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Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor¹

Quanxing Wang^2,*, Yushan Liu^2,*, Jianli Wang, Guoshan Ding^*, Weiping Zhang^*, Guoyou Chen^*, Minghui Zhang^*, Shusen Zheng and Xuetao Cao^3,*

^* Institute of Immunology, Second Military Medical University, Shanghai, People’s Republic of China; and Institute of Immunology and Center for Organ Transplantation, Zhejiang University, Hangzhou, People’s Republic of China

The ability of dendritic cells (DC) to initiate immune responses or induce immune tolerance is strictly dependent on their maturation state. TNF- plays a pivotal role in the differentiation and maturation of DC. Blockade of TNF- 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- receptor type I (sTNFRI), a specific inhibitor of TNF-. 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- 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.

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