. Both OT-II and major histocompatibility complex class II-deficient mice lacking a CD4+ T cell compartment showed a fatal clinical postinfarction outcome characterized by disturbed scar tissue construction that resulted in impaired survival due to a prevalence of left-ventricular ruptures. To assess the contribution of anti-inflammatory Treg cells on wound healing after MI, the Treg cell compartment was depleted using DEREG mice that specifically express the human diphtheria toxin receptor in Foxp3-positive cells, resulting in Treg cell ablation after diphtheria toxin administration. In a parallel line of experiments, a second model of anti-CD25 antibody-mediated Treg cell immuno-depletion was used. Treg cell ablation prior to MI resulted in adverse postinfarction left-ventricular dilatation associated with cardiac deterioration. Mechanistically, Treg cell depletion resulted in an increased recruitment of pro-inflammatory neutrophils and Ly-6Chigh monocytes into the healing myocardium. Furthermore, Treg cell-ablated mice exhibited an adverse activation of conventional non-regulatory CD4+ and CD8+ T cells that showed a reinforced infiltration into the infarct zone. Increased synthesis of TNFα and IFNγ by conventional CD4+ and CD8+ T cells in hearts of Treg cell-depleted mice provoked an M1-like macrophage polarization characterized by heightened expression of healing-compromising induced NO synthase, in line with a reduced synthesis of healing-promoting transglutaminase factor XIII (FXIII), osteopontin (OPN) and transforming growth factor beta 1 (TGFβ1). Therapeutic Treg cell activation by a superagonistic anti-CD28 monoclonal antibody stimulated Treg cell accumulation in the infarct zone and led to an increased expression of mediators inducing an M2-like macrophage polarization state, i.e. interleukin-10, interleukin-13 and TGFβ1. M2-like macrophage differentiation in the healing infarct was associated with heightened expression of scar-forming procollagens as well as scar-stabilizing FXIII and OPN, resulting in improved survival due to a reduced incidence of left-ventricular ruptures. Therapeutic Treg cell activation and the induction of a beneficial M2-like macrophage polarization was further achieved by employing a treatment modality of high clinical potential, i.e. by therapeutic administration of IL-2/ anti-IL-2 monoclonal antibody complexes. The findings of the present study suggest that therapeutic Treg cell activation and the resulting improvement of healing may represent a suitable strategy to attenuate adverse infarct expansion, left-ventricular remodeling, or infarct ruptures in patients with MI., Die kardiale Wundheilung nach einem Herzinfarkt ist unabdingbare Voraussetzung um das unwideruflich beschädigte Myokard zu ersetzen. Im Gegensatz zur Rolle der angeborenen Immunität ist zur Bedeutung der adaptiven Immunität für die kardiale Wundheilung nur wenig bekannt. Im Fokus der Studie stand deshalb die Rolle von CD4+ T-Zellen bei der Wundheilung und kardialem Remodeling nach einem experimentellen Herzinfarkt im Mausmodell. Sowohl konventionelle, als auch Foxp3-positive regulatorische CD4+ T Zellen (Treg-Zellen) wurden im Lymphknoten infarzierter Tiere aktiviert und akkumulierten im Infarktareal. Die Aktivierung von CD4+ T Zellen nach MI setzte die Erkennung von Selbstantigenen voraus, da OT-II Tiere, die ein stark eingeschränktes T-Zell-Rezeptor-Repertoire aufweisen, keine T-Zell-Aktivierung zeigten. Sowohl OT-II Tiere, als auch Haupthistokompatibilitätskomplex Klasse II Knock-out Mäuse, die kein CD4+ T-Zell Kompartment aufweisen, zeigten einen fatalen klinischen Phänotyp, welcher durch eine gestörte Narbenbildung und damit verbunden einem verstärkten Auftreten linksventrikulärer Rupturen verbunden war. Um den Einfluss anti-inflammatorischer Treg-Zellen auf die kardiale Wundheilung nach Herzinfarkt zu untersuchen, wurde das Treg-Zell Kompartment vor MI Induktion depletiert. Hierzu wurden DEREG Mäuse verwendet, in denen Foxp3-positive Zellen den humanen Diphtherietoxin-Rezeptor exprimieren, sodass nach nach Diphtierietoxin-Applikation die Treg-Zellen spezifisch depletiert werden. In einer dazu parallel verlaufenden Versuchsreihe wurden die Treg-Zellen mittels anti-CD25 monoklonaler Antikörper depletiert. Die Depletion des Treg-Zell Kompartments 2 Tage vor MI Induktion bewirkte ein verschlechtertes links-ventrikuläres Remodeling und damit einhergehend eine signifikante Verschlechterung der Herzfunktion. Mechanistisch führte die Treg-Zell Depletion zu einer verstärkten Rekrutierung pro-inflammatorischer Ly-6Chigh Monozyten und neutrophilen Granulozyten ins Infarktareal. Die Depletion von Treg-Zellen war weiterhin mit einer adversen Aktivierung konventioneller CD4+ und CD8+ T-Zellen assoziiert, die eine verstärkte Infiltration ins infarzierte Myokard zeigten. Die erhöhte Synthese von TNFα und IFNγ in konventionellen T-Zellen führte zu einer M1-Makrophagen Polarisierung, welche durch eine verstärkte Expression der induzierbaren NO Synthase charakterisiert war. Weiterhin exprimierten diese M1 Makrophagen signifikant weniger der für eine geordnete Heilung essentiellen Faktoren Osteopontin, Transglutaminase Faktor XIII und transforming growth factor beta 1 (TGFβ1). Im Gegensatz zu den Depletionsversuchen führte die therapeutische Aktivierung der Treg-Zellen durch einen superagonistischen anti-CD28 monoklonalen Antikörper zu einer verstärkten Rekrutierung von Treg-Zellen ins Infarktareal und bewirkte eine erhöhte Synthese von Interleukin (IL)-10, IL-13 sowie TGFβ1. Die damit einhergehende M2 Makrophagenpolarisierung im Infarktareal war mit einer verstärkten Narbenbildung sowie der Synthese von Osteopontin und Transglutaminase Faktor XIII verbunden, welche sich stabilisierend auf die Narbenbildung auswirken. Folgerichtig zeigten die behandelten Tiere ein verbessertes Überleben aufgrund einer signifikant verringerten Inzidenz linksventrikulärer Rupturen. Alternativ zum superagonistischen anti-CD28 monoklonalen Antikörper wurde ein weiterer klinisch relevanter Ansatz zur therapeutischen Aktivierung von Treg-Zellen verfolgt. Durch die Applikation von IL-2/ anti-IL-2 Antikörper-Komplexen konnte ebenfalls eine M2 Makrophagenpolarisierung hervorgerufen werden, die mit einer verstärkten Narbenbildung einherging. Die Ergebnisse der vorliegenden Studie deuten darauf hin, dass eine therapeutische Aktivierung von Treg-Zellen bei Infarktpatienten und die dadurch hervorgerufene Verbesserung der Wundheilung potentiell einen geeigneten Ansatz darstellt, durch welchen adverses linksventrikuläres Remodeling sowie Infarktrupturen verhindert werden können.

Published
2014

32. Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction

Author

Chen, Wen, primary, Spitzl, Annett, additional, Mathes, Denise, additional, Nikolaev, Viacheslav O., additional, Werner, Franziska, additional, Weirather, Johannes, additional, Špiranec, Katarina, additional, Röck, Katharina, additional, Fischer, Jens W., additional, Kämmerer, Ulrike, additional, Stegner, David, additional, Baba, Hideo A., additional, Hofmann, Ulrich, additional, Frantz, Stefan, additional, and Kuhn, Michaela, additional

Published
2016
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37. Targeting P-Selectin by Gallium-68–Labeled Fucoidan Positron Emission Tomography for Noninvasive Characterization of Vulnerable Plaques

Author

Li, Xiang, primary, Bauer, Wolfgang, additional, Israel, Ina, additional, Kreissl, Michael C., additional, Weirather, Johannes, additional, Richter, Dominik, additional, Bauer, Elisabeth, additional, Herold, Volker, additional, Jakob, Peter, additional, Buck, Andreas, additional, Frantz, Stefan, additional, and Samnick, Samuel, additional

Published
2014
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39. Specific somatostatin receptor II expression in arterial plaque: 68Ga-DOTATATE autoradiographic, immunohistochemical and flow cytometric studies in apoE-deficient mice

Author

Li, Xiang, primary, Bauer, Wolfgang, additional, Kreissl, Michael C., additional, Weirather, Johannes, additional, Bauer, Elisabeth, additional, Israel, Ina, additional, Richter, Dominik, additional, Riehl, Gabriele, additional, Buck, Andreas, additional, and Samnick, Samuel, additional

Published
2013
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47. Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Author

Salles, Gilles Andre, Duell, Johannes, González-Barca, Eva, Jurczak, Wojciech, Liberati, Anna Marina, Nagy, Zsolt, Papajik, Tomáš, Gaidano, Gianluca, Andre, Marc, Kalakonda, Nagesh, Dreyling, Martin, Zinzani, Pier Luigi, Ambarkhane, Sumeet, Weirather, Johannes, Dirnberger-Hertweck, Maren, and Maddocks, Kami J.

Abstract

Introduction:The B-lymphocyte antigen CD19 is broadly and homogeneously expressed across different B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), and enhances B-cell receptor signaling and tumor cell proliferation. MOR208 is an Fc-enhanced, humanized, monoclonal antibody that targets CD19 on tumor cells leading to natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity, macrophage-mediated antibody-dependent cell-mediated phagocytosis and direct cytotoxicity. The immunomodulatory drug, lenalidomide (LEN), has both antiproliferative and antiangiogenic effects, and can stimulate the activity of immune effectors, such as NK cells. In clinical studies, both MOR208 and LEN have demonstrated single agent activity in patients with relapsed or refractory (R-R) DLBCL. In addition, MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing, multicenter phase II study was designed to assess the safety and efficacy of MOR208 combined with LEN in patients with R-R DLBCL (NCT02399085).

Published
2017
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48. Abstract 163.

Author

Hofmann, Ulrich, Knorr, Susanne, Weirather, Johannes, Frey, Anna, and Frantz, Stefan

Published
2012

49. Specific somatostatin receptor II expression in arterial plaque: 68Ga-DOTATATE autoradiographic, immunohistochemical and flow cytometric studies in apoE-deficient mice.

Author

Li, Xiang, Bauer, Wolfgang, Kreissl, Michael C., Weirather, Johannes, Bauer, Elisabeth, Israel, Ina, Richter, Dominik, Riehl, Gabriele, Buck, Andreas, and Samnick, Samuel

Subjects
*SOMATOSTATIN receptors, *GENE expression, *ATHEROSCLEROTIC plaque, *AUTORADIOGRAPHY, *IMMUNOHISTOCHEMISTRY, *FLOW cytometry, *LABORATORY mice
Abstract

Abstract: Background: The rupture of atherosclerotic plaques is triggered by inflammation. Specific detection of inflammation is therefore the focus of many investigations. Noninvasive imaging methods, such as positron emission tomography (PET), also are suited for this purpose. 68Ga-DOTATATE is a 68Ga-labeled radiotracer with specific affinity to somatostatin receptor subtype-2 (SSTR-2). SSTR-2 was found specifically expressed on human macrophages/monocytes. Objective: We aimed to confirm the distribution of SSTR-2 in inflammatory plaques, and to assess its co-localization with macrophages within the plaques. We also assessed 68Ga-DOTATATE uptakes in plaques by autoradiography. Method: Apolipoprotein E (ApoE)−/− mice on a high-cholesterol diet were injected with 68Ga-DOTATATE. The animals were sacrificed and aorta sections were examined using autoradiography and immunohistochemistry. Furthermore, expression of SSTR-2 was analyzed by flow cytometry. Western blot was conducted to assess SSTR-2 regulation in basal and lipopolysaccharide (LPS)-activated state. To evaluate the specificity of the 68Ga-DOTATATE, the sections were pre-incubated with monoclonal SSTR-2 antibody before autoradiography. Result: Autoradiographic imaging showed uptake of 68Ga-DOTATATE co-localized with the macrophage-rich plaques by immunohistochemical examination. A high expression of SSTR-2 on macrophages was found by flow cytometry and western blot. Stimulation with lipopolysaccharide did not alter expression of SSTR-2 in macrophages. Conclusion: Due to its specific binding to macrophages, 68Ga-DOTATATE might be a suitable radiotracer for the evaluation of inflammatory activity in unstable plaques. [Copyright &y& Elsevier]

Published
2013
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50. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.

Author

Weirather J, Hofmann UD, Beyersdorf N, Ramos GC, Vogel B, Frey A, Ertl G, Kerkau T, and Frantz S

Subjects
Animals, Cell Polarity, Lymphocyte Activation, Macrophages physiology, Mice, Mice, Inbred C57BL, Myeloid Cells physiology, Myocardial Infarction immunology, T-Lymphocytes, Regulatory immunology, Cell Differentiation, Forkhead Transcription Factors physiology, Macrophages cytology, Monocytes cytology, Myocardial Infarction physiopathology, T-Lymphocytes, Regulatory physiology, Wound Healing
Abstract

Rationale: An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3(+) CD4(+) regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI., Objective: Our aim was to study the functional role of Treg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation., Methods and Results: Using a model of genetic Treg-cell ablation (Foxp3(DTR) mice), we depleted the Treg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, Treg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in Treg-cell-ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody-mediated depletion. In contrast, therapeutic Treg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA-treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic Treg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing., Conclusions: Our data indicate that Treg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of Treg cells constitutes a novel approach to improve healing post-MI., (© 2014 American Heart Association, Inc.)

Published
2014
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