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

AbstractFollowing 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.

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Immunosuppressive Drugs Upregulate the Immunoinhibitory Receptor Osteoactivin in Monocyte-Derived Dendritic Cells,

Blood ◽

10.1182/blood.v118.21.3232.3232 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3232-3232

Author(s):

Mark-Alexander Schwarzbich ◽

Michael Gutknecht ◽

Lisa Guettler ◽

Lothar Kanz ◽

Helmut R. Salih ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cyclosporine A ◽

Cell Activation ◽

Immunosuppressive Agents ◽

Immunosuppressive Drugs ◽

Type I ◽

Transmembrane Glycoprotein

Abstract Abstract 3232 Osteoactivin, also known as transmembrane glycoprotein NMB (GPNMB) and dendritic cell-associated transmembrane protein (DC-HIL), is a type I transmembrane glycoprotein that is detected abundantly in dendritic cells (DC), but not or only at low levels in monocytes. Its expression on antigen-presenting cells (APC) can inhibit T cell activation by binding the type I transmembrane proteoglycan syndecan-4 (SD-4) on T cells. We here studied the influence of different therapeutically used immunosuppressive agents such as the corticosteroid prednisolone and the calcineurin inhibitors tacrolimus or cyclosporine A on the expression of osteoactivin in human monocyte-derived DC. Therefore, DC were generated from blood monocytes isolated by plastic adherence and exposed to GM-CSF and IL-4. Prednisolone, tacrolimus or cyclosporine A were added to the culture medium at concentrations obtained upon clinical application in patients (cyclosporine A: 1μg/ml, prednisolone: 3.5μg/ml, tacrolimus: 10ng/ml) every second day starting from the first day of culture. Cells were harvested for immunophenotyping and osteoactivin expression analysis by immunostaining, western-blotting and real-time RT-PCR or for functional analyses in mixed lymphocyte reactions (MLR) on day 7 of culture. DC generated in the presence of therapeutic concentrations of the immunosuppressant drugs showed a reduced expression of CD1a. Furthermore, we observed a clear upregulation of osteoactivin on DC that had been treated with the immunosuppressive agents. In line with osteoactivin up-regulation, exposure to the immunosuppressive drugs resulted in reduced stimulatory capacity of the DC in MLR with allogenic T cells, and this could be restored by addition of blocking osteoactivin antibody. In summary, our results demonstrate that upregulation of osteoactivin is critically involved in the inhibition of DC function upon exposure to different classes of immunosuppressive agents. These findings suggest that upregulation of osteoactivin in DC constitutes a ubiquitous mechanism that may underlie inhibition of T cell activation by these drugs. Disclosures: No relevant conflicts of interest to declare.

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Immunosuppressive Drugs up-Regulate the Immunoinhibitory Receptor Osteoactivin On Human Monocyte-Derived Dendritic Cells

Blood ◽

10.1182/blood.v120.21.3284.3284 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3284-3284

Author(s):

Sabine Braun ◽

Michael Gutknecht ◽

Mark-Alexander Schwarzbich ◽

Lothar Kanz ◽

Helmut R Salih ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cyclosporine A ◽

Cell Activation ◽

Immunosuppressive Drugs ◽

Type I ◽

Transmembrane Glycoprotein ◽

The Impact

Abstract Abstract 3284 Introduction: Dendritic cells (DC) abundantly express the type I transmembrane glycoprotein Osteoactivin (OA) - also known as transmembrane glycoprotein NMB and DC-HIL - compared to low expression levels on monocytes. Antigen-presenting cells interact via OA with the type I transmembrane proteoglycan syndecan-4 (SD-4) on T cells which inhibits T cell activation. We previously reported on increased expression of OA upon exposure of monocyte-derived DC (moDC) to immunosuppressive drugs (e.g., Gutknecht et al ASH annual meeting 2011). Here we extended these analyses and comparatively analyzed the impact of various immunsuppressive drugs (ID) on moDC phenotype and function. Methods: The moDC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Clinically relevant concentrations of ID were added to the culture medium every second day starting with the first day of culture (cyclosporine A: 1μg/ml, prednisolone: 3.5μg/ml, tacrolimus: 10ng/ml, mycophenolat-mofetil 0.1μM, methotrexat 230ng/ml). Cells were harvested for immunophenotyping by flow cytometry, western-blotting and real-time PCR. Cytokine release by moDC was determined on day 7 by ELISA. Functional properties were determined by mixed lymphocyte reactions (MLR) on day 7 of culture. Results: Exposure of moDC to therapeutic concentrations of prednisolone resulted in significantly reduced expression of the costimulatory molecules CD83 and CD86 and increased levels of the monocyte marker CD14, indicative of impaired differentiation. Tacrolimus significantly increased CD14 expression and reduced CD83 expression, while the other ID did not cause significant alterations. All ID altered the release of the immunomodulatory cytokines IL-10, IL-6 and TGF-ß. Notably, all ID except cyclosporine A caused a substantial upregulation of the immunoinhibitory receptor OA in moDC. The extent of OA expression increased over time of exposure to ID during differentiation and resulted in reduced capacity of the moDC to stimulate allogenic T cells which could be restored by disruption of OA/SD-4 interaction using a blocking OA antibody. Conclusion: Increased expression of OA on moDC upon exposure to ID contributes to inhibition of T-cell activation. The mechanisms underlying the differential effect of cyclosporine A are presently under study. Our results indicate that targeting OA/SD-4 interaction may hold promise for modulation of T cell responses in various pathophysiological conditions and immunotherapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

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Functional Ambivalence of Dendritic Cells: Tolerogenicity and Immunogenicity

International Journal of Molecular Sciences ◽

10.3390/ijms22094430 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4430

Author(s):

Ji-Hee Nam ◽

Jun-Ho Lee ◽

So-Yeon Choi ◽

Nam-Chul Jung ◽

Jie-Young Song ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Inflammatory Diseases ◽

Immunosuppressive Agents ◽

Treg Cells ◽

Peripheral Tolerance ◽

Cell Mediated Immunity ◽

Antigen Presenting

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and inducers of T cell-mediated immunity. Although DCs play a central role in promoting adaptive immune responses against growing tumors, they also establish and maintain peripheral tolerance. DC activity depends on the method of induction and/or the presence of immunosuppressive agents. Tolerogenic dendritic cells (tDCs) induce immune tolerance by activating CD4+CD25+Foxp3+ regulatory T (Treg) cells and/or by producing cytokines that inhibit T cell activation. These findings suggest that tDCs may be an effective treatment for autoimmune diseases, inflammatory diseases, and infertility.

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The Effect of Immunosuppressive Drugs on MDSCs in Transplantation

Journal of Immunology Research ◽

10.1155/2018/5414808 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 4

Author(s):

Fan Yang ◽

Yang Li ◽

Qian Zhang ◽

Liang Tan ◽

Longkai Peng ◽

...

Keyword(s):

Immune Tolerance ◽

Immunosuppressive Agents ◽

Tolerance Induction ◽

Suppressor Cells ◽

Immunosuppressive Drugs ◽

Negative Effects ◽

Transplant Tolerance ◽

Immune Tolerance Induction ◽

Positive Effects ◽

Transplant Immunology

Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in different transplant cases. We herein summarized our recent insights into the regulatory roles of MDSCs in transplantation specially focusing on the effects of immunosuppressive drugs on MDSCs and their mechanisms of action. Studies on the effects of immunosuppressive drugs on MDSCs will significantly expand our understanding of immunosuppressive drugs on immune regulatory cells in transplantation and offer new insights into transplant tolerance. We hope to emphasize our concern for the negative effects of immunosuppressive agents on MDSCs, which may potentially attenuate the immune tolerance induction in transplanted recipients.

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Cognate CD4+ T-cell–dendritic cell interactions induce migration of immature dendritic cells through dissolution of their podosomes

Blood ◽

10.1182/blood-2007-08-107755 ◽

2008 ◽

Vol 111 (7) ◽

pp. 3579-3590 ◽

Cited By ~ 17

Author(s):

Cinzia Nobile ◽

Marianne Lind ◽

Francesc Miro ◽

Karine Chemin ◽

Marie Tourret ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Interactions ◽

Immature Dendritic Cells ◽

Specific Contact ◽

Cc Chemokines ◽

And Migration

Abstract Dendritic cells (DCs) control T cell–based immunity. To do so they need to mature and migrate to sites of T-cell priming. We have previously shown that cognate interactions of human CD4+ T cells with DCs induce DC maturation. We show here that CC chemokines produced during antigen-specific T-DC interactions also induce strong morphologic modifications and migration of immature DCs. These modifications are required for efficient T-cell activation. Moreover, we show that CC chemokines produced during antigen-specific DC–T-cell interactions induce the dissolution of structures involved in cell motility and present on immature DCs (ie, podosomes). We thus propose a model in which chemokines secreted during Ag-specific contact between T cells and DCs induce disassembly of interacting and neighboring immature DC podosomes, leading to recruitment of more immature DCs toward sites of antigenic stimulation and to amplification of T-cell responses.

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Enhanced T-cell activation by immature dendritic cells loaded with HSP70-expressing heat-killed melanoma cells

Experimental Dermatology ◽

10.1111/j.1600-0625.2009.00962.x ◽

2010 ◽

Vol 19 (2) ◽

pp. 108-116 ◽

Cited By ~ 8

Author(s):

Susanne Knudsen ◽

Anke Schardt ◽

Timo Buhl ◽

Lars Boeckmann ◽

Michael P. Schön ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Melanoma Cells ◽

Immature Dendritic Cells

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Induction of Immune Tolerance in Islet Transplantation Using Apoptotic Donor Leukocytes

Journal of Clinical Medicine ◽

10.3390/jcm10225306 ◽

2021 ◽

Vol 10 (22) ◽

pp. 5306

Author(s):

Naoya Sato ◽

Shigeru Marubashi

Keyword(s):

Islet Transplantation ◽

T Cell Activation ◽

Immune Tolerance ◽

Chronic Rejection ◽

Cell Activation ◽

Tolerance Induction ◽

Effective Treatment Option ◽

Transplant Tolerance ◽

Primate Model ◽

Maintenance Immunosuppression

Allogeneic islet transplantation has become an effective treatment option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment. The development of donor-specific immune tolerance to the allograft is the ultimate goal given its potential ability to overcome chronic rejection and disregard the need for maintenance immunosuppression, which may be toxic to islet grafts. Recently, a breakthrough in tolerance induction during allogeneic islet transplantation using apoptotic donor lymphocytes (ADLs) in a non-human primate model had been reported. Several studies have suggested that the clonal depletion, anergy, and expansion of the antigen-specific regulatory immune network are the mechanisms for donor-specific tolerance with ADLs, which act synergistically to induce robust transplant tolerance. This achievement represents a huge step forward toward the clinical application of immune tolerance induction. We herein summarize the reported operational induction therapies in islet transplantation using the ADLs. Moreover, a few obstacles for the engraftment of transplanted islets, such as islet immunogenicity and instant blood-mediated response, which need to be resolved in the future, are also discussed.

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Long-lived immature dendritic cells mediated by TRANCE-RANK interaction

Blood ◽

10.1182/blood-2002-01-0312 ◽

2002 ◽

Vol 100 (10) ◽

pp. 3646-3655 ◽

Cited By ~ 64

Author(s):

Isabelle Cremer ◽

Marie-Caroline Dieu-Nosjean ◽

Sylvie Maréchal ◽

Colette Dezutter-Dambuyant ◽

Sarah Goddard ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Cd40 Ligand ◽

Immature Dendritic Cells ◽

Receptor Activator ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Necrosis Factor

Immature dendritic cells (DCs) reside in interstitial tissues (int-DC) or in the epidermis, where they capture antigen and, thereafter, mature and migrate to draining lymph nodes (LNs), where they present processed antigen to T cells. We have identified int-DCs that express both TRANCE (tumor necrosis factor–related activation-induced cytokine) and RANK (receptor activator of NF-κB) and have generated these cells from CD34+ human progenitor cells using macrophage colony-stimulating factor (M-CSF). These CD34+-derived int-DCs, which are related to macrophages, are long-lived, but addition of soluble RANK leads to significant reduction of cell viability and Bcl-2 expression. This suggests that constitutive TRANCE-RANK interaction is responsible for CD34+-derived int-DC longevity. Conversely, CD1a+ DCs express only RANK and are short-lived. However, they can be rescued from cell death either by recombinant soluble TRANCE or by CD34+-derived int-DCs. CD34+-derived int-DCs mature in response to lipopolysaccharide (LPS) plus CD40 ligand (L) and become capable of CCL21/CCL19-mediated chemotaxis and naive T-cell activation. Upon maturation, they lose TRANCE, making them, like CD1a+DCs, dependent on exogenous TRANCE for survival. These findings provide evidence that TRANCE and RANK play important roles in the homeostasis of DCs.

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