Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model
ObjectivesDespite their efficacy, some immunotherapies have been shown to induce immune-related adverse events, including the potentially life-threatening cytokine release syndrome (CRS), calling for reliable and translational preclinical models to predict potential safety issues and investigate the...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1357716/full |
| _version_ | 1797321733927075840 |
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| author | Gaëlle H. Martin Alexis Gonon Perrine Martin-Jeantet Florence Renart-Depontieu Zuzana Biesova Anokhi Cifuentes Arnab Mukherjee Thomas Thisted Astrid Doerner Dean O. Campbell Ludovic Bourré Edward H. van der Horst Amélie Rezza Kader Thiam |
| author_facet | Gaëlle H. Martin Alexis Gonon Perrine Martin-Jeantet Florence Renart-Depontieu Zuzana Biesova Anokhi Cifuentes Arnab Mukherjee Thomas Thisted Astrid Doerner Dean O. Campbell Ludovic Bourré Edward H. van der Horst Amélie Rezza Kader Thiam |
| author_sort | Gaëlle H. Martin |
| collection | DOAJ |
| description | ObjectivesDespite their efficacy, some immunotherapies have been shown to induce immune-related adverse events, including the potentially life-threatening cytokine release syndrome (CRS), calling for reliable and translational preclinical models to predict potential safety issues and investigate their rescue. Here, we tested the reliability of humanized BRGSF mice for the assessment of therapeutics-induced CRS features in preclinical settings.MethodsBRGSF mice reconstituted with human umbilical cord blood CD34+ cells (BRGSF-CBC) were injected with anti-CD3 antibody (OKT3), anti-CD3/CD19 bispecific T-cell engager Blinatumomab, or VISTA-targeting antibody. Human myeloid and dendritic cells’ contribution was investigated in hFlt3L-boosted BRGSF-CBC mice. OKT3 treatment was also tested in human PBMC-reconstituted BRGSF mice (BRGSF-PBMC). Cytokine release, immune cell distribution, and clinical signs were followed.ResultsOKT3 injection in BRGSF-CBC mice induced hallmark features of CRS, specifically inflammatory cytokines release, modifications of immune cell distribution and activation, body weight loss, and temperature drop. hFlt3L-boosted BRGSF-CBC mice displayed enhanced CRS features, revealing a significant role of myeloid and dendritic cells in this process. Clinical CRS-managing treatment Infliximab efficiently attenuated OKT3-induced toxicity. Comparison of OKT3 treatment’s effect on BRGSF-CBC and BRGSF-PBMC mice showed broadened CRS features in BRGSF-CBC mice. CRS-associated features were also observed in hFlt3L-boosted BRGSF-CBC mice upon treatment with other T-cell or myeloid-targeting compounds.ConclusionsThese data show that BRGSF-CBC mice represent a relevant model for the preclinical assessment of CRS and CRS-managing therapies. They also confirm a significant role of myeloid and dendritic cells in CRS development and exhibit the versatility of this model for therapeutics-induced safety assessment. |
| first_indexed | 2024-03-08T05:02:56Z |
| format | Article |
| id | doaj.art-f1b517b31b7b45c781d7edf8fa9804ce |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T05:02:56Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f1b517b31b7b45c781d7edf8fa9804ce2024-02-07T10:28:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-02-011510.3389/fimmu.2024.13577161357716Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical modelGaëlle H. Martin0Alexis Gonon1Perrine Martin-Jeantet2Florence Renart-Depontieu3Zuzana Biesova4Anokhi Cifuentes5Arnab Mukherjee6Thomas Thisted7Astrid Doerner8Dean O. Campbell9Ludovic Bourré10Edward H. van der Horst11Amélie Rezza12Kader Thiam13genOway, Lyon, FrancegenOway, Lyon, FrancegenOway, Lyon, FrancegenOway, Lyon, FranceSensei Biotherapeutics Inc., Boston, MA, United StatesSensei Biotherapeutics Inc., Boston, MA, United StatesSensei Biotherapeutics Inc., Boston, MA, United StatesSensei Biotherapeutics Inc., Boston, MA, United StatesCrown Bioscience Inc., San Diego, CA, United StatesCrown Bioscience Inc., San Diego, CA, United StatesCrown Bioscience Inc., San Diego, CA, United StatesSensei Biotherapeutics Inc., Boston, MA, United StatesgenOway, Lyon, FrancegenOway, Lyon, FranceObjectivesDespite their efficacy, some immunotherapies have been shown to induce immune-related adverse events, including the potentially life-threatening cytokine release syndrome (CRS), calling for reliable and translational preclinical models to predict potential safety issues and investigate their rescue. Here, we tested the reliability of humanized BRGSF mice for the assessment of therapeutics-induced CRS features in preclinical settings.MethodsBRGSF mice reconstituted with human umbilical cord blood CD34+ cells (BRGSF-CBC) were injected with anti-CD3 antibody (OKT3), anti-CD3/CD19 bispecific T-cell engager Blinatumomab, or VISTA-targeting antibody. Human myeloid and dendritic cells’ contribution was investigated in hFlt3L-boosted BRGSF-CBC mice. OKT3 treatment was also tested in human PBMC-reconstituted BRGSF mice (BRGSF-PBMC). Cytokine release, immune cell distribution, and clinical signs were followed.ResultsOKT3 injection in BRGSF-CBC mice induced hallmark features of CRS, specifically inflammatory cytokines release, modifications of immune cell distribution and activation, body weight loss, and temperature drop. hFlt3L-boosted BRGSF-CBC mice displayed enhanced CRS features, revealing a significant role of myeloid and dendritic cells in this process. Clinical CRS-managing treatment Infliximab efficiently attenuated OKT3-induced toxicity. Comparison of OKT3 treatment’s effect on BRGSF-CBC and BRGSF-PBMC mice showed broadened CRS features in BRGSF-CBC mice. CRS-associated features were also observed in hFlt3L-boosted BRGSF-CBC mice upon treatment with other T-cell or myeloid-targeting compounds.ConclusionsThese data show that BRGSF-CBC mice represent a relevant model for the preclinical assessment of CRS and CRS-managing therapies. They also confirm a significant role of myeloid and dendritic cells in CRS development and exhibit the versatility of this model for therapeutics-induced safety assessment.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1357716/fullhumanized preclinical modelscytokine release syndromemyeloid cellsBRGSF micesafety assessmentimmunotherapy |
| spellingShingle | Gaëlle H. Martin Alexis Gonon Perrine Martin-Jeantet Florence Renart-Depontieu Zuzana Biesova Anokhi Cifuentes Arnab Mukherjee Thomas Thisted Astrid Doerner Dean O. Campbell Ludovic Bourré Edward H. van der Horst Amélie Rezza Kader Thiam Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model Frontiers in Immunology humanized preclinical models cytokine release syndrome myeloid cells BRGSF mice safety assessment immunotherapy |
| title | Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model |
| title_full | Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model |
| title_fullStr | Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model |
| title_full_unstemmed | Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model |
| title_short | Myeloid and dendritic cells enhance therapeutics-induced cytokine release syndrome features in humanized BRGSF-HIS preclinical model |
| title_sort | myeloid and dendritic cells enhance therapeutics induced cytokine release syndrome features in humanized brgsf his preclinical model |
| topic | humanized preclinical models cytokine release syndrome myeloid cells BRGSF mice safety assessment immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1357716/full |
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