Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms

Maja Machcińska,Aleksandra Jankowska,Zuzanna Kotkowska,Monika Kotur,Artur Łaski,Marta Maruszewska-Cheruiyot,Katarzyna Bocian,Grażyna Korczak-Kowalska

doi:10.1007/s00005-021-00632-7

Maja Machcińska, Aleksandra Jankowska + Show 6 more

Open Access

https://doi.org/10.1007/s00005-021-00632-7

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Abstract

Following organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Immature dendritic cells (DCs) are considered to promote transplant tolerance and may minimize the risk of graft rejection. The aim of the study was to evaluate the effects of immunosuppressive agents: rapamycin (Rapa) and cyclosporine A (CsA) on generation of human tolerogenic DCs (tolDCs) and also to evaluate the ability of these cells to induce mechanisms of immune tolerance. tolDCs were generated in the environment of Rapa or CsA. Next, we evaluated the effects of these agents on surface phenotypes (CD11c, MHC II, CD40, CD80, CD83, CD86, CCR7, TLR2, TLR4), cytokine production (IL-4, IL-6, IL-10, IL-12p70, TGF-β), phagocytic capacity and resistant to lipopolysaccharide activation of these DCs. Moreover, we assessed ability of such tolDCs to induce T cell activation and apoptosis, Treg differentiation and production of Th1- and Th2-characteristic cytokine profile. Data obtained in this study demonstrate that rapamycin is effective at generating maturation-resistant tolDCs, however, does not change the ability of these cells to induce mechanisms of immune tolerance. In contrast, CsA affects the ability of these cells to induce mechanisms of immune tolerance, but is not efficient at generating maturation-resistant tolDCs.

Highlights

Following organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs
To confirm whether Rapa or cyclosporine A (CsA) affect the differentiation of dendritic cells (DCs) from monocytes, monocytes were cultured with granulocyte–macrophage colony-stimulating factor (GM-CSF)
One important discovery in this regard is that tolerogenic DCs (tolDCs) may induce transplant tolerance, but may avoid the use of immunosuppressive agents and minimize immunosuppressionrelated side effects

Summary

Introduction

It is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Existing therapies are focused on effector cells, a great deal of attention is being paid to dendritic cells (DCs), which may promote transplant tolerance (Marín et al 2016; Svajger et al 2014) Owing to their capacity to regulate both the innate and adaptive immune responses, DCs are considered to play crucial roles in directing the alloimmune response towards transplant tolerance or rejection. Transplant tolerance itself comprises a number of distinct mechanisms, such as the induction of T cell anergy and apoptosis, the induction of T regulatory cell (Tregs) proliferation and the selective activation of Th2 cells (Horton et al 2017; Ochando et al 2020) These properties enable tolDCs to be used as a base for therapeutic strategies to promote organ transplant tolerance (Moreau et al 2017). An approach combining tolDCs with various immunosuppressive agents can ensure long-term allograft survival or transplant tolerance (Que et al 2020; Švajger and Rožman 2020; Thomson et al 2018, 2019)

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