Seeking biomarkers for acute graft-versus-host disease: where we are and where we are heading?

Zhao, Xiaosu; Huang, Xiao‐Jun

doi:10.1186/s40364-019-0167-x

Cited by 18 publications

(18 citation statements)

References 91 publications

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“…Our findings of significant positive correlation between fecal volume as well as stool frequency and CRP levels may reflect similar associations in inflammatory bowel disease where CRP levels represent one relevant marker of disease activity 72,73 . Moreover, the relevance of CRP alone or in combination with other markers for staging of GvHD has been an issue of ongoing investigations 56,74‐76 …”

Section: Discussionsupporting

confidence: 58%

Fecal microbiota transfer for refractory intestinal graft‐versus‐host disease — Experience from two German tertiary centers

Goeser

Sifft

Stein‐Thoeringer

et al. 2021

European J of Haematology

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Rationale Steroid refractory graft‐vs‐host disease (sr‐GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo‐HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr‐GvHD. Objectives We studied the effects of FMT on sr‐GvHD in allo‐HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre‐ and post‐FMT (day ‐14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre‐ and post‐FMT by 16S rRNA sequencing. Results Post‐FMT, we observed no intervention‐associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis—each 3/11 and vomiting—1/11). Stool frequencies and volumes were significantly reduced [pre‐ vs post‐FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr‐GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post‐FMT. Conclusions In our study, we observed positive effects on sr‐GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr‐GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.

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Section: Discussionsupporting

confidence: 58%

Fecal microbiota transfer for refractory intestinal graft‐versus‐host disease — Experience from two German tertiary centers

Goeser

Sifft

Stein‐Thoeringer

et al. 2021

European J of Haematology

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“…Biomarkers that could reliably predict the onset of aGvHD and ensure preemptive interventions are lacking, meaning that diagnosis and treatment rely on clinical signs and symptoms and tissue biopsies only. Although several molecules/proteins have been investigated ( 16 , 21 , 26 – 28 ), in the present study, we evaluated the antigenic profile and miRNA cargo of EVs in the setting of Haplo-HCT using PT-Cy as GvHD prophylaxis.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles as Biomarkers of Acute Graft-vs.-Host Disease After Haploidentical Stem Cell Transplantation and Post-Transplant Cyclophosphamide

et al. 2022

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Even with high-dose post-transplant cyclophosphamide (PT-Cy) which was initially introduced for graft-versus-host disease (GvHD) prevention in the setting of HLA-haploidentical transplantation, both acute and chronic GvHDs remain a major clinical challenge. Despite improvements in the understanding of the pathogenesis of both acute and chronic GvHDs, reliable biomarkers that predict their onset have yet to be identified. We recently studied the potential correlation between extracellular vesicles (EVs) and the onset of acute (a)GvHD in transplant recipients from related and unrelated donors. In the present study, we further investigated the role of the expression profile of membrane proteins and their microRNA (miRNA) cargo (miRNA100, miRNA155, and miRNA194) in predicting the onset of aGvHD in haploidentical transplant recipients with PT-Cy. Thirty-two consecutive patients were included. We evaluated the expression profile of EVs, by flow cytometry, and their miRNA cargo, by real-time PCR, at baseline, prior, and at different time points following transplant. Using logistic regression and Cox proportional hazard models, a significant association between expression profiles of antigens such as CD146, CD31, CD140a, CD120a, CD26, CD144, and CD30 on EVs, and their miRNA cargo with the onset of aGvHD was observed. Moreover, we also investigated a potential correlation between EV expression profile and cargo with plasma biomarkers (e.g., ST2, sTNFR1, and REG3a) that had been associated with aGVHD previously. This analysis showed that the combination of CD146, sTNFR1, and miR100 or miR194 strongly correlated with the onset of aGvHD (AUROC >0.975). A large prospective multicenter study is currently in progress to validate our findings.

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“…GvHD is an immune-mediated disease and dysregulation of miRNAs in immune cells is associated with GvHD pathophysiology [ 38 ]. Accordingly, the top five positively correlated GvHD miRNAs identified herein have been demonstrated to have critical immune-regulatory roles in different contexts.…”

Section: Discussionmentioning

confidence: 99%

Development of acoustically isolated extracellular plasma vesicles for biomarker discovery in allogeneic hematopoietic stem cell transplantation

et al. 2021

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Background Infection and graft-versus-host disease (GvHD) are the major causes for mortality and morbidity of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Plasma-derived extracellular vesicles (EVs) contain disease-related proteins, DNAs and RNAs, and have recently been suggested as potential biomarker candidates for transplantation complications. However, EV isolation from small plasma volumes in clinical biomarker studies using conventional methods is challenging. We therefore investigated if EVs isolated by novel automated acoustic trapping could be developed as potential biomarkers for allo-HSCT complications by performing a clinical proof-of-principle study. Results Plasma samples were collected from twenty consecutive patients with high-risk/relapsed hematologic malignancies undergoing allo-HSCT before transplantation and post-transplant up to 12 weeks. EVs were isolated from small plasma sample volumes (150 μl) by an automated, acoustofluidic-based particle trapping device, which utilizes a local λ/2 ultrasonic standing wave in a borosilicate glass capillary to capture plasma EVs among pre-seeded polystyrene microbeads through sound scatter interactions. We found that EVs could be reliably isolated from all plasma samples (n = 173) and that EV numbers increased more than 2-fold in the majority of patients after transplantation. Also, sufficient quantities of RNA for downstream microRNA (miRNA) analysis were obtained from all samples and EV miRNA profiles were found to differ from whole plasma profiles. As a proof of principle, expression of platelet-specific miR-142-3p in EVs was shown to correlate with platelet count kinetics after transplantation as expected. Importantly, we identified plasma EV miRNAs that were consistently positively correlated with infection and GvHD, respectively, as well as miRNAs that were consistently negatively correlated with these complications. Conclusions This study demonstrates that acoustic enrichment of EVs in a clinical biomarker study setting is feasible and that downstream analysis of acoustically-enriched EVs presents a promising tool for biomarker development in allo-HSCT. Certainly, these findings warrant further exploration in larger studies, which will have significant implications not only for biomarker studies in transplantation but also for the broad field of EV-based biomarker discovery.

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Seeking biomarkers for acute graft-versus-host disease: where we are and where we are heading?

Cited by 18 publications

References 91 publications

Fecal microbiota transfer for refractory intestinal graft‐versus‐host disease — Experience from two German tertiary centers

Fecal microbiota transfer for refractory intestinal graft‐versus‐host disease — Experience from two German tertiary centers

Extracellular Vesicles as Biomarkers of Acute Graft-vs.-Host Disease After Haploidentical Stem Cell Transplantation and Post-Transplant Cyclophosphamide

Development of acoustically isolated extracellular plasma vesicles for biomarker discovery in allogeneic hematopoietic stem cell transplantation

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