Induction of allospecific tolerance by immature dendritic cells genetically modified to express soluble TNF receptor.
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.
Wang
Quanxing
Q
Institute of Immunology, Second Military Medical University, 800 Yiangyin Road, Shanghai 200433, People's Republic of China.
Liu
Yushan
Y
Wang
Jianli
J
Ding
Guoshan
G
Zhang
Weiping
W
Chen
Guoyou
G
Zhang
Minghui
M
Zheng
Shusen
S
Cao
Xuetao
X
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
D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha