Hematopoietic Stem Cell Transplant and Healthy Donor Single cell RNA-seq (scRNA-seq) combined with T Cell Receptor (TCR) and B Cell Receptor (BCR) sequencing on Timepoints Surrounding SARS-CoV-2 Vaccination and Infection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266519 | GEO | 2025/04/29
REPOSITORIES: GEO
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Project description:Engraftment and differentiation of donor hematopoietic stem cells is decisive for the clinical success of allogeneic stem cell transplantation (alloSCT) and depends on the recipient’s bone marrow (BM) niche. Presumably, a damaged niche contributes to poor graft function post-alloSCT, but the underlying mechanisms and specifically the role of BM multipotent mesenchymal stroma cells (MSC) are ill defined. Upon multivariate analysis in a cohort of 732 individuals, we observed a reduced presence of proliferation-capable MSC in BM-aspirates from patients (N=196) who had undergone alloSCT (OR 0.61, p=.028). This was confirmed by paired analysis in 30 patients showing a higher frequency of samples with a lack of MSC presence post-alloSCT compared to pre-alloSCT. This reduced MSC presence was associated with reduced survival of patients following alloSCT and specifically with impaired graft function. Post-alloSCT MSC showed diminished in vitro proliferation along with a transcriptional antiproliferative signature, upregulation of epithelial-mesenchymal transition and extracellular matrix pathways and abnormal cytokine release in coculture with hematopoietic cells. In order to avoid in-vitro-culture bias we isolated the CD146+/CD45-/HLA-DR- BM cell fraction, which comprised the entire MSC population. The post-alloSCT isolated native CD146+MSC showed a similar reduction in proliferation capacity and shared the same antiproliferative transcriptomic signature as for post-alloSCT adherence-isolated MSC. Taken together, our data show that alloSCT confers damage to the proliferative capacity of native MSC, which is associated with reduced patient survival after alloSCT and impaired engraftment of allogeneic hematopoiesis. These data represent the basis to elucidate mechanisms of BM-niche reconstitution post-alloSCT and its therapeutic manipulation.
2023-05-01 | GSE203246 | GEO
Project description:We conducted a phase I trial (NCT04628338) of IFN-γ combined with donor leukocyte infusions (DLI) in myeloblastic malignancies that relapsed post-HLA-matched allogeneic stem cell transplantation (alloSCT). Patients self-administered IFN-γ for 1-4 weeks, followed by DLI and concurrent IFN-γ for 12 weeks. IFN-γ monotherapy was well tolerated by all subjects (n=7). Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. Single cell RNA sequencing (scRNAseq) was performed on bone marrow (BM) samples collected before IFN-γ treatment and 48-60 hours after the 1st or 2nd dose of IFN-γ from three patients: one responder (Patient 1) and two non-responders (Patients 5 and 7). Recipient-derived cells were distinguished from donor-derived cells based on single nucleotide polymorphisms (SNP) in expressed genes. As expected, most immature pluripotent and myeloid lineage cells (HSC, myeloid progenitor cells, early erythroid cells) at relapse were of recipient genotypic origin, while lymphoid progenitors were mainly donor derived. Genomic copy number in single cells showed that most HSCs or myeloid progenitor cells harbored recurrent chromosome abnormalities known to each patient. To investigate the effects of in vivo IFN-γ within the major lineage clusters, we performed single-cell pathway analyses (SCPA). Transcription changes in the post-IFN-γ specimens were predominantly found in the non-lymphoid subsets (HSC-like cells, myeloid progenitors, CD14 or CD16 monocytes, and erythroid cells). IFN-γ response pathway was activated in HSC-like cells (Patients 1 and 7) and myeloid progenitor cells (Patients 1, 5, 7) in the post-IFN-γ samples. Post-IFN-γ samples also had evidence of activation of “TNF-alpha signaling via NFkb” in HSC-like and myeloid progenitor cell populations. “IL2 STAT5 signaling” and “inflammatory response” pathways were also engaged in post-IFN-γ myeloid populations. These scRNAseq analysis confirmed in vivo IFN-γ action on the dominant malignant myeloid population.
2025-03-17 | GSE291800 | GEO
Project description:Hematopoietic Stem Cell Transplant and Healthy Donor Single cell RNA-seq (scRNA-seq) combined with T Cell Receptor (TCR) and B Cell Receptor (BCR) sequencing on Timepoints Surrounding SARS-CoV-2 Vaccination and Infection
| PRJNA1107496 | ENA
Project description:Background: Primary immunodeficiency patients are ineligible for lung transplant (LTX) due to futility and bone marrow transplant (BMT) for lung failure. We hypothesized that using marrow extracted from the vertebral bodies (VB) of a deceased lung donor with partial HLA-match would be able to establish persistent hematopoiesis and generate immunity and tolerance. Methods: A teenager with severe combined immunodeficiency in lung failure due to recurrent pneumonias underwent LTX in 2016 from a 1/8 HLA allele-matched unrelated donor followed by reduced intensity conditioning and infusion of T cell/B cell-depleted cryopreserved VB marrow 4 months later. Results: Immune competence and donor-derived thymopoiesis were evident by six months post-BMT, while immunosuppression was withdrawn at 16-month post-BMT. Donor T cell (>95%) and myeloid chimerism (7-10%) have persisted for over nine years. At two years post-BMT, circulating donor-derived T cells were hyporesponsive to host dendritic cells in vitro. T-cell receptor clonotyping revealed the disappearance of host-reactive clones identifiable in the marrow graft, while circulating donor T cells exhibited downmodulation of signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, circulating predominantly host monocytes upregulated signaling pathways compared to their donor-derived counterparts, indicating active interactions between post-thymic donor T cells and host monocytes. Conclusion: In summary, durable hematopoietic engraftment and protective immunity were demonstrable for the first time in a patient receiving deceased donor vertebral bone marrow graft. Moreover, tolerance exceeding 8-years without immunosuppression was attainable.
2025-09-01 | GSE305710 | GEO
Project description:Introduction: Responses to allogeneic human leukocyte antigen (HLA) molecules limit the survival of transplanted organs. The changes in T-cell alloreactivity that contribute to this process, however, are not fully understood. We defined a set of donor reactive T-cell clones (DRTC) with the goal to elucidate signatures of kidney allograft rejection. Methods: DRTC were identified pretransplant using an anti-donor mixed lymphocyte reaction assay: CFSE-diluting CD4+ and CD8+ DRTC were flow-sorted, and the TCR sequences were identified using Adaptive Immunosequencing. DRTC were then tracked in post-transplant biopsies, blood, and urine samples in a cohort of kidney transplant recipients. Results: In patients with an abnormal biopsy, the majority of CD8+ DRTC found within the allograft were detected in the circulating pre-transplant repertoire. Circulating CD8+ DRTC were more abundant pre- and post-transplant in patients that received non-lymphodepletional induction and developed an abnormal biopsy when compared to stable patients. Additionally, DRTC were detected as early as two weeks post-transplant in the urine of some patients, with some of these clones subsequently identified in follow-up kidney biopsy samples. Discussion: The findings of our study add to our understanding of T-cell alloreactivity following kidney transplantation and provide evidence for the role of pre-defined alloreactive T-cells in the development of allograft rejection.
2025-02-10 | GSE288648 | GEO
Project description:Gene expression profile at single cell level of bone marrow (BM) T cells and hematopoietic stem and progenitor cells (HSPCs) of acute myeloid leukemia patients post allogeneic stem cell transplantation (alloSCT) of patients in complete remission (CR) and relapse (REL).
2024-01-11 | GSE216187 | GEO
Project description:Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. By undertaking a longitudinal case-control study, we explored the possibility to identify novel non-invasive human biomarkers candidates for IPA in patients post allogeneic stem cell transplantation (alloSCT). Using both RNA-sequencing and immunoassays, we investigated 66 blood samples of 3 probable IPA cases and 3 matched controls without Aspergillus infection. Selected potential biomarker candidates were evaluated further in additional alloSCT (n=23) and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and their appropriate control patients (n=65). Profiling analysis suggested LGALS2, MMP1 and caspase-3 as potential biomarker candidates indicating IPA in investigated alloSCT patients. Significant differences in IL-8 and caspase-3 levels were observed among CAPA patients compared to control patients. Given our conceptual work we demonstrate the value of seeking human IPA indicating biomarkers, which together with already established fungal biomarkers potentially improve the accuracy of IPA diagnostic.
2022-03-02 | GSE174825 | GEO
Project description:This pilot phase II trial studies how well giving donor T cells after donor stem cell transplant works in treating patients with hematologic malignancies. In a donor stem cell transplant, the donated stem cells may replace the patient’s immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor’s T cells (donor lymphocyte infusion) after the transplant may help increase this effect.
| 2143763 | ecrin-mdr-crc
Project description:BACKGROUND - IL-6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem cell transplantation (alloSCT) and is an attractive therapeutic target. METHODS - A registered phase I/II study (ACTRN12612000726853) of IL-6 receptor (IL-6R) neutralizing antibody administration on day -1 to patients receiving full or reduced-intensity conditioning (RIC) and alloSCT from HLA-matched sibling or unrelated donors with standard cyclosporin and methotrexate GVHD prophylaxis. The primary endpoint was incidence of grade II-IV acute GVHD. Outcomes were compared to a non-randomized but contemporaneous group of study patients receiving the same alloSCT in the absence of IL-6R mAb. FINDINGS - Cytokine and pharmacokinetic analysis confirmed transient IL-6 dysregulation in the first month after alloSCT with complete inhibition following IL-6R mAb administration. With median follow up of 497 days, the incidence of grade II-IV GVHD was 12.5% in recipients of IL-6R inhibition (n = 48) versus 41.5% in the (n = 53) control cohort (P = 0.001). Low rates of acute GVHD were noted in patients receiving IL-6R inhibition relative to control patients following both myeloablative (12.5% vs. 46.4%, P = 0.03) and RIC (12.5% vs. 36.0%, P = 0.04). The incidence of severe (grade III/IV) acute GVHD was 4.2% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.012). Relapse and chronic GVHD were unchanged. Immune reconstitution was preserved in recipients of IL-6R inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION - IL-6 is the principal detectable and dysregulated cytokine secreted after alloSCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution and a sustained graft-versus-leukemia effect. Single colour, Illumina Human HT12v4 Beadarrays.
2014-09-09 | E-GEOD-61201 | biostudies-arrayexpress
Project description:Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.
| S-EPMC6511301 | biostudies-literature