title: Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8(+) T cells in vitro and in vivo.
abstract: Dendritic cells (DC) are "professional" bone marrow-derived antigen (Ag)-presenting cells of interest both as therapeutic targets and potential cellular vaccines due to their ability to regulate innate and adaptive immunity. Harnessing the inherent tolerogenicity of DC is a promising and incompletely explored approach to the prevention of allograft rejection. Previously, we and others have reported the ability of pharmacologically-modified DC, that resist maturation, to inhibit CD4(+) T cell responses and prolong allograft survival. Here we evaluated the ability of murine myeloid DC conditioned with the immunosuppressive pro-drug rapamycin (RAPA) to acquire and directly present alloAg to syngeneic CD8(+) T cells. RAPA-conditioned DC (RAPA-DC) pulsed with allogeneic splenocyte lysate acquired and expressed donor MHC class I and enhanced the apoptotic death of directly-reactive donor Ag-specific CD8(+) T cells in vitro. Moreover, following their adoptive transfer, they reduced the survival of these T cells in vivo. The ability of RAPA-DC to inhibit the survival of alloAg-specific CD8(+) T cells provides a potential mechanism by which host-derived DC may act as negative regulators of T cell alloreactivity and support donor-specific unresponsiveness. Adoptive cell therapy with alloAg-pulsed RAPA-DC may offer an effective approach to suppression of alloimmunity, with reduced dependence on systemic immunosuppression.
authors: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15238, USA. freemanm@upmc.edu
authors: Ryan T
authors: RT
authors: Fischer
authors: Hēth R
authors: HR
authors: Turnquist
authors: Zhiliang
authors: Z
authors: Wang
authors: Donna
authors: D
authors: Beer-Stolz
authors: Angus W
authors: AW
authors: Thomson
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