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 rapamycins 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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04182005-162550 |
| Date | 28 April 2005 |
| Creators | Taner, Timucin |
| Contributors | Adriana Zeevi, Walter J. Storkus, Pawel Kalinski, Paul D. Robbins, Angus W. Thomson, Adrian E. Morelli |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04182005-162550/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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