Abstract
Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II+ donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1389-1408 |
| Number of pages | 20 |
| Journal | Blood |
| Volume | 139 |
| Issue number | 9 |
| DOIs | |
| State | Published - Mar 3 2022 |
Bibliographical note
Funding Information:NZeg-eGFP mice were provided by Klaus Matthaei (John Curtin School of Medical Research). The authors acknowledge the assistance of the University of Queensland School of Biomedical Sciences Imaging Facility, QIMR Animal Facility, QIMR Berghofer Flow Cytometry and Imaging Facility. The authors thank Michael Rist, Amanda Stanley, and Grace Chojnowski for cell sorting, Madeleine Flynn for graphic design, and QIMR Berghofer Scientific Services, the Genome Informatics Group, and Medical Genomics Group for their support in the RNA-seq analysis. Behavioral tests were performed at the QBI Behaviour and Surgical Facility and the QIMR Animal Facility. This work was supported by grants 1188584 (K.P.A.M.) and 1124503 (J.V.) from the National Health and Medical Research Council; 1147499 (K.P.A.M.) from Cancer Council Queensland; and R37 AI34495, P01 AI056299, and P01 CA142109 (B.R.B.) from the National Institutes of Health and by Discovery Early Career Research Award 150101578 (J.V.) from the Australian Research Council. J.V. holds a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Foundation.
Funding Information:
This work was supported by grants 1188584 (K.P.A.M.) and 1124503 (J.V.) from the National Health and Medical Research Council; 1147499 (K.P.A.M.) from Cancer Council Queensland; and R37 AI34495, P01 AI056299, and P01 CA142109 (B.R.B.) from the National Institutes of Health and by Discovery Early Career Research Award 150101578 (J.V.) from the Australian Research Council. J.V. holds a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Foundation.
Publisher Copyright:
© 2022 American Society of Hematology
