title: Absence of miR-182 Augments Cardiac Allograft Survival.
abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate the posttranscriptional expression of target genes and are important regulators in immune responses. Previous studies demonstrated that the miRNA, miR-182 was significantly increased during allograft rejection. Further, the transcription factor Forkhead box (FOX) protein 1, (FOXO1) was shown to be a target of miR-182. The aim of this study is to further examine the role of miR-182 in alloimmune responses.
  
  
  
  Transplantation of BALB/c cardiac allografts was performed in C57BL/6, miR-182, B6.129S-H2 (MHC II and CD4 T cell-deficient) and B6.129S2-Tap1 (MHC I and CD8 T cell-deficient) mice, with or without CTLA-4Ig administration. T cell phenotype, FOXO1 protein levels and graft infiltrating lymphocytes were determined in C57BL/6 or miR-182 mice by flow cytometric analysis, Western blot, and immunohistochemistry, respectively.
  
  
  
  We now show that T cells, mainly CD4 are the main cellular source of miR-182 during allograft rejection. In the absence of miR-182, CTLA-4Ig treatment significantly increased allograft survival (31.5 days C57BL/6 vs 60 days miR-182; P < 0.01). Further, CTLA4-Ig treatment inhibits miR-182 expression, increases FOXO1 levels, and reduces the percentage of CD4CD44 T cells after transplantation. Fewer T cells infiltrate the cardiac allografts, and memory T cells are significantly decreased in allograft recipients deficient in miR-182 with CTLA4-Ig treatment (P < 0.01).
  
  
  
  Our findings suggest that miR-182 contributes to the T-cell responses to alloantigen especially under costimulation blockade. Therapeutics that target specific miRNAs may prove beneficial in transplantation.
authors.affiliation: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine.
authors.forename: Liang
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine.
authors.forename: Vandana
authors.initials: V
authors.lastname: Kaul
authors.affiliation: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine.|Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Stanford University School of Medicine.
authors.forename: Audrey H
authors.initials: AH
authors.lastname: Lau
authors.affiliation: Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Naoharu
authors.initials: N
authors.lastname: Iwai
authors.affiliation: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine.|Program in Immunology, Stanford University School of Medicine.
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Martinez
authors.affiliation: Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine.|Program in Immunology, Stanford University School of Medicine.
authors.forename: Sheri M
authors.initials: SM
authors.lastname: Krams
mesh_terms: D000069594:Abatacept / Q000494:pharmacology; D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D007166:Immunosuppressive Agents; D007519:Isoantigens; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; D000069594:Abatacept; D007371:Interferon-gamma