Flt3L Combined with Rapamycin Promotes Cardiac Allograft Tolerance by Inducing Regulatory Dendritic Cells and Allograft Autophagy in Mice

Abstract

The induction of immune tolerance is still a formidable challenge in organ transplantation. Dendritic cells (DCs) play an important role in orchestrating immune responses by either mediating protective immune responses or inducing antigen specific tolerance. Previous studies demonstrated that the fms-like tyrosine kinase 3 receptor (Flt3) and its ligand (Flt3L) play an essential role in the regulation of DC commitment and development. Here, we report a synergic effect between Flt3L and low-dose rapamycin (Rapa) in the protection of allograft rejction. It was found that Flt3L combined with Rapa significantly prolonged murine cardiac allograft survival time as compared with that of untreated recipients or recipients treated with Rapa or Flt3L alone. Mechanistic studies revealed that Flt3L combined with low-dose of Rapa induced the generation of tolerogenic DCs along with the production of CD25+ Foxp3+ regulatory T cells and IL-10 secretion. We also observed enhanced autophagy in the cardiac allograft, which could be another asset contributing to the enhanced allograft survival. All together, these data suggest that Flt3L combined with low-dose of Rapa could be an effective therapeutic approach to induce tolerance in clinical setting of transplantation.

Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell–dependent induction of CD4+CD25+FoxP3+ Treg

“…Interestingly, others found that rapamycin and Flt3L could be combined to improve engraftment of cardiac allografts in mice. 38 Consistent with our findings, these authors also noticed an increase in pDC and Treg frequencies (without however further addressing the underlying mechanism). 38 These data illustrate the wide range of potential applicability of the Flt3L/rapamycin combination.…”

“…38 Consistent with our findings, these authors also noticed an increase in pDC and Treg frequencies (without however further addressing the underlying mechanism). 38 These data illustrate the wide range of potential applicability of the Flt3L/rapamycin combination. Conversely, these findings have implications for immunotherapy, as discussed previously for breast cancer.…”

“…Upon administering Flt3L (80 mg/kg, 3 per week for 3 weeks) to DO11.10-tg x Rag-2 2/2 mice, 14,38 we found a significant expansion of pDCs (CD11c The sum of results obtained thus far suggest that selective pDC expansion augments Treg induction.…”

High-mobility group box 1 accelerates early acute allograft rejection via enhancing IL-17+γδ T-cell response

“…Total proteins were extracted from cardiac allograft and subjected to immunoblots assay as described previously . The primary antibodies used in the study include rabbit anti‐HMGB1 (Abcam, Cambridge, MA, USA) and rabbit anti‐GAPDH (Santa Cruz Biotechnology, Santa Cruz, CA, USA).…”

New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

“…This effect appears to be mediated via the selective expansion of ‘tolerogenic’ pDCs . Moreover, a combination of rapamycin and Flt3L promotes organ allograft survival in mice by inducing regulatory DC and allograft autophagy . Myeloid‐derived suppressor cells (MDSCs) …”