title: Induction of allospecific tolerance by immature dendritic cells genetically modified to express soluble TNF receptor.
abstract: The ability of dendritic cells (DC) to initiate immune responses or induce immune tolerance is strictly dependent on their maturation state. TNF-alpha plays a pivotal role in the differentiation and maturation of DC. Blockade of TNF-alpha action may arrest DC in an immature state, prolonging their window of tolerogenic opportunity. Immature DC (imDC) were transfected with recombinant adenovirus to express soluble TNF-alpha receptor type I (sTNFRI), a specific inhibitor of TNF-alpha. The capacity of sTNFRI gene-modified imDC (DC-sTNFRI) to induce immune tolerance was analyzed. sTNFRI expression renders imDC resistant to maturation induction and impairs their capacity to migrate or present Ag. This process leads to induction of allogeneic T cell hyporesponsiveness and the generation of IL-10-producing T regulatory-like cells. In vivo pretreatment of transplant recipients with DC-sTNFRI induces long-term survival of cardiac allografts in 50% of cases, and leads to a substantial increase in the generation of microchimerism and T regulatory cell numbers. Thus, blockade of TNF-alpha action by sTNFRI genetic modification can inhibit the maturation of DC and potentiate the in vivo capacity of imDC to induce donor-specific immune tolerance and prolong allograft survival.
authors.affiliation: Institute of Immunology, Second Military Medical University, 800 Yiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Wang
authors.forename: Yushan
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.forename: Guoshan
authors.initials: G
authors.lastname: Ding
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhang
authors.forename: Guoyou
authors.initials: G
authors.lastname: Chen
authors.forename: Minghui
authors.initials: M
authors.lastname: Zhang
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016027:Heart Transplantation / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D016038:Skin Transplantation / Q000276:immunology; D012995:Solubility; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014162:Transfection / Q000379:methods; D023001:Transplantation Tolerance / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha