Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease

Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.European CommissionCOST (European Cooperation in Science and Technology

Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease

Copyright © 2022 Doglio, Crossland, Alho, Penack, Dickinson, Stary, Lacerda, Eissner and Inngjerdingen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.This work was supported by COST (European Cooperation in Science and Technology). www.cost.eu - COST Action 17138 EUROGRAFT.info:eu-repo/semantics/publishedVersio

Differential MicroRNA Expression Levels in Cutaneous Acute Graft-versus Host Disease

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for numerous haematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40-70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In the present study we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n=5, stage 1-3) and healthy volunteers (n=4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n=8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n=17) for their association with aGvHD. Expression of miR-34a-5p (p<0.001), miR-34a-3p (p=0.013), miR-503-5p (p=0.021) and let-7c-5p (p=0.037) was elevated in cutaneous aGvHD and significantly associated with survival outcome (miR-34a-3p ROC AUC=0.93, p=0.003, Log Rank p=0.004; miR-503-5p ROC AUC=0.83 p=0.021, Log Rank p=0.003). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p=0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2=0.44, p=0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p=0.001), miR-34a-5p (p=0.005) and miR-34a-3p (p=0.004) were significantly elevated in the sera of patients who developed aGvHD vs. no-aGvHD (n=30) and miR-503-5p was associated with overall survival (ROC AUC=0.80, p=0.04, Log Rank p=0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for overall survival. Additionally, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes

Experiences of venue based exercise interventions for people with stroke in the UK: a systematic review and thematic synthesis of qualitative research

Background The physical benefits of exercise following stroke are research evidenced and the UK stroke population is increasingly encouraged to engage with exercise interventions. A synthesis of qualitative research is required to further understand the perceived experience and psychosocial effect of exercise for people with stroke. Objectives To provide a systematic search and synthesis of evidence about the experiences and reported impact of participation in venue based exercise following stroke in the UK. Data sources Eligible studies were identified through a rigorous search of Medline, Cinahl, AMED, PsycINFO, SportDiscus, Proquest and ETHOS from January 2000 until December 2017. Study eligibility criteria Full text qualitative studies or service evaluations conducted in the UK which explored the reported experience of venue based exercise amongst people with stroke. Study synthesis and appraisal Included studies were evaluated through application of the Consolidated Criteria for Reporting Qualitative Research. Data synthesis using a thematic approach generated descriptive and analytical themes. Results Six research studies and one service evaluation met the inclusion criteria; methodological quality was variable. These studies highlighted that people with stroke gain confidence and renewed identity through exercise participation. Perceived improvements in physical function were reported and participants enjoyed stroke specific exercise programmes in de-medicalised venues. Limitations The studies only accessed people who had completed the exercise programmes; non-completers were not represented. Conclusion Venue based exercise programmes have a positive effect on perceived wellbeing following stroke. Further research into the reasons for discontinuation of exercise participation following stroke is required

Anti-Angiogenic miR-222, miR-195, and miR-21a Plasma Levels in T1DM Are Improved by Metformin Therapy, Thus Elucidating Its Cardioprotective Effect: The MERIT Study

Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, 23 T1DM patients without CVD were treated with metformin for eight weeks (TG), matched with nine T1DM patients on standard treatment (SG) and 23 controls (CG). Plasma miR-222, miR-195, miR-21a and miR-126 were assayed by real-time RT-qPCR. The results were correlated with: endothelial function (RHI), circulating endothelial progenitor cells (cEPCs) (vascular repair marker, CD45dimCD34+VEGFR2+ cells) and circulating endothelial cells (cECs) (vascular injury marker, CD45dimCD34+CD133-CD144+ cells). miR-222, miR-195 and miR-21a were higher in T1DM than CG; p = 0.009, p &lt; 0.0001, p = 0.0001, respectively. There was an inverse correlation between logmiR-222 and logRHI (p &lt; 0.05) and a direct correlation between logmiR-222 and logCD34+ (p &lt; 0.05) in TG. Metformin reduced miR-222, miR-195 and miR-21a levels in TG; p = 0.007, p = 0.002 p = 0.0012, respectively. miRs remained unchanged in SG. miR-126 was similar in all groups. There was a positive association between changes in logmiR-222 and logcECs after metformin in TG (p &lt; 0.05). Anti-angiogenic miRs are increased in T1DM. Metformin has cardioprotective effects through downregulating miR-222, miR-195 and miR-21a, beyond improving glycemic control

Serum and Extracellular Vesicle MicroRNAs miR-423, miR-199, and miR-93* As Biomarkers for Acute Graft-versus-Host Disease

Acute graft-versus-host disease (aGvHD) is a major cause of adverse outcome in hematopoietic stem cell transplantation (HSCT), with a high incidence (20–50%). A novel, non-invasive diagnostic test to predict for prevalence and severity would enable improved prophylaxis and reduce morbidity. Circulatory microRNAs (miRNAs) miR-423, miR-199, miR-93*, and miR-377 have previously been associated with aGvHD in post-HSCT patient plasma, but validation is lacking and their expression within extracellular vesicles (EVs) has not been explored. This study replicated elevated serum expression of miR-423 (p &lt; 0.001), miR-199 (p = 0.04), miR-93* (p &lt; 0.001), and miR-377 (p = 0.03) in aGvHD, using a prognostic cohort of day 14 (D14) post-HSCT patient samples (n = 81). Expression also associated with disease severity. Further analysis at aGvHD diagnosis in an independent cohort (n = 65) confirmed high miR-423 (p = 0.02), miR-199 (p = 0.007), and miR-93* (p = 0.004) expression at disease onset. Investigation of expression patterns during early HSCT sequential timepoints (pre-HSCT to D28) identified elevated miRNAs at D7 post-HSCT in all transplant patients. In a novel investigation of miRNA expression in serum EVs (n = 15), miR-423 (p = 0.09), miR-199 (p = 0.008), and miR-93* (p = 0.001) levels were lower at D14 in patients who later developed aGvHD, and this was replicated for miR-423 (p = 0.02) and miR-199 (p = 0.04) (n = 47). Comparing serum to circulating EVs, at D14 patients remaining aGvHD-free had higher expression of miR-423 (p = 0.03), miR-199 (p = 0.009), and miR-93* (p = 0.002) in the EV fraction. Results verify the capacity for circulating miR-423, miR-199, and miR-93* as diagnostic and prognostic aGvHD biomarkers. The novel finding of their differential expression in EVs suggests a potential role in aGvHD etiology

Tissue-Specific Expression Patterns of MicroRNA during Acute Graft-versus-Host Disease in the Rat

MicroRNAs (miRNA) have emerged as central regulators of diverse biological processes, and contribute to driving pathology in several diseases. Acute graft-versus-host disease (aGvHD) represents a major complication after allogeneic hematopoietic stem cell transplantation, caused by alloreactive donor T cells attacking host tissues leading to inflammation and tissue destruction. Changes in miRNA expression patterns occur during aGvHD, and we hypothesized that we could identify miRNA signatures in target tissues of aGvHD that may potentially help understand the underlying molecular pathology of the disease. We utilized a rat model of aGvHD with transplantation of fully MHC-mismatched T cell depleted bone marrow, followed by infusion of donor T cells. The expression pattern of 423 rat miRNAs was investigated in skin, gut, and lung tissues and intestinal T cells with the NanoString hybridization platform, in combination with validation by quantitative PCR. MHC-matched transplanted rats were included as controls. In the skin, up-regulation of miR-34b and down-regulation of miR-326 was observed, while in the intestines we detected down-regulation of miR-743b and a trend towards down-regulation of miR-345-5p. Thus tissue-specific expression patterns of miRNAs were observed. Neither miR-326 nor miR-743b has previously been associated with aGvHD. Moreover, we identified up-regulation of miR-146a and miR-155 in skin tissue of rats suffering from aGvHD. Analysis of intestinal T cells indicated 23 miRNAs differentially regulated between aGvHD and controls. Two of these miRNAs were differentially expressed either in skin (miR-326) or in intestinal (miR-345-5p) tissue. Comparison of intestinal and peripheral blood T cells indicated common dysregulated expression of miR-99a, miR-223, miR-326, and miR-345-5p. Analysis of predicted gene targets for these miRNAs indicated potential targeting of an inflammatory network both in skin and in the intestines that may further regulate inflammatory cytokine production. In conclusion, comprehensive miRNA profiling in rats suffering from aGvHD demonstrate tissue specific differences in the expression patterns of miRNA that may not be detected by profiling of peripheral blood T cells alone. These tissue specific miRNAs may contribute to distinct pathologic mechanisms, and could represent potential targets for therapy