Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model
BackgroundGraft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogenei...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00756/full |
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| author | Aude Burlion Simon Brunel Nicolas Y. Petit Daniel Olive Gilles Marodon |
| author_facet | Aude Burlion Simon Brunel Nicolas Y. Petit Daniel Olive Gilles Marodon |
| author_sort | Aude Burlion |
| collection | DOAJ |
| description | BackgroundGraft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278) molecule is beneficial, but it is unclear whether the same applies to human cells.MethodsHere, we assessed whether a monoclonal antibody (mAb) to human ICOS was able to antagonize the costimulatory signal delivered in vivo to human T cells. To test this hypothesis, we used a xenogeneic model of GVHD where human peripheral blood mononuclear cells were adoptively transferred in immunocompromised NOD.SCID.gc-null mice (NSG).ResultsIn this model, control mice invariably lost weight and died by day 50. In contrast, 65% of the mice receiving a single injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained in a curative xeno-GVHD setting. Mechanistically, administration of the anti-hICOS mAb was associated with a strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell line, mimicking GVL in humans.ConclusionA mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a promising target in the management of BMT, preventing GVHD while preserving GVL. |
| first_indexed | 2024-12-11T14:46:34Z |
| format | Article |
| id | doaj.art-f5b97b1f961e405c82050ab78594453b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T14:46:34Z |
| publishDate | 2017-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f5b97b1f961e405c82050ab78594453b2022-12-22T01:01:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-06-01810.3389/fimmu.2017.00756279507Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine ModelAude Burlion0Simon Brunel1Nicolas Y. Petit2Daniel Olive3Gilles Marodon4Sorbonne Universités, UPMC Université Paris 06, CIMI-PARIS (Centre d’Immunologie et des Maladies Infectieuses), INSERM U 1135, CNRS ERL 8255, Paris, FranceSorbonne Universités, UPMC Université Paris 06, CIMI-PARIS (Centre d’Immunologie et des Maladies Infectieuses), INSERM U 1135, CNRS ERL 8255, Paris, FranceSorbonne Universités, UPMC Université Paris 06, CIMI-PARIS (Centre d’Immunologie et des Maladies Infectieuses), INSERM U 1135, CNRS ERL 8255, Paris, FranceCentre de recherche en Cancérologie de Marseille, INSERM U1068, CNRS U7258, Aix Marseille Université, Institut Paoli – Calmettes, Marseille, FranceSorbonne Universités, UPMC Université Paris 06, CIMI-PARIS (Centre d’Immunologie et des Maladies Infectieuses), INSERM U 1135, CNRS ERL 8255, Paris, FranceBackgroundGraft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278) molecule is beneficial, but it is unclear whether the same applies to human cells.MethodsHere, we assessed whether a monoclonal antibody (mAb) to human ICOS was able to antagonize the costimulatory signal delivered in vivo to human T cells. To test this hypothesis, we used a xenogeneic model of GVHD where human peripheral blood mononuclear cells were adoptively transferred in immunocompromised NOD.SCID.gc-null mice (NSG).ResultsIn this model, control mice invariably lost weight and died by day 50. In contrast, 65% of the mice receiving a single injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained in a curative xeno-GVHD setting. Mechanistically, administration of the anti-hICOS mAb was associated with a strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell line, mimicking GVL in humans.ConclusionA mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a promising target in the management of BMT, preventing GVHD while preserving GVL.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00756/fullgraft-vs-host diseasegraft vs leukemia effectantibodiesmonoclonalmiceNSG |
| spellingShingle | Aude Burlion Simon Brunel Nicolas Y. Petit Daniel Olive Gilles Marodon Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model Frontiers in Immunology graft-vs-host disease graft vs leukemia effect antibodies monoclonal mice NSG |
| title | Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model |
| title_full | Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model |
| title_fullStr | Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model |
| title_full_unstemmed | Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model |
| title_short | Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model |
| title_sort | targeting the human t cell inducible costimulator molecule with a monoclonal antibody prevents graft vs host disease and preserves graft vs leukemia in a xenograft murine model |
| topic | graft-vs-host disease graft vs leukemia effect antibodies monoclonal mice NSG |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00756/full |
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