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Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation

Macedo, C and Turquist, H and Metes, D and Thomson, AW (2012) Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation. Transplantation Research, 1 (1).

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Abstract

In efforts to minimize the chronic administration of immunosuppression (IS) drugs in transplantation and autoimmune disease, various cell-based tolerogenic therapies, including the use of regulatory or tolerogenic dendritic cells (tolDC) have been developed. These DC-based therapies aim to harness the inherent immunoregulatory potential of these professional antigen-presenting cells. In this short review, we describe both the demonstrated tolerogenic properties, and current limitations of rapamycin-conditioned DC (RAPA-DC). RAPA-DC are generated through inhibition of the integrative kinase mammalian target of rapamycin (mTOR) by the immunosuppressive macrolide rapamycin during propagation of monocyte-derived DC. Consistent with the characteristics of tolDC, murine RAPA-DC display resistance to phenotypic maturation induced by pro-inflammatory stimuli; exhibit the ability to migrate to secondary lymphoid tissue (important for 'cross-presentation' of antigen to T cells), and enrich for naturally-occurring CD4<sup>+</sup> regulatory T cells. In rodent models, delivery of recipient-derived RAPA-DC pulsed with donor antigen prior to organ transplantation can prolong allogeneic heart-graft survival indefinitely, especially when combined with a short course of IS. These encouraging data support ongoing efforts to develop RAPA-DC for clinical testing. When compared to murine RAPA-DC however, human RAPA-DC have proven only partially resistant to maturation triggered by pro-inflammatory cytokines, and display heterogeneity in their impact on effector T-cell expansion and function. In total, the evidence suggests the need for more in-depth studies to better understand the mechanisms by which mTOR controls human DC function. These studies may facilitate the development of RAPA-DC therapy alone or together with agents that preserve/enhance their tolerogenic properties as clinical immunoregulatory vectors. © 2012 Macedo et al.; licensee BioMed Central Ltd.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Macedo, C
Turquist, H
Metes, Ddim4@pitt.eduDIM4
Thomson, AW
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 28 September 2012
Date Type: Publication
Journal or Publication Title: Transplantation Research
Volume: 1
Number: 1
DOI or Unique Handle: 10.1186/2047-1440-1-16
Schools and Programs: School of Medicine > Immunology
School of Medicine > Surgery
Refereed: Yes
Article Type: Review
Date Deposited: 11 Oct 2016 18:31
Last Modified: 04 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/29826

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