Project description:The aim of this study is to assess the Fecal Microbiota Transplantation (FMT) efficacy in the prevention of allogeneic hematopoietic stem cell transplantation (allo-HSCT) complications and particularly Graft versus Host Disease (GvHD).
The hypothesis of this study is that allogeneic FMT may improve outcomes of these patients.
Project description:A protein signature that could identify graft-versus-tumor (GVT) activity without graft-versus-host disease (GVHD), would allow for customized treatment plans following hematopoietic cell transplantation (HCT). Using orthogonal three-dimensional intact-protein analysis system (IPAS)
coupled with protein tagging and novel systems biology pipeline, we identified a signature of 49 proteins that are significantly increased in the plasma of HCT patients who received donor lymphocyte injection for tumor relapse and develop GVT without GVHD.
Project description:To assess if gene expression signatures could predict acute graft-versus-host disease, we examined the global gene expression profiles of peripheral blood mononuclear cells at day +14 post-transplantation from 94 patients undergoing allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.
Project description:Allogeneic hematopoietic stem cell transplantation remains the most efficacious treatment for many hematological malignancies. However, its therapeutic potential is affected by the most prominent side effect graft versus host disease. Despite advances in the treatment of graft versus host disease in recent years, morbidity and mortality remains high, which requires the development of new treatment approaches. We therefore implemented mouse models to assess potential treatment options for graft versus host disease. In in vivo experiments, we had observed a protective effect of LCN2 on graft versus host disease of the gastrointestinal tract. We also observed higher numbers of anti-inflammatory macrophages in the intestinal tissues of these animals. Therefore, we aimed to determine potentially regulated genes in these cells by using an in vitro approach of LCN2-treated macrophages.
Project description:<p><strong>BACKGROUND:</strong> Hematopoietic stem cell transplantation is a curative procedure for a variety of conditions. Despite major advances, a plethora of adverse clinical outcomes can develop post-transplantation including graft-versus-host disease and infections, which remain the major causes of morbidity and mortality. There is increasing evidence that the gastrointestinal microbiota is associated with clinical outcomes post-hematopoietic stem cell transplantation. Herein, we investigated the longitudinal dynamics of the gut microbiota and metabolome and potential associations to clinical outcomes in pediatric hematopoietic stem cell transplantation at a single centre.</p><p><strong>RESULTS:</strong> On admission (baseline), the majority of patients presented with a different gut microbial composition in comparison to healthy control children with a significantly lower alpha diversity. A further, marked decrease in alpha diversity was observed immediately post-transplantation and in most microbial diversity, and composition did not return to baseline status while hospitalized. Longitudinal trajectories identified continuous fluctuations in microbial composition, with the dominance of a single taxon in a significant proportion of patients. Using pam clustering, three clusters were observed in the dataset. Cluster 1 was common pre-transplantation, characterized by a higher abundance of <em>Clostridium XIVa</em>, <em>Bacteroides</em> and <em>Lachnospiraceae</em>; cluster 2 and cluster 3 were more common post-transplantation with higher abundance of <em>Streptococcus</em> and <em>Staphylococcus</em> in the former whilst <em>Enterococcus</em>, <em>Enterobacteriaceae</em> and <em>Escherichia</em> predominated in the latter. Cluster 3 was also associated with a higher risk of viraemia. Likewise, further multivariate analysis reveals <em>Enterobacteriaceae</em>, viraemia, use of total parenteral nutrition and various antimicrobials contributing towards cluster 3, <em>Streptococcaceae</em>, <em>Staphylococcaceae</em>, <em>Neisseriaceae</em>, vancomycin and metronidazole contributing towards cluster 2. <em>Lachnospiraceae</em>, <em>Ruminococcaceae</em>, <em>Bifidobacteriaceae</em> and not being on total parenteral nutrition contributed to cluster 1. Untargeted metabolomic analyses revealed changes that paralleled fluctuations in microbiota composition; importantly, low fecal butyrate was associated with higher risk of viraemia.</p><p><strong>CONCLUSIONS:</strong> These findings highlight the frequent shifts and dominations in the gut microbiota of pediatric patients undergoing hematopoietic stem cell transplantation. The study reveals associations between the fecal microbiota, metabolome and viraemia. To identify and explore the potential of microbial biomarkers that may predict risk of complications post-HSCT, larger multi-centre studies investigating longitudinal microbial profiling in pediatric hematopoietic stem cell transplantation are warranted.</p>
Project description:Graft-versus-host disease (GvHD) is critical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The immunosuppressants given to patients undergoing allogeneic HSCT disturb the microbiome and the host immune system, potentially leading to dysbiosis and inflammation. The intestinal microbiome is a target for the development of novel therapies for GvHD. We determined the effect of the combination of tacrolimus (FK506) and Lactobacillus acidophilus on GvHD.
Project description:<p>Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to Graft versus host disease (GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota.</p><p>Here we used high throughput metabolomics (UPLC-MS/MS) in two cohorts of genotypically HLA-identical related recipient and donor pairs. A first monocentric cohort from Saint Louis hospital (Paris, France) was used as an exploratory cohort (n=43) and a second multicentric national cohort from Cryostem biobank was used as a confimatory cohort (n=56).</p><p>Metabolomic profile markedly differed between recipients and donors. At the onset of acute GvHD, in addition to host-derived metabolites, we identified significant variation in microbiota-derived metabolites, especially in Aryl hydrocarbon Receptor (AhR) ligands, bile acids and plasmalogens. Altogether, our findings support that the allogeneic immune response during acute GvHD might be influenced by bile acids and by the decreased production of AhR ligands by microbiota that could limit indoleamine 2,3-dioxygenase (IDO) induction and influence allogeneic T-cell reactivity.</p><p><br></p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS204/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS204</a> contains study information relating to cohort 1.</p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS205/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS205</a> contains study information relating to cohort 2.</p>
Project description:<p>Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to Graft versus host disease (GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota.</p><p>Here we used high throughput metabolomics (UPLC-MS/MS) in two cohorts of genotypically HLA-identical related recipient and donor pairs. A first monocentric cohort from Saint Louis hospital (Paris, France) was used as an exploratory cohort (n=43) and a second multicentric national cohort from Cryostem biobank was used as a confimatory cohort (n=56).</p><p>Metabolomic profile markedly differed between recipients and donors. At the onset of acute GvHD, in addition to host-derived metabolites, we identified significant variation in microbiota-derived metabolites, especially in Aryl hydrocarbon Receptor (AhR) ligands, bile acids and plasmalogens. Altogether, our findings support that the allogeneic immune response during acute GvHD might be influenced by bile acids and by the decreased production of AhR ligands by microbiota that could limit indoleamine 2,3-dioxygenase (IDO) induction and influence allogeneic T-cell reactivity.</p><p><br></p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS204/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS204</a> contains study information relating to cohort 1.</p><p><a href='https://www.ebi.ac.uk/metabolights/editor/study/MTBLS205/descriptors' rel='noopener noreferrer' target='_blank'>MTBLS205</a> contains study information relating to cohort 2.</p>
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>