Donor bone marrow-derived macrophage MHC II drives neuroinflammation and cognitive deficits during chronic GVHD in mice
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ABSTRACT:
PROVIDER: PRJNA743850 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15042502_1.fastq.gz | Fastqsanger.gz | |||
| SRR15042502_2.fastq.gz | Fastqsanger.gz | |||
| SRR15042503_1.fastq.gz | Fastqsanger.gz | |||
| SRR15042503_2.fastq.gz | Fastqsanger.gz | |||
| SRR15042504_1.fastq.gz | Fastqsanger.gz |
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Project description:Graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation for haematological 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 in the CNS are yet to be elucidated. Our studies of murine chronic GVHD revealed a spatial learning and memory deficit associated with inflammation in the hippocampus underlain by persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the chronic GVHD brain from early CD8 dominance to later CD4 sequestration. Hippocampal RNA sequencing identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with IFN-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 TNF. In contrast, infiltration of pro-inflammatory MHC class II+ donor bone marrow-derived macrophages (BMDM) was identified as a distinguishing feature of CNS chronic GVHD. Donor BMDM, which comprised up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout bone marrow grafts exhibited attenuated neuroinflammation, suggestive of a critical role for donor BMDM in chronic CNS GVHD. 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.
2021-08-18 | GSE179441 | GEO
Project description:Expression profiling of rat major histocompatibility complex and natural killer complex genes in skin explant assays reveals genes that are regulated in graft versus host disease. The major histocompatibility complex (MHC) is the most important genomic region that contributes to the genetic risk of graft rejection and graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Therefore, MHC matching is most essential for the success of clinical transplantations. However, the MHC contains in addition to MHC class I and class II genes that are genotyped for selection of donors further so far unidentified genes that also contribute significantly to the risk to develop acute GVHD. It is difficult to identify these MHC genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes that might be involved in the pathohysiology of GVHD by expression profiling. To reduce the complexity of our model, we used genetically well-defined inbred rat strains (PVG and BN) and skin explant assays, an in-vitro-model of graft versus host reaction (GVHR), to analyse the expression of MHC and natural killer complex (NKC) genes in a cutaneous GVHR by a custom microarray. A higher percentage of genes in these immunologically highly important genomic regions were regulated than in the rest of the genome. We observed a statistically significant regulation of 25 MHC and 6 NKC genes and 168 other genes (i.e., 4.9%, 14.0%, and 6.6%, respectively) in rat skin explants cultured in the presence of pre-stimulated allogeneic lymphocytes compared to control samples cultured in the presence of syngeneic lymphocytes. Seven MHC and 3 NKC genes were selected for analysis by quantitative real-time polymerase chain reaction PCR. Most of the results of the microarray were confirmed in the same experimental set that was used for the microarray analysis and in a second independent experimental set of skin explant samples. In addition, GVHD-affected skin lesions of transplanted rats were analysed and similar regulations of most of the selected MHC and NKC genes were observed. Thus, our skin explant model of GVHR is informative for the gene regulation during GVHD. Interestingly, the human homologues of several of the regulated genes are polymorphic and could therefore contribute to the genetic risk of GVHD. These genes include RT1-Dmb, C2, Aif1, Spr1, Ubd, and Olr1. The human homologues of these genes might be useful for risk assessment and diagnosis of GVHD in patients. Two-condition experiment, Stimulated vs. NonSimulated cells. 12 Biological replicates, 2 Technical Replicates (Dye Swap) per Biological Replicate.
2011-01-04 | E-GEOD-17928 | biostudies-arrayexpress
Project description:Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor 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 hypothesised 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 post-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 where CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse GVHD-induced behavioural changes. Moreover, we observed aberrant behaviour 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.
2023-10-18 | GSE245360 | GEO
Project description:Expression profiling of rat major histocompatibility complex and natural killer complex genes in skin explant assays reveals genes that are regulated in graft versus host disease. The major histocompatibility complex (MHC) is the most important genomic region that contributes to the genetic risk of graft rejection and graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Therefore, MHC matching is most essential for the success of clinical transplantations. However, the MHC contains in addition to MHC class I and class II genes that are genotyped for selection of donors further so far unidentified genes that also contribute significantly to the risk to develop acute GVHD. It is difficult to identify these MHC genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes that might be involved in the pathohysiology of GVHD by expression profiling. To reduce the complexity of our model, we used genetically well-defined inbred rat strains (PVG and BN) and skin explant assays, an in-vitro-model of graft versus host reaction (GVHR), to analyse the expression of MHC and natural killer complex (NKC) genes in a cutaneous GVHR by a custom microarray. A higher percentage of genes in these immunologically highly important genomic regions were regulated than in the rest of the genome. We observed a statistically significant regulation of 25 MHC and 6 NKC genes and 168 other genes (i.e., 4.9%, 14.0%, and 6.6%, respectively) in rat skin explants cultured in the presence of pre-stimulated allogeneic lymphocytes compared to control samples cultured in the presence of syngeneic lymphocytes. Seven MHC and 3 NKC genes were selected for analysis by quantitative real-time polymerase chain reaction PCR. Most of the results of the microarray were confirmed in the same experimental set that was used for the microarray analysis and in a second independent experimental set of skin explant samples. In addition, GVHD-affected skin lesions of transplanted rats were analysed and similar regulations of most of the selected MHC and NKC genes were observed. Thus, our skin explant model of GVHR is informative for the gene regulation during GVHD. Interestingly, the human homologues of several of the regulated genes are polymorphic and could therefore contribute to the genetic risk of GVHD. These genes include RT1-Dmb, C2, Aif1, Spr1, Ubd, and Olr1. The human homologues of these genes might be useful for risk assessment and diagnosis of GVHD in patients.
2011-01-04 | GSE17928 | GEO
Project description: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.
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