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Taner, Timucin (2005) DENDRITIC CELLS, RAPAMYCIN AND TRANSPLANT TOLERANCE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Dendritic cells (DC) are uniquely well-equipped, professional antigen-presenting cells (APC), with the ability to initiate and regulate immune responses. In transplantation, DC of both donor and host origin contribute to graft rejection by inducing T cell activation and proliferation, via the direct and indirect pathways of allorecognition, respectively. Evidence has also accumulated, however, that DC, particularly in an immature state, can promote tolerance induction and prolong organ allograft survival. Rapamycin is a potent immunosuppressant pro-drug that is well-recognized for its inhibitory effects on T cell proliferation. Despite extensive research on rapamycin's impact on lymphocytes, little is known to date regarding its effects on DC. The central hypothesis in these studies was that, rapamycin interferes with the DC maturation and enhances their tolerogenic potential. We first analyzed the influence of rapamycin, in pharmacologically-relevant concentrations, on the maturation, functional activation and T cell stimulatory potential of murine myeloid DC. Herein we show that rapamycin targets DC antigen (Ag)-uptake and IL-4-mediated maturation both in vitro (in bone marrow-derived DC), and in vivo (in freshly-isolated DC, following in vivo administration of rapamycin). Exposure to rapamycin impairs inflammatory cytokine production and effective T cell stimulation by DC. Furthermore, rapamycin-treated DC induce Ag-specific T cell anergy. Next, we determined that presentation of alloAgs to T cells by rapamycin-pretreated DC of host origin, under in vivo (pre-transplant) steady-state conditions, could induce hyporesponsiveness to subsequent challenge and prolong organ (heart) graft survival. A single infusion of these cells, seven days prior to transplant, led to a significant improvement in transplant outcome in an Ag-specific manner. Furthermore, repeated infusion resulted in marked prolongation of graft survival. These studies demonstrate, for the first time, that the immunosuppressive action of rapamycin can be ascribed, in part, to its inhibitory effects on DC and that rapamycin can potentiate the tolerogenic properties of DC. They also reveal the potential of rapamycin-treated DC as therapeutic vectors of transplant tolerance.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairThomson, Angus Wthomsonaw@upmc.eduATHOMSON
Committee MemberMorelli, Adrian Emorelli@pitt.eduMORELLI
Committee MemberZeevi,
Committee MemberRobbins, Paul Dprobb@pitt.eduPROBB
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberStorkus, Walter Jstorkuswj@upmc.eduSTORKUSW
Date: 28 April 2005
Date Type: Completion
Defense Date: 25 February 2005
Approval Date: 28 April 2005
Submission Date: 18 April 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Dendritic cells; Immune tolerance; Rapamycin; Transplantation
Other ID:, etd-04182005-162550
Date Deposited: 10 Nov 2011 19:38
Last Modified: 19 Dec 2016 14:35


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