Background/Purpose: Several tolerogenic dendritic cell (DC) subsets have been identified in human such as CD1c⁺ DCs, which could be elevated by injection of Flt-3 ligand (FLT3L). CD1c⁺ tolerogenic DCs play important roles in the induction of peripheral tolerance and control of adaptive immune response, hence, they have become appealing targets in the treatment of systemic lupus erythematosus (SLE). Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) also exhibit immunoregulatory effects in SLE. However, the underlying immunosuppression mechanism of MSCs via tolerogenic DCs in SLE remains largely unknown. The aim of this study is to examine tolerogenic DCs levels in SLE patients, and to further investigate the mechanism of MSCs in the regulation of tolerogenic DCs.

Methods: Tolerogenic DCs were isolated as Lin(CD3/19/56/14)^– HLA DR⁺CD11c⁺CD1c⁺ from peripheral blood mononuclear cells (PBMCs). Level of tolerogenic DCs was determined by flow cytometry, and serum concentration of FLT3L was assessed by ELISA from 17 healthy controls and 25 SLE patients. Eight SLE patients were given UC MSCs infusions. We compared the levels of tolerogenic DCs and serum FLT3L before and 24 hours after UC MSCs transplantation. PBMCs from 8 patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1 and 50:1, for 24 hours, 48 hours and 72 hours, respectively, to detect the level of tolerogenic DCs. The level of FLT3L in the supernatant solution was analyzed. FLT3L siRNA was added to the co-culture system, and the level of tolerogenic DCs was detected.

Results: The levels of peripheral CD1c⁺ DCs and serum FLT3L were significantly decreased in SLE patients compared to healthy controls. Moreover, the level of CD1c⁺ DCs was remarkably negatively correlated with SLE disease activity index (SLEDAI) scores. After UC MSCs transplantation, the level of CD1c⁺ DCs increased, along with an increase in serum FLT3L. In vitro studies showed that UC MSCs time-dependently up-regulated peripheral CD1c⁺ DCs, but not dose-dependently. The supernatant FLT3L level significantly increased after co-cultured with MSCs. However, the addition of FLT3L siRNA significantly abrogated the up-regulation of CD1c⁺ DCs by MSCs, which could be reversed by adding extra FLT3L to the co-culture system.

Conclusion: UC MSCs induce CD1c⁺ tolerogenic DCs through up-regulating FLT3L in lupus patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mesenchymal-stem-cells-induce-cd1c-tolerogenic-dendritic-cells-via-up-regulating-flt3l-in-systemic-lupus-erythematosus/