Contributions
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30
Location: Room Lehar 3 + 4
Background
To date, many studies investigating acute graft-versus-host disease (aGVHD) have focused on seeking potential biomarkers to initiate early intervention. MicroRNAs (miRNAs) have been reported to be promising diagnostic biomarkers for various types of diseases. A few studies have also demonstrated roles for miRNAs in the pathogenesis of aGVHD. However, data regarding the function of these miRNAs in human GVHD are limited. Using a miRNA polymerase chain reaction (PCR) chip, miR-153-3p was detected as a potential biomarker of aGVHD. Interestingly, indoleamine-2,3-dioxygenase (IDO) was found to be a potential target of miR-153-3p. Many previous studies have demonstrated that IDO plays important roles in the immunosuppression. Increased IDO expression may serve as a protective mechanism during aGVHD.
Aims
This study was aim to confirm the regulation of miRNA-153-3p on IDO both in vitro and mice model experiments, and to elucidate its role during GVHD development.
Methods
Plasma samples from 70 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from Sep 2012 to Jun 2013 were prospectively collected at fixed time points from Peking University Institute of Hematology. RQ-PCR analysis was performed to examine the miRNA expression of plasma. BALB/c (H-2d) and C57BL/6 (H-2b) mice were used to establish the GVHD model. Antagomir and its control of miRNA-153-3p were administered via tail vein injection after allo-HSCT. Clinical and histological assessment of GVHD was performed. The expression levels of miRNA-153-3p and IDO in mice organs were also examined by Western Blot and RQ-PCR analysis.
Results
In this study, elevated plasma miR-153-3p levels at +7 d after transplant appeared to be a good predictor for subsequent aGVHD. IDO was found to be a potential target protein of miR-153-3p using bio-informative analysis. In vitro experiments confirmed that miRNA-153 could bind directly to the promoter region of IDO gene and affect its transcription and protein expression (above data have been reported on 2014 ASH meeting as a poster). In addition, the expression of plasma IDO was also lower in the aGVHD group at +7d compared to that of control group after allo-HSCT.
To confirm the relationship between miR-153-3p and aGVHD, we established the MHC-mismatched murine GVHD model. Two groups received antagomir-control and antagomir-153-3p injection, respectively. The incidence and severity of the aGVHD were significantly decreased in the recipients of antagomir-153-3p infusion, as evidenced by the clinical GVHD scores (p<0.0001). Recipients of the antagomir-153-3p infusion survived longer compared to those of the antagomir-control infusion (log-rank test, p=0.0089). The pathological severity of aGVHD at day +21 in the liver and colon was also reduced in recipients who received antagomir-153-3p with positively stained granzyme B cell proportions as a marker. Besides, recipient mice of antagomir-153-3p displayed relatively higher IDO expression at the early stage after transplantation.
Summary
This is the first study to demonstrate, using in vitro and animal model experiments, that IDO can be directly regulated by miR-153-3p and that this miRNA might participate in aGVHD development by down-regulating IDO. Therefore, miR-153-3p may be a putative bio-target for a novel strategy for aGVHD intervention.
Session topic: Stem cell transplantation: Experimental
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:15 to 13.06.2015 16:30
Location: Room Lehar 3 + 4
Background
To date, many studies investigating acute graft-versus-host disease (aGVHD) have focused on seeking potential biomarkers to initiate early intervention. MicroRNAs (miRNAs) have been reported to be promising diagnostic biomarkers for various types of diseases. A few studies have also demonstrated roles for miRNAs in the pathogenesis of aGVHD. However, data regarding the function of these miRNAs in human GVHD are limited. Using a miRNA polymerase chain reaction (PCR) chip, miR-153-3p was detected as a potential biomarker of aGVHD. Interestingly, indoleamine-2,3-dioxygenase (IDO) was found to be a potential target of miR-153-3p. Many previous studies have demonstrated that IDO plays important roles in the immunosuppression. Increased IDO expression may serve as a protective mechanism during aGVHD.
Aims
This study was aim to confirm the regulation of miRNA-153-3p on IDO both in vitro and mice model experiments, and to elucidate its role during GVHD development.
Methods
Plasma samples from 70 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from Sep 2012 to Jun 2013 were prospectively collected at fixed time points from Peking University Institute of Hematology. RQ-PCR analysis was performed to examine the miRNA expression of plasma. BALB/c (H-2d) and C57BL/6 (H-2b) mice were used to establish the GVHD model. Antagomir and its control of miRNA-153-3p were administered via tail vein injection after allo-HSCT. Clinical and histological assessment of GVHD was performed. The expression levels of miRNA-153-3p and IDO in mice organs were also examined by Western Blot and RQ-PCR analysis.
Results
In this study, elevated plasma miR-153-3p levels at +7 d after transplant appeared to be a good predictor for subsequent aGVHD. IDO was found to be a potential target protein of miR-153-3p using bio-informative analysis. In vitro experiments confirmed that miRNA-153 could bind directly to the promoter region of IDO gene and affect its transcription and protein expression (above data have been reported on 2014 ASH meeting as a poster). In addition, the expression of plasma IDO was also lower in the aGVHD group at +7d compared to that of control group after allo-HSCT.
To confirm the relationship between miR-153-3p and aGVHD, we established the MHC-mismatched murine GVHD model. Two groups received antagomir-control and antagomir-153-3p injection, respectively. The incidence and severity of the aGVHD were significantly decreased in the recipients of antagomir-153-3p infusion, as evidenced by the clinical GVHD scores (p<0.0001). Recipients of the antagomir-153-3p infusion survived longer compared to those of the antagomir-control infusion (log-rank test, p=0.0089). The pathological severity of aGVHD at day +21 in the liver and colon was also reduced in recipients who received antagomir-153-3p with positively stained granzyme B cell proportions as a marker. Besides, recipient mice of antagomir-153-3p displayed relatively higher IDO expression at the early stage after transplantation.
Summary
This is the first study to demonstrate, using in vitro and animal model experiments, that IDO can be directly regulated by miR-153-3p and that this miRNA might participate in aGVHD development by down-regulating IDO. Therefore, miR-153-3p may be a putative bio-target for a novel strategy for aGVHD intervention.
Session topic: Stem cell transplantation: Experimental