Homo sapiens
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PROVIDER: PRJNA378820 | ENA |
REPOSITORIES: ENA
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Project description:Longitudinal Study of Immune Mediated Disorders after Allogeneic HCT Protocol (Immune Mediated Disorders after Allo-HCT) - cGVHD 6501
| PRJNA378819 | ENA
Project description:<p>Allogeneic hematopoietic cell transplantation (HCT) is the only known curative option for many hematologic disorders. After transplantation, many patients develop immune mediated disorders that may be life-threatening. Post-HCT immune mediated disorders are rare relative to other diseases but the prototype of graft versus host disease (GVHD) develops in 30-70% of patients. The morbidity and mortality associated with these HCT-associated immune mediated disorders are major barriers to successful use of transplantation to cure rare hematologic malignancies such as leukemia, lymphoma, multiple myeloma, myelodysplastic/myeloproliferative syndromes amongst other diseases.</p> <p>The purpose of this study is to characterize and more completely define the onset and course of immune mediated disorders after allogeneic HCT, focusing on participants who develop cutaneous sclerosis, bronchiolitis obliterans syndrome (BOS), late acute graft-vs.-host disease (GVHD), and chronic GVHD. <ul> <li>Of the participants undergoing allogeneic hematopoietic cell transplantation (HCT), can we, the researchers better identify who will develop immune-mediated disorders, what types of disorders participants will have, and whether these disorders will be severe or respond to currently available therapies?</li> </ul> </p> <p>This is a longitudinal study of 1118 individuals (1081 adults and 100 children). Those participating in this study will be evaluated over a 3 year period at 9 study sites. Participants will be enrolled pre-transplant, or up to day 121 post transplantation. This wide enrollment window will allow sites to use recruitment methods that are most efficient at their institutions. At least 2 years of follow-up will ensure an adequate sample size, and sufficient time for observation of the full spectrum of immune mediated disorders. The data of 1023 individuals have been submitted to dbGaP.</p>
| phs001331 | dbGaP
Project description:The direct integration of chimeric-antigen-receptor (CAR) T cell with allogeneic hematopoietic cell transplantation (allo-HCT) carries the risk of graft-versus-host disease (GVHD) induction by allogeneic CAR-T cells. Based on our past experiments, it has been shown that post-transplantation cyclophosphamide (PTCy) prevents GVHD induction by other cell infusions after T-cell-replete MHC-haploidentical murine allo-HCT models. In this study, we investigated whether CAR-T cells, given in a similar manner in the same MHC-haploidentical murine allo-HCT model, could safely exert anti-tumor effects. We showed that anti-CD19 CAR-T cells administered early after (day +5 of transplant) or prior to (day 0 of transplant) PTCy for allo-HCT cleared leukemia without toxicity or GVHD exacerbation. Using next generation single-cell RNA sequencing approaches, we demonstrated that in comparison to CAR-T cells infused early after PTCy (day +5), CAR-T cells infused prior to PTCy (day 0) exhibited transcriptional changes consistent with increased CD4+ T-cell activation and CD8+ T-cell cytotoxicity.
2022-10-09 | GSE214788 | GEO
Project description:Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.
2017-12-19 | GSE95770 | GEO
Project description:Identifying the targets of immune response after allogeneic hematopoietic cell transplantation (HCT) promises to provide relevant immune therapy candidate proteins. We used protein microarrays to serologically identify Nucleolar and Spindle Associated Protein 1 (NuSAP1) and Chromatin Assembly Factor 1, subunit B (p60) [CHAF1b] as targets of new antibody responses that developed after allogeneic HCT. Western blots and ELISA validated their post-HCT recognition and enabled ELISA testing of 120 other allo-HCT patients. CHAF1b specific antibodies were predominantly detected in AML patients whereas NuSAP1 specific antibodies were exclusively detected in AML patients one year post-transplant (p<0.0001). Complete genomic exon sequencing failed to identify a nonsynonymous SNP for NuSAP1 and CHAF1b between the donor and recipient cells. Expression profiles and RT-PCR showed NuSAP1 was predominately expressed in the bone marrow CD34+CD90+ hematopoietic stem cells (HSC), leukemic cell lines and B lymphoblasts as compared to other tissues or cells. Thus, NuSAP1 is recognized as an immunogenic antigen in 65% AML patients and suggests a tumor antigen role. In conclusion, clinically important tumor antigens can be identified as new antibody targets after allogeneic HCT using high density protein microarrays
2009-03-19 | GSE15255 | GEO
Project description:Notch signaling promotes T-cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like ligand DLL4. To assess if Notch’s effects are evolutionarily conserved and identify key mechanisms, we studied antibody-mediated DLL4 blockade in a non-human primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved post-transplant survival with striking, durable protection from gastrointestinal GVHD, out of proportion to other disease sites. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T-cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T-cells while preserving α4β7 in regulatory T-cells, with findings suggesting increased 1 competition for 4 binding in conventional T-cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T-cells after allo-HCT. Altogether, DLL4/Notch blockade decreased effector T-cell infiltration into the gut, with increased regulatory to conventional T-cell ratios early after allo-HCT. Our results identify a conserved, biologically unique and targetable role of DLL4/Notch signaling in GVHD.
2023-07-14 | GSE228838 | GEO
Project description:Relapse after allo-HCT is a major cause of death of AML patients and results from immune evasion of AML blasts. Dysfunction of the p53 signaling pathway is frequent in AML and often caused by upregulation of the central p53 negative regulator Murine Double Minute 2 (MDM2). Besides its oncogenic effects p53 also regulates immune function and immune surveillance of solid cancer. We hypothesize that p53 also controls immune-related genes in AML cells and that p53 reactivation via MDM2-inhibition may enhance the immunogenicity of AML cells to allogeneic T cells.
2022-09-20 | GSE158103 | GEO
Project description:Wildtype (WT) BALB/c mice were treated with allogeneic hematopoietic cell transplantation (allo-HCT) in order to induce acute GVHD. C57BL/6 mice were used bone marrow (BM) and T cell donor mice. We studied the effect of oral hBD-2 treatment versus vehicle (PBS) control treatment on the gene expression in the colon, as main GVHD target organ.
2022-12-23 | GSE190796 | GEO
Project description:Biologic markers of immune tolerance may facilitate tailoring of immune suppression duration after allogeneic hematopoietic cell transplantation (HCT). In a cross-sectional study, peripheral blood samples were obtained from tolerant (n=15, median 38.5 months post-HCT) and non-tolerant (n=17, median 39.5 post-HCT) HCT recipients and healthy control subjects (n=10) for analysis of immune cell subsets and differential gene expression. There were no significant differences in immune subsets across groups. We identified 281 probe sets unique to the tolerant (TOL) group and 122 for non-tolerant (non-TOL). These were enriched for process networks including NK cell cytotoxicity, antigen presentation, lymphocyte proliferation, and cell cycle and apoptosis. Differential gene expression was enriched for CD56, CD66, and CD14 human lineage-specific gene expression. Differential expression of 20 probe sets between groups was sufficient to develop a classifier with > 90% accuracy, correctly classifying 14/15 TOL cases and 15/17 non-TOL cases. These data suggest that differential gene expression can be utilized to accurately classify tolerant patients following HCT. Prospective investigation of immune tolerance biologic markers is warranted. Samples were collected after allogeneic hematopoietic cell transplantation (HCT) or in healthy control subjects. Peripheral blood samples were obtained from tolerant (n=15, median 38.5 months post-HCT) and non-tolerant (n=17, median 39.5 post-HCT) HCT recipients and healthy control subjects (n=10).
2015-05-25 | E-GEOD-64300 | biostudies-arrayexpress
Project description:We conducted immune- and RNA-sequencing of HLA-A24-restricted CMVpp65-specific CTLs to better understand the immune reconstitution of CMV-CTLs after allo-HCT. To the best of our knowledge, this is the first report on the features of TCRβ-CDR3, diversity, and GEP of HLA-A24 CMV-CTLs according to the CMV-reactivation pattern among recipients after allo-HCT. In addition, we further sought to demonstrate homogeneity or heterogeneity according to individual CTL clones using single-cell RNA-sequencing technology.
2021-06-28 | GSE179009 | GEO