دورية أكاديمية
CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice.
| العنوان: | CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice. |
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| المؤلفون: | Adams RC; Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.; Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.; Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Carter-Cusack D; Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Llanes GT; Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Hunter CR; Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Vinnakota JM; Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany., Ruitenberg MJ; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia., Vukovic J; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia., Bertolino P; Centenary Institute and University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Chand KK; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia., Wixey JA; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.; Perinatal Research Centre, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia., Nayler SP; Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Hill GR; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA.; Division of Oncology, Department of Medicine, University of Washington, Seattle, WA., Furlan SN; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA., Zeiser R; Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.; German Cancer Consortium, Partner Site Freiburg, Freiburg, Germany, and German Cancer Research Centre, Heidelberg, Germany., MacDonald KPA; Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| المصدر: | Blood [Blood] 2024 Mar 07; Vol. 143 (10), pp. 912-929. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Graft vs Host Disease*/etiology , Hematopoietic Stem Cell Transplantation*/adverse effects, Humans ; Mice ; Animals ; Neuroinflammatory Diseases ; CD4-Positive T-Lymphocytes ; Macrophages/pathology ; Receptor Protein-Tyrosine Kinases ; Receptors, Colony-Stimulating Factor |
| مستخلص: | Abstract: Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.) |
| التعليقات: | Comment in: Blood. 2024 Mar 7;143(10):841-842. (PMID: 38451516) |
| المشرفين على المادة: | EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) 0 (Receptors, Colony-Stimulating Factor) |
| تواريخ الأحداث: | Date Created: 20231204 Date Completed: 20240308 Latest Revision: 20240324 |
| رمز التحديث: | 20240324 |
| DOI: | 10.1182/blood.2023022040 |
| PMID: | 38048572 |
| قاعدة البيانات: | MEDLINE |
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