title: 5-Aminolevulinic acid with ferrous iron induces permanent cardiac allograft acceptance in mice via induction of regulatory cells.
abstract: BACKGROUND
  5-Aminolevulinic acid (5-ALA), a precursor of heme biosynthesis, plays a fundamentally important role in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO) and iron (Fe(2+)). The anti-inflammatory properties of biliverdin and CO help to alleviate ischemia/reperfusion injury as well as acute and/or chronic allograft rejection. We investigated whether 5-ALA and Fe(2+) exerts salutary effects in the setting of organ transplantation.
  
  
  METHODS
  An in vitro mixed-lymphocyte reaction (MLR) assay and cardiac allotransplantation model (CBA to C57BL/10) were used to evaluate the effects of 5-ALA and Fe(2+) on transplantation tolerance.
  
  
  RESULTS
  Treatment with 5-ALA and sodium ferrous citrate (SFC) resulted in permanent acceptance in the murine cardiac allografts in a dose-, SFC- and HO-1-dependent manner. The number of graft-infiltrating CD8 T cells was lower and the survival response of recipient spleen T cells to donor-type alloantigens was less compared with control recipients; however, numbers of both regulatory T cells and dendritic cells were significantly increased in 5-ALA/SFC-treated recipients.
  
  
  CONCLUSIONS
  Our findings show that 5-ALA/SFC inhibits T-cell proliferation in response to alloantigens and an increased number of regulatory cells, resulting in permanent cardiac allograft acceptance in mice. These findings highlight the major roles of CO and/or HO-1 in inducing tolerance and suggest that 5-ALA/SFC may be a clinically effective treatment for allograft rejection.
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo; Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Hou
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo; Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo; AIDS Research Center, National Institute of Infectious Diseases, Tokyo.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo.
authors.forename: Songjie
authors.initials: S
authors.lastname: Cai
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ito
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Abe
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: SBI Pharmaceuticals Co., Ltd., Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Hejian
authors.initials: H
authors.lastname: Zou
authors.affiliation: Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo. Electronic address: ri-k@ncchd.go.jp.
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation; D007501:Iron / Q000494:pharmacology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D017319:Photosensitizing Agents / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*
chemical_list: D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid; D007501:Iron
keywords: 5-ALA; allograft; cardiac transplantation; foxp3; regulatory T cell; tolerance