Dataset Information

Radiation and host retinoic acid signaling promote the induction of gut-homing donor T cells after allogeneic hematopoietic stem cell transplantation.

ABSTRACT: Intestinal graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut-tropic donor T cells expressing integrin ?4?7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing ?4?7 expression on T cells. In this study, we showed that gene expression of retinaldehyde dehydrogenase, the key enzyme involved in RA biosynthesis, is significantly increased in the spleen and mesenteric lymph nodes (MLNs) of irradiated mice. In a C57BL/6-into-B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of ?4?7⁺ -donor T cells in mesenteric lymph nodes and spleen. Furthermore, we found that the RA pathway modulates the ability of dendritic cells to imprint gut-homing specificity on alloreactive T cells. We also showed that host dendritic cell RA signaling influences GVHD risk. Our studies identified radiation and recipient RA signaling as 2 primary factors that dictate the magnitude of gut-homing donor T cell induction after allogeneic HSCT. Attenuating radiation-associated inflammation and modulating host RA signaling represent feasible strategies to mitigate intestinal GVHD by reducing gut-seeking pathogenic donor T cells.

SUBMITTER: Zheng J

PROVIDER: S-EPMC6918002 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Radiation and host retinoic acid signaling promote the induction of gut-homing donor T cells after allogeneic hematopoietic stem cell transplantation.

Zheng Jianwei J Taylor Brian B Dodge Joseph J Stephans Allison A Zheng Song Guo SG Chen Qiang Q Chen Xiao X

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20190715 1

Intestinal graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut-tropic donor T cells expressing integrin α4β7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing α4β7 expression on T cells. In this study, we showed that gene exp ...[more]

PMID: 31207088

Similar Datasets

Project description:Pulmonary complications (PCs) cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Shifts in gut microbiota have been linked to HCT outcomes; however, their effect on PCs is unknown.To investigate whether changes in gut microbiota are associated with PCs after HCT.A single-center observational study was performed on 94 patients who underwent HCT from 2009 to 2011 and who were previously enrolled in a protocol for 16S ribosomal RNA sequencing of fecal microbiota. The primary endpoint, PC, was defined by new abnormal parenchymal findings on chest imaging in the setting of respiratory signs and/or symptoms. Outcomes were collected up to 40 months after transplant. Clinical and microbiota risk factors for PCs and mortality were evaluated using survival analysis.One hundred twelve PCs occurred in 66 (70.2%) subjects. A high comorbidity index (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.30-4.00; P?=?0.004), fluoroquinolones (HR, 2.29, 95% CI, 1.32-3.98; P?=?0.003), low baseline diversity (HR, 2.63; 95% CI, 1.22-5.32; P?=?0.015), and ?-proteobacteria domination of fecal microbiota (HR, 2.64; 95% CI, 1.10-5.65; P?=?0.031), which included common respiratory pathogens, predicted PCs. In separate analyses, low baseline diversity was associated with PCs that occurred preengraftment (HR, 6.30; 95% CI, 1.42-31.80; P?=?0.016), whereas ?-proteobacteria domination predicted PCs postengraftment (HR, 3.68; 95% CI, 1.49-8.21; P?=?0.006) and overall mortality (HR, 3.52; 95% CI, 1.28-9.21; P?=?0.016). Postengraftment PCs were also independent predictors of death (HR, 2.50; 95% CI, 1.25-5.22; P?=?0.009).This is the first study to demonstrate prospective changes in gut microbiota associated with PCs after HCT. Postengraftment PCs and ?-proteobacteria domination were predictive of mortality. This suggests an adverse relationship between the graft and lung, which is perhaps mediated by bacterial composition in the gut. Further study is warranted.

Project description:BackgroundIdentification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.MethodsWe performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011.FindingsUsing meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10-8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 × 10-8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 × 10-8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 × 10-8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 × 10-8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 × 10-9) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p = 2.6 × 10-8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 × 10-8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 × 10-9). Results publicly available at https://fuma.ctglab.nl/browse.InterpretationThese data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies.FundingThis project was funded by grants from the National Institutes of Health, USA.

Dataset Information

Radiation and host retinoic acid signaling promote the induction of gut-homing donor T cells after allogeneic hematopoietic stem cell transplantation.

Publications

Radiation and host retinoic acid signaling promote the induction of gut-homing donor T cells after allogeneic hematopoietic stem cell transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets