title: Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.
abstract: The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-β-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.
authors.affiliation: 1] Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan [2] Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ichimaru
authors.affiliation: NapaJen Pharma, Inc., Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
authors.affiliation: 1] Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan [2] Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Cai
authors.affiliation: 1] Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan [2] Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Hou
authors.affiliation: 1] Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan [2] AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujino
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nonomura
authors.affiliation: NapaJen Pharma, Inc., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: NapaJen Pharma, Inc., Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ando
authors.affiliation: NapaJen Pharma, Inc., Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Uno
authors.affiliation: Department of Chemistry and Biochemistry, University of Kitakyushu, Kitakyushu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: Department of Chemistry and Biochemistry, University of Kitakyushu, Kitakyushu, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ohno
authors.affiliation: Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Zou
authors.affiliation: Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: X-K
authors.initials: XK
authors.lastname: Li
authors.affiliation: Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takahara
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000378:metabolism*; D064591:Allografts / Q000166:cytology / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D016027:Heart Transplantation; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D022423:Myeloid Cells / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012566:Sizofiran / Q000737:chemistry / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014162:Transfection
chemical_list: D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D034741:RNA, Small Interfering; D012566:Sizofiran