Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?

Sadeghi, Behnam; Al-Chaqmaqchi, Heevy; Al-Hashmi, Sulaiman; Brodin, David; Hassan, Zuzana; Abedi‐Valugerdi, Manuchehr; Moshfegh, Ali; Hassan, Moustapha

doi:10.1038/bmt.2012.120

Cited by 23 publications

(17 citation statements)

References 48 publications

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“…Recent data postulate that vascular endothelium is a target of GVHD and that diffuse alveolar hemorrhage and thrombotic microangiopathy are manifestations of endothelial acute GVHD (23). Although liver involvement with GVHD is well recognized, renal involvement is not; however, a mouse model of GVHD showed similar expression profiles in liver and kidney of pathways involved with antigen processing and inflammation with CD3 + T cells and expression of vascular cell adhesion molecule and intracellular adhesion molecule, reflecting endothelial injury (24). Our working hypothesis suggests that kidney injury results from inflammatory mediators and cytokines, with tubular and endothelial injury resulting from the systemic inflammatory milieu of GVHD or direct injury mediated by T cells and cytokines.…”

Section: Discussionmentioning

confidence: 99%

Urinary Elafin and Kidney Injury in Hematopoietic Cell Transplant Recipients

Hingorani

Finn

Pao

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.Design, setting, participants, & measurements Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry.Results Mean urinary elafin levels to day 100 were higher in patients with micro-or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P,0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P,0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro-or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P,0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P,0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P,0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules. ConclusionHigher urinary elafin levels are associated with an increased risk of micro-and macroalbuminuria, AKI and CKD, and death after HCT.

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Section: Discussionmentioning

confidence: 99%

Urinary Elafin and Kidney Injury in Hematopoietic Cell Transplant Recipients

Hingorani

Finn

Pao

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…CXCL8 , encoding IL-8, was upregulated in PBMC from patients who developed aGVHD (92). Moreover, Cxcl9 (101) and Cxcl10 were also elevated during murine aGvHD (100). Interestingly, the use of CXCR3-transfected T regs , as a novel therapeutic strategy, resulted in decreased severity of GvHD due to attraction of T regs to the target tissues of GvHD (145).…”

Section: Mirna and Mrna Expression Profiling In Hsctmentioning

confidence: 99%

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

Gam

Shah²,

Crossland

et al. 2017

Front. Immunol.

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The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP–mRNA–miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.

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“…Previous experimental studies have confirmed that pretransplantation conditioning intensity influences the severity of aGVHD by affecting the release of inflammatory cytokines [8]. Moreover, different gene expression profiles of the liver following total body-irradiated or Busulfan-Cyclophosphamide (Bu-Cy) conditioned mice have been reported [9]. The conditioning regimens Bu-Cy and Fludarabine-Busulfan (Flu-Bu) are commonly used in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

et al. 2016

BioMed Research International

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Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2 × 107 bone marrow cells and 2 × 107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P < 0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage.

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Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?

Cited by 23 publications

References 48 publications

Urinary Elafin and Kidney Injury in Hematopoietic Cell Transplant Recipients

Urinary Elafin and Kidney Injury in Hematopoietic Cell Transplant Recipients

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

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