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Altered thymic NKT1 and NKT2 differentiation in murine haploidentical bone marrow transplantation with chronic GvHD

ABSTRACT: To investigate whether intermediate iNKT precursor cells were affected in GvHD mice along the differentiation journey toward mature effector cells, we performed scRNA-seq on thymic iNKT precursors from BMT mice with and without cGvHD and non-BMT mice. We identified Multiple early and late NKT1 precursor clusters and further explored the development of NKT1 under physiological as well as transplantation condition.

ORGANISM(S): Mus musculus

PROVIDER: GSE228645 | GEO | 2023/07/31

REPOSITORIES: GEO

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Peripheral blood T helper cells circulate with pathogenic tissue resident T helper cells in chronic GVHD

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Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70 [II]

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Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70 [RNA-Seq]

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CSF1R inhibition promotes neuroinflammation and behavioural deficits during graft-versus-host disease in mice.

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

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