Role of Circulating MicroRNAs in the Immunopathogenesis of Rejection After Pediatric Lung Transplantation

Background Acute rejection (AR) and development of chronic rejection, bronchiolitis obliterans syndrome (BOS) remain major limiting factors for lung transplantation (LTx). This retrospective study is to identify differentially expressed circulating microRNAs (miRNAs) that associate with development of AR and BOS in pediatric lung transplant recipients (LTxR). Methods We determined the circulating levels of 7 selected candidate miRNAs in 14 LTxR with AR, 7 with BOS, and compared them against 13 stable pediatric LTxR at 1, 6, and 12 months after LTx. In addition, 6 AR, 7 BOS, and 8 stable pediatric LTxR, 16 AR, 17 BOS, and 16 stable adult LTxR were included for validation. Results MiR-10a, -195, -133b were significantly lower in AR and miR-144, -142-5p, -155 were higher in AR compared to stable (P < 0.05). In addition, circulating levels of miR-134, -10a, -195, -133b were significantly lower and miR-144, -142-5p, -155 were higher (P < 0.05) with development of BOS. The receiver-operating characteristic demonstrated that miR-142-5p, miR-155, and miR-195 strongly discriminated patients with AR from stable LTxR (P < 0.001 for all comparisons): miR-142-5p (area under the curve [AUC], 0.854), miR-155 (AUC, 0.876), and miR-195 (AUC, 0.872). Further, miR-10a, miR-142-5p, miR-144, and miR-155 strongly discriminated BOS from stable LTxR (P < 0.001 for all comparisons). Conclusions We demonstrated that differential expression of circulating miRNAs occurs in LTxR with AR and BOS, suggesting that they can provide not only important clues to pathogenesis but also may serve as potential noninvasive biomarkers for AR and BOS after pediatric LTx.

[1]  D. Kreisel,et al.  MicroRNA-144 dysregulates the transforming growth factor-β signaling cascade and contributes to the development of bronchiolitis obliterans syndrome after human lung transplantation. , 2015, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[2]  T. Mohanakumar,et al.  Dysregulated MicroRNA Expression and Chronic Lung Allograft Rejection in Recipients With Antibodies to Donor HLA , 2015, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  T. Mohanakumar,et al.  De Novo–Developed Antibodies to Donor MHC Antigens Lead to Dysregulation of MicroRNAs and Induction of MHC Class II , 2015, The Journal of Immunology.

[4]  Guo-fu Huang,et al.  Electroacupuncture Stimulates Remodeling of Extracellular Matrix by Inhibiting Apoptosis in a Rabbit Model of Disc Degeneration , 2015, Evidence-based complementary and alternative medicine : eCAM.

[5]  X. Jouven,et al.  MicroRNAs as non-invasive biomarkers of heart transplant rejection. , 2014, European heart journal.

[6]  P. Friend,et al.  Examination of serum miRNA levels in kidney transplant recipients with acute rejection. , 2014, Transplantation.

[7]  P. Ohashi,et al.  Mir‐155, a central modulator of T‐cell responses , 2014, European journal of immunology.

[8]  Hiroya Tamaki,et al.  Allogeneic T cell responses are regulated by a specific miRNA-mRNA network. , 2013, The Journal of clinical investigation.

[9]  J. Yang,et al.  Profiling circulating microRNA expression in a mouse model of nerve allotransplantation , 2013, Journal of Biomedical Science.

[10]  David M. Rocke,et al.  Stability of miRNA in human urine supports its biomarker potential. , 2013, Biomarkers in medicine.

[11]  M. Ardalan,et al.  MicroRNA and Renal Allograft Monitoring , 2013, Nephro-urology monthly.

[12]  M. Delahousse,et al.  Expression of miR-142-5p in Peripheral Blood Mononuclear Cells from Renal Transplant Patients with Chronic Antibody-Mediated Rejection , 2013, PloS one.

[13]  O. Gidlöf,et al.  Altered serum miRNA profiles during acute rejection after heart transplantation: potential for non-invasive allograft surveillance. , 2013, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[14]  W. Chapman,et al.  Modulation of immune responses following solid organ transplantation by microRNA. , 2012, Experimental and molecular pathology.

[15]  J. Bluestone,et al.  MicroRNA 10a Marks Regulatory T Cells , 2012, PloS one.

[16]  Mario Medvedovic,et al.  Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1. , 2012, Cardiovascular research.

[17]  J. Lozano,et al.  Upregulation of miR-142-3p in peripheral blood mononuclear cells of operationally tolerant patients with a renal transplant. , 2012, Journal of the American Society of Nephrology : JASN.

[18]  G. Kazemier,et al.  Hepatocyte‐derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation , 2012, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[19]  M. Scian,et al.  MicroRNA Profiles in Allograft Tissues and Paired Urines Associate With Chronic Allograft Dysfunction With IF/TA , 2011, American Journal of Transplantation.

[20]  T. Korn,et al.  Expression of miRNAs miR-133b and miR-206 in the Il17a/f Locus Is Co-Regulated with IL-17 Production in αβ and γδ T Cells , 2011, PloS one.

[21]  Chengwen Li,et al.  MicroRNAs: potential biomarker in organ transplantation. , 2011, Transplant immunology.

[22]  M. Peltz,et al.  HLA mismatches influence lung transplant recipient survival, bronchiolitis obliterans and rejection: implications for donor lung allocation. , 2011, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[23]  O. Martinez,et al.  MicroRNAs as Immune Regulators: Implications for Transplantation , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  Darshana Dadhania,et al.  MicroRNA expression profiles predictive of human renal allograft status , 2009, Proceedings of the National Academy of Sciences.

[25]  S. Palmer,et al.  Acute rejection and humoral sensitization in lung transplant recipients. , 2009, Proceedings of the American Thoracic Society.

[26]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[27]  G. Calin,et al.  Expression and function of micro RNAs in immune cells during normal or disease state , 2008, International journal of medical sciences.

[28]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[29]  Chris Sander,et al.  MicroRNA profiling of the murine hematopoietic system , 2005, Genome Biology.

[30]  Matthias Merkenschlager,et al.  T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer , 2005, The Journal of experimental medicine.

[31]  M. Estenne,et al.  Bronchiolitis obliterans after human lung transplantation. , 2002, American journal of respiratory and critical care medicine.

[32]  Marshall Hertz,et al.  Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. , 2002, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[33]  B. Griffith,et al.  Does histologic acute rejection in lung allografts predict the development of bronchiolitis obliterans? , 1991, Transplantation.