title: Induction of kidney allograft tolerance by soluble CD83 associated with prevalence of tolerogenic dendritic cells and indoleamine 2,3-dioxygenase.
abstract: BACKGROUND
  Tolerogenic dendritic cells (Tol-DCs) play a critical role in inducing and maintaining tolerance. Recognizing that both T-cell inactivation and activation are contingent on signals provided by DCs and that graft-specific activated T cells are major mediators of transplant rejection, we aimed to create an environment favoring Tol-DCs with a novel reagent, human soluble CD83 (hsCD83).
  
  
  METHODS
  Life-supporting orthotopic kidney transplantation was performed in a C57BL/6-to-BALB/c mouse model. The study group was treated with hsCD83 (100 μg/mouse/day, postoperative days -1 to +7, intravenously) and compared with untreated controls.
  
  
  RESULTS
  Treatment with hsCD83 achieved kidney allograft tolerance (>100 days), with negligible antidonor antibody detected. In contrast, kidney grafts in untreated recipients demonstrated severe rejection after 35 days, characterized by cellular infiltration, interstitial hemorrhage and edema, and glomerular and tubular necrosis, as well as high antidonor antibody titers. In addition, splenic DCs of tolerant recipients exhibited significantly decreased levels of surface major histocompatibility complex class II, CD40, CD80, and intracellular interleukin-12, as well as reduced allogeneic stimulatory capacity. Adoptive transfer of CD11c+ DCs from tolerant hsCD83-treated animals induced kidney allograft tolerance in syngeneic recipients. Blocking indoleamine 2,3-dioxygenase with 1-methyl-tryptophan (15 mg/mouse/day; gavage) prevented the immunosuppressive effect of hsCD83, abrogating hsCD83-induced Tol-DCs and graft tolerance, and leading to acute kidney graft rejection in 22 days.
  
  
  CONCLUSIONS
  hsCD83 alone was capable of inducing kidney allograft tolerance through a mechanism involving Tol-DC generation and, at least in part, indoleamine 2,3-dioxygenase activity. Because sCD83 is of human origin, the therapeutic approach used in our mouse transplant model holds significant promise for clinical transplantation.
authors.affiliation: Department of Surgery, University of Western Ontario, London, ON, Canada.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Lan
authors.forename: Wei
authors.initials: W
authors.lastname: Ge
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Arp
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Dina
authors.initials: D
authors.lastname: Gordon
authors.forename: Don
authors.initials: D
authors.lastname: Healey
authors.forename: Mark
authors.initials: M
authors.lastname: DeBenedette
authors.forename: Charles
authors.initials: C
authors.lastname: Nicolette
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000097:blood; D015703:Antigens, CD / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007136:Immunoglobulins / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D000097802:CD83 Antigen