title: Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation.
abstract: The interaction of donor passenger leukocytes and host leukocytes in recipient secondary lymphoid tissues during the early posttransplantation period is crucial in directing host immune reactions toward allograft rejection or acceptance. Responsible T cell clones could be activated through the direct and indirect pathways of allorecognition. We examined the role of the indirect pathway in liver transplantation (LT) tolerance by depleting host antigen-presenting cells (APC) with phagocytic activity [e.g., cluster domain (CD)68+/CD163+ macrophages, CD11c+ dendritic cells (DC)] using liposome-encapsulating clodronate (LP-CL). After Lewis rat cell or liver graft transplantation, Brown Norway (BN) rat recipients pretreated with LP-CL showed a significantly reduced type 1 helper T cell cytokine up-regulation than control-LP-treated recipients. In the LT model, LP-CL treatment and host APC depletion abrogated hepatic tolerance; Lewis liver grafts in LP-CL-treated-BN recipients developed mild allograft rejection, failed to maintain donor major histocompatibility complex (MHC) class II+ leukocytes, and developed chronic rejection in challenged donor heart allografts, while control-LP-treated BN recipients maintained tolerance status and donor MHC class II+ hepatic leukocytes. Furthermore, in the BN to Lewis LT model, LP-CL recipient treatment abrogated spontaneous hepatic allograft acceptance, and graft survival rate was reduced to 43% from 100% in the control-LP group. In conclusion, the study suggests that host cells with phagocytic activity could play significant roles in developing LT tolerance.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Toyokawa
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bailey
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalesnik
authors.forename: Takashi
authors.initials: T
authors.lastname: Kaizu
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Lemoine
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Tomiyama
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Papworth
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Starzl
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D004002:Clodronic Acid / Q000008:administration & dosage; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008081:Liposomes; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D010587:Phagocytosis / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D008081:Liposomes; D004002:Clodronic Acid