title: Tolerance induction by exosomes from immature dendritic cells and rapamycin in a mouse cardiac allograft model.
abstract: BACKGROUND
  Dendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation. Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. However, this effect is limited and does not induce immunological tolerance when imDex are administered alone. Thus, we tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model.
  
  
  METHODS
  ImDex were obtained from the culture supernatant of immature DCs derived from donor mouse (C57BL/6) bone marrow and were injected with suboptimal doses of rapamycin into recipient mouse (BALB/c) before and after transplantation. The capacity of this treatment to induce immune tolerance was analyzed in vitro and in vivo using the mouse cardiac transplantation model.
  
  
  RESULTS
  Donor imDex expressed moderate levels of MHC class II and low levels of MHC class I and co-stimulatory molecules, but neither imDex nor subtherapeutic rapamycin dose alone induced cardiac allograft tolerance. Combined treatment with imDex and rapamycin, however, led to donor specific cardiac allograft tolerance. This effect was accompanied by decreased anti-donor antigen cellular response and an increased percentage of spleen CD4(+)CD25(+) T cells in recipients. Furthermore, this donor specific tolerance could be further transferred to naïve allograft recipients through injection of splenocytes, but not serum, from tolerant recipients.
  
  
  CONCLUSIONS
  Combined with immunosuppressive treatment, donor imDex can prolong cardiac allograft survival and induce donor specific allograft tolerance.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Li
authors.forename: Jing-Yue
authors.initials: JY
authors.lastname: Yang
authors.forename: De-Sheng
authors.initials: DS
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Song
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Li
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Zhuo-Chao
authors.initials: ZC
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Cao
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Dou
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D055354:Exosomes / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D020123:Sirolimus / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000941:Antigens; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D020123:Sirolimus