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-α plays a pivotal role in the differentiation and maturation of DC. Blockade of TNF-α 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-α receptor type I (sTNFRI), a specific inhibitor of TNF-α. 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-α 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.

Apoptotic cell administration enhances pancreatic islet engraftment by induction of regulatory T cells and tolerogenic dendritic cells

“…[20][21][22] We also show that soluble TNF-a receptor gene-modified immature DCs can prolong allograft survival more significantly than immature DCs used alone, indicating soluble TNF-a receptor gene-modified DCs exhibit more tolerogenicity. 23 Bone marrow-derived DCs (BMDCs) could also be rendered tolerogenic in the presence of IL-10, TGF-b and vascular endothelia growth factor or immunosuppressive drugs. [24][25][26] Tol-DCs can induce alloantigen specific T cell anergy and drive de novo differentiation of Tregs from naive T cells.…”

Suppressive dendritic cells as a tool for controlling allograft rejection in organ transplantation: Promises and difficulties

“…Blockade of TNF-␣ may arrest the DCs in an immature state and enhance their tolerogenic properties. Transgene immature DCs expressing the specific inhibitor TNF-␣ receptor type I are resistant to maturation and show an impaired capacity to migrate or to present antigens [52]. Furthermore they induce allogeneic T-cell hyporesponsiveness and generate IL-10 -producing T reg -like cells in vitro.…”

“…Furthermore they induce allogeneic T-cell hyporesponsiveness and generate IL-10 -producing T reg -like cells in vitro. Infusion of donor-derived DCs expressing TNF-␣ receptor type I into recipients induces long-term survival of cardiac allografts in mice [52].…”

Dendritic Cell Biology in Animal Models of Arthritis

“…CIA has also been inhibited using TNF matured DCs [65], a surprising finding given the important proinflammatory role of this cytokine in RA, but likely exemplifying endogenous cytokine-mediated homeostasis. Indeed blockade of TNF signalling by DCs via their overexpression of soluble TNF receptor type I (sTNFRI) prevented their maturation and migration resulting in allospecific tolerance [66]. Nevertheless, vaccination with CII pulsed, TNF matured bone marrow derived cDCs prior to induction of CIA resulted in delayed onset of disease [65].…”