CD70 identifies donor derived alloreactive T cells in severe acute Graft vs Host Disease post allogeneic SCT
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ABSTRACT:
PROVIDER: PRJNA1037577 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26780900.fastq.gz | Fastqsanger.gz | |||
| SRR26780901.fastq.gz | Fastqsanger.gz | |||
| SRR26780902.fastq.gz | Fastqsanger.gz | |||
| SRR26780903.fastq.gz | Fastqsanger.gz | |||
| SRR26780904.fastq.gz | Fastqsanger.gz |
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Project description:Graft-versus-host disease (GvHD) remains a major challenge post allogeneic hematopoietic stem cell transplantation (allo-HSCT) and understanding its immunopathology is crucial for effective therapeutic intervention. Here we investigated the significance of CD70, a co-stimulatory molecule, in the context of aGvHD. CD70 was found to be transiently expressed on activated T cells during early immune reconstitution post-transplantation but persisted longer in aGvHD. Our findings illustrate that CD70+ T cells are characterized by upregulated activation receptors and enhanced cytokine production, while displaying signs of exhaustion. Remarkably, CD70+ T cells expressed chemokine receptors CCR4 and CCR6 and were actively recruited to inflamed tissues, implicating them in aGvHD pathogenesis. The chromatin at transcription factor MGA and NFAT5 loci was found to be selectively altered upon allo-antigenic stimulation in CD70+ T cells ex-vivo. Gene transcriptions of Toll-like receptors and MAPK signalling pathway were also found to differ in CD70+ and CD70- T cells of aGvHD patients. Insights into the clonality and antigen specificity of CD70+ T cell populations revealed potential novel antigenic targets. Further blocking CD70 in allogeneic T cells from aGvHD patients primed with autologous antigen presenting cells prior to HSCT demonstrated that anti-CD70 antibody reduced T cell proliferation and cytokine production. These findings implicate CD70 as a potential therapeutic target to modulate T cell responses and mitigate aGvHD. Targeting the CD70-CD27 co-stimulation pathway holds promise for prophylactic treatment.
2024-10-02 | GSE247452 | GEO
Project description:Analysis of donor CD4+ and CD8+ T cells purified from spleens and ovaries after murine syngeneic and allogeneic hematopoietic stem cell transplantation Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). While the role of pretransplant conditioning regimen has been well appreciated, increasing application of reduced-intensity conditioning facilitated us to revisit the other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. To study transcriptomes of donor T cells infiltrating into the ovary, donor T cells were sorted from recipients' ovaries and microarray analysis was performed.
2017-05-12 | GSE81397 | GEO
Project description:Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency.
2021-10-31 | GSE184963 | GEO
Project description:Graft-versus-host disease (GvHD) is still one of the major complications following allogeneic stem cell transplantation (SCT) triggered by alloreactive donor T cells. Whereas murine data have clearly shown the beneficial effects of regulatory T cells (Tregs) on the development of GvHD, data from the human system are rare mainly due to low cell numbers of circulating or organ-infiltrating Tregs in lymphopenic patients. Here, we present a comparative analysis of Tregs from patients with and without acute/ chronic GvHD designed as a dynamical approach studying the whole genome profile over the first 6 months after SCT. For this purpose, blood samples were collected monthly for FACS-based isolation of CD4+CD25highCD127low/- Tregs. The Treg transcriptome showed a high stability in the first half year representing the most sensitive time window for tolerance induction. However, the comparison of the Treg transcriptome from patients with and without GvHD uncovered regulated gene transcripts that point to a reduced suppressive function of Tregs with diminished migration capacity to the target organs likely contributing to the development of GvHD. These findings highlight the critical role of human Tregs in the pathophysiology of GvHD and identify novel targets for the manipulation of Tregs to optimize cellular immune intervention strategies. Keywords: cell type comparison
2010-12-31 | GSE23332 | GEO
Project description:Graft-versus-host disease (GvHD) is still one of the major complications following allogeneic stem cell transplantation (SCT) triggered by alloreactive donor T cells. Whereas murine data have clearly shown the beneficial effects of regulatory T cells (Tregs) on the development of GvHD, data from the human system are rare mainly due to low cell numbers of circulating or organ-infiltrating Tregs in lymphopenic patients. Here, we present a comparative analysis of Tregs from patients with and without acute/ chronic GvHD designed as a dynamical approach studying the whole genome profile over the first 6 months after SCT. For this purpose, blood samples were collected monthly for FACS-based isolation of CD4+CD25highCD127low/- Tregs. The Treg transcriptome showed a high stability in the first half year representing the most sensitive time window for tolerance induction. However, the comparison of the Treg transcriptome from patients with and without GvHD uncovered regulated gene transcripts that point to a reduced suppressive function of Tregs with diminished migration capacity to the target organs likely contributing to the development of GvHD. These findings highlight the critical role of human Tregs in the pathophysiology of GvHD and identify novel targets for the manipulation of Tregs to optimize cellular immune intervention strategies. Keywords: cell type comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of 2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.
2010-12-31 | E-GEOD-23332 | biostudies-arrayexpress
Project description:Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemic (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4 iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8 iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT. Indeed, the combinational therapy was superior to CD4 or CD8 iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4 and CD8 effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8 iTregs possess elevated expression of multiple cytolytic molecules compared to CD4 iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4 and CD8 iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.
2016-11-17 | GSE75118 | GEO
Project description:Alloreactive T cells mediate graft-versus-leukemia (GvL) reactions and acute graft-versus-host disease (aGvHD) in AML patients following allogeneic hematopoietic stem cell transplantation. To investigate biomarkers that identify alloreactive T cells associated with either beneficial GvL or detrimental aGvHD, we collected graft samples and two post-transplant follow-up blood samples (day 30 and day 100) of ten AML patients undergoing hematopoietic stem cell transplantation and profiled over 777,000 CD45+ leukocytes in total by combinatorial barcoding-based mega-scale single-cell RNA sequencing. Using immune receptor sequences as intrinsic clonal barcodes, we observed that especially CD8+ graft-derived T cells persisted and displayed enhanced proliferation, clonal expansion, and likely alloreactivity. Notably, patient-derived peripheral leukocytes that survived the conditioning, as identified by sex-chromosome-related genes, were primarily CD4+ T helper cells. MDGA1 expression on T cells and NK cells emerged as a novel biomarker potentially associated with aGvHD. Additionally, we observed a significant deficiency of ADGRG1 expression, a marker of alloreactive cytotoxic T cells, by αβ and γδ T cells from relapsed patients. In conclusion, mega-scale single-cell monitoring of graft and hematopoietic immune cell reconstitution allowed us to demonstrate that MDGA1 and ADGRG1 may function as complementary biomarkers expressed by distinct circulating T cells that are associated with divergent outcomes in AML patients, enabling precise risk stratification of alloHSCT outcomes and presenting potential therapeutic targets.
2025-12-03 | GSE295359 | GEO
Project description:CD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CAR T cells is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo by using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression in the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that CD70 interaction in cis with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70 KO CD70-specific nanoCAR T cells are protected from antigen-induced exhaustion. Our data show that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target, in this case CD70.
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Project description:We analysed the DNA methylation patterns of inguinal white adipose tissue in M-SCT floxed and M-SCT KO, the results indicated a significant widepread hypermethylation modification in M-SCT floxed which contributed to the increased obesity susceptibility of M-SCT floxed
2020-12-02 | GSE162406 | GEO
Project description:CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T-cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T-cells with malignant rhabdoid tumor organoids, and in vivo using a diffuse large B-cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T-cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR, as validated by imaging flowcytometry, induces exhaustion. Knocking out CD70 expression in nanoCAR T-cells using CRISPR/Cas9, resulted in dramatically enhanced functionality in the DLBCL PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knock out (KO) CD70-specific nanoCAR T-cells were protected from antigen-induced exhaustion. In addition, we were able to demonstrate that WT CD70-specific nanoCAR T-cells already exhibit signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T-cells. On the other hand, the gene signature of KO nanoCAR T-cells overlapped with the gene signature of CAR T-cell infusion products that led to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens, negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target, in this case CD70.
2024-06-17 | GSE265937 | GEO