Review

Transplantation Research

, 1:16

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

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

  • Camila MacedoAffiliated withThomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine
  • , Hēth TurquistAffiliated withThomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of MedicineDepartment of Immunology, University of Pittsburgh School of Medicine
  • , Diana MetesAffiliated withThomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of MedicineDepartment of Immunology, University of Pittsburgh School of Medicine
  • , Angus W ThomsonAffiliated withThomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of MedicineDepartment of Immunology, University of Pittsburgh School of Medicine Email author 

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+ 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.

Keywords

Dendritic cells Antigen presentation Rapamycin T cells Regulatory T cells Tolerance Transplantation