title: Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells.
abstract: BACKGROUND
  Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation.
  
  
  METHODS
  Naïve CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed.
  
  
  RESULTS
  CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to that from splenocytes of untreated recipients. Flow cytometry studies showed an increased CD4+CD25+ Forkhead box P3 (Foxp3)+ cell population in splenocytes from those mice.
  
  
  CONCLUSIONS
  Our findings indicate that exposure to opera music, such as La traviata, could affect such aspects of the peripheral immune response as generation of regulatory CD4+CD25+ cells and up-regulation of anti-inflammatory cytokines, resulting in prolonged allograft survival.
authors.affiliation: Department of Surgery, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Jin
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Toshihito
authors.initials: T
authors.lastname: Hirai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Amano
authors.forename: Hisashi
authors.initials: H
authors.lastname: Bashuda
authors.forename: Masanori
authors.initials: M
authors.lastname: Niimi
mesh_terms: D000161:Acoustic Stimulation; D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009147:Music Therapy / Q000379:methods*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D011897:Random Allocation; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014184:Transplantation, Homologous / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D016207:Cytokines; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit