title: Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation.
abstract: The prevailing idea regarding the mechanism(s) by which therapeutic immunosuppressive dendritic cells (DCs) restrain alloimmunity is based on the concept that they interact directly with antidonor T cells, inducing anergy, deletion, and/or regulation. However, this idea has not been tested in vivo. Using prototypic in vitro-generated maturation-resistant (MR) DCs, we demonstrate that once MR-DCs carrying donor antigen (Ag) are administered intravenously, they decrease the direct and indirect pathway T-cell responses and prolong heart allograft survival but fail to directly regulate T cells in vivo. Rather, injected MR-DCs are short-lived and reprocessed by recipient DCs for presentation to indirect pathway CD4(+) T cells, resulting in abortive activation and deletion without detrimental effect on the number of indirect CD4(+) FoxP3(+) T cells, thus increasing the regulatory to effector T cell relative percentage. The effect on the antidonor response was independent of the method used to generate therapeutic DCs or their viability; and in accordance with the idea that recipient Ag-presenting cells mediate the effects of therapeutic DCs in transplantation, prolongation of allograft survival was achieved using donor apoptotic MR-DCs or those lacking surface major histocompatibility complex molecules. We therefore conclude that therapeutic DCs function as Ag-transporting cells rather than Ag-presenting cells to prolong allograft survival.
authors.affiliation: T. E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Sherrie J
authors.initials: SJ
authors.lastname: Divito
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: William J
authors.initials: WJ
authors.lastname: Shufesky
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.forename: Olga A
authors.initials: OA
authors.lastname: Tkacheva
authors.forename: Angela
authors.initials: A
authors.lastname: Montecalvo
authors.forename: Geza
authors.initials: G
authors.lastname: Erdos
authors.forename: Adriana T
authors.initials: AT
authors.lastname: Larregina
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D007165:Immunosuppression Therapy; D007275:Injections, Intravenous; D007519:Isoantigens; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D017931:DNA Primers; D007519:Isoantigens