CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice
Abstract Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood–brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition..
Key points PLX3397 treatment during the progression phase of chronic graft-versus-host disease (cGVHD) attenuates pathology in multiple organ systems and reduces T-cell infiltration into the skin.PLX3397 treatment during cGVHD progression attenuates microglia/macrophage reactivity and major histocompatibility complex class II (MHCII) expression in the brain.PLX3397 treatment during cGVHD progression alleviates cognitive impairment..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Journal of neuroinflammation - 20(2023), 1 vom: 15. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shaikh, Samreen N. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Bone-marrow transplant |
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| Anmerkungen: |
© The Author(s) 2023 |
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| doi: |
10.1186/s12974-023-02984-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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SPR054105773 |
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| 520 | |a Abstract Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood–brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition. | ||
| 520 | |a Key points PLX3397 treatment during the progression phase of chronic graft-versus-host disease (cGVHD) attenuates pathology in multiple organ systems and reduces T-cell infiltration into the skin.PLX3397 treatment during cGVHD progression attenuates microglia/macrophage reactivity and major histocompatibility complex class II (MHCII) expression in the brain.PLX3397 treatment during cGVHD progression alleviates cognitive impairment. | ||
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