Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation

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http://www3.interscience.wiley.com/cgi-bin/abstract/117924692/ABSTRACT?CRETRY=1 & SRETRY=0

Original Articles

Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation

Hideyoshi Toyokawa 1 4, Atsunori Nakao 1 4, J. 1 4, A. Nalesnik 1 5, Takashi Kaizu 1 4, Jerome L. Lemoine 2, Atsushi Ikeda 1 4, Koji Tomiyama 1 4, Glenn D. Papworth 3, Leaf Huang 2 6, J. Demetris 1 5, E. Starzl 1 4, Noriko Murase 1 4 *

1 E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA2Center for Pharmacogenetics, University of Pittsburgh Medical Center, Pittsburgh, PA3Center for Biologic Imaging, University of Pittsburgh Medical Center, Pittsburgh, PA4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA5Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA6Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC

email: Noriko Murase (murase@...)

*Correspondence to Noriko Murase, Transplantation Institute, E1555 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261

Telephone: ; FAX:

Funded by: National Institutes of Health grants; Grant Number: AI048851, AI38899

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 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; 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 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. Liver Transpl 14:346-357, 2008. © 2008 AASLD.

Received: 1 June 2007; Accepted: 30 September 2007

Digital Object Identifier (DOI)10.1002/lt.21378 About DOI