Jiangang Hou1, Qi Zhang1, Masayuki Fujino2, Songjie Cai3, Hidenori Ito4, Kiwamu Takahashi4, Fuminori Abe4, Motowo Nakajima4, Tohru Tanaka4, Jinhua Xu5, Hejian Zou5, Qiang Ding5, Xiao-Kang Li6. 1. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo; Huashan Hospital, Fudan University, Shanghai, China. 2. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo; AIDS Research Center, National Institute of Infectious Diseases, Tokyo. 3. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo. 4. SBI Pharmaceuticals Co., Ltd., Tokyo, Japan. 5. Huashan Hospital, Fudan University, Shanghai, China. 6. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo. Electronic address: ri-k@ncchd.go.jp.
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.
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: Weichen Zhou; Yi Wang; Masayuki Fujino; Leming Shi; Li Jin; Xiao-Kang Li; Jiucun Wang Journal: FEBS Open Bio Date: 2018-01-25 Impact factor: 2.693
Authors: Vipul Yadav; Yang Mai; Laura E McCoubrey; Yasufumi Wada; Motoyasu Tomioka; Satofumi Kawata; Shrikant Charde; Abdul W Basit Journal: Biomedicines Date: 2021-05-20