Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia

Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing–based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER Tnffl/– mice reduced MHC-II expression and decreased CNS T cell infiltrates and VCAM-1+ endothelial cells. GVHD increased microglia TGF-β–activated kinase-1 (TAK1) activation and NF-κB/p38 MAPK signaling. Selective Tak1 deletion in microglia using Cx3cr1creER Tak1fl/fl– mice resulted in reduced TNF production and microglial MHC-II and improved neurocognitive activity. Pharmacological TAK1 inhibition reduced TNF production and MHC-II expression by microglia, Th1 and Th17 T cell infiltrates, and VCAM-1+ endothelial cells and improved neurocognitive activity, without blocking graft-versus-leukemia effects. Consistent with these findings in mice, we observed increased activation and TNF production of microglia in the CNS of GVHD patients. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as a mediator of CNS-GVHD, and provide a TAK1 inhibitor–based approach against GVHD-induced neurotoxicity.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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In conclusion, the decreased numbers of VZV-specific CD8+T-cells during the acute phase and VZV-specific CD4+T-cells during the convalescent phase of disease may account for severe varicella in immunocompromised children. PMID: 32213753 [PubMed - in process]
Source: The Tohoku Journal of Experimental Medicine - Category: Research Authors: Tags: Tohoku J Exp Med Source Type: research
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Source: Cadernos de Saude Publica - Category: International Medicine & Public Health Authors: Tags: Cad Saude Publica Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
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Source: Asian Pacific Journal of Cancer Prevention - Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research
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Source: Current Hematologic Malignancy Reports - Category: Hematology Source Type: research
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Source: Pediatric Surgery International - Category: Surgery Source Type: research
ojo Fujii Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has b...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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Source: Targeted Oncology - Category: Cancer & Oncology Source Type: research
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