Abstract
AbstractGraft-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.
Highlights
Chronic graft-versus-host disease is the leading cause of non-relapse mortality after otherwise curative allogeneic stem cell transplantation (SCT) for haematological malignancies1,2. cGVHD can be inflammatory and/or fibrotic with organ-specific or multiorgan symptomatology, and complex and protean presentations make diagnosis challenging[3]
Using the Forced Swim test (FST) to assess the behavioural response of cGVHD mice to an aversive situation[29] we confirmed in our model the previous report that acute GVHD (aGVHD) mice (D14) exhibit increased mobility as a dysfunctional response in the FST30 (Supplemental Figures 1I). Testing at both early and late phases of cGVHD (D35 and D70, respectively) demonstrated significantly increased mobility in cGVHD mice compared to T-cell depleted (TCD) controls (Figure 1C)
Improvement over the 5-day testing period beginning at D70 (Figure 1F) was significantly reduced in cGVHD mice compared to TCD controls
Summary
Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse mortality after otherwise curative allogeneic stem cell transplantation (SCT) for haematological malignancies1,2. cGVHD can be inflammatory and/or fibrotic with organ-specific or multiorgan symptomatology, and complex and protean presentations make diagnosis challenging[3]. Consistent with alloreactive donor T-cells driving peripheral GVHD pathology[9,10], murine and non-human primate CNS aGVHD models showed alloreactive T-cells to infiltrate the CNS and induce neuronal damage[6,7,11]. Post-mortem brain samples and experimental disease models, such as in Alzheimer’s disease and multiple sclerosis/experimental autoimmune encephalitis, suggest that CNS infiltration of pathogenic T-cells with associated proinflammatory cytokine production are common features of chronic neuroinflammation[12,13]. Microglia may restore a quiescent state following activation or contribute to ongoing inflammation[16], exemplified by the recent description of microglial TNF production as a critical mediator of acute CNS GVHD7. Elucidating resident microglia phenotype and function, and the temporal contribution of donor BMDM will be instrumental for understanding biological disease mechanisms and informing effective therapeutic strategies late post-transplant
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