Differential effects of immunosuppressive drugs on chemokine receptor CCR7 in human monocyte-derived dendritic cells

Selective upregulation by rapamycin

Valeria Sordi, Giancarlo Bianchi, Chiara Buracchi, Alessia Mercalli, Federica Marchesi, Giovanna D'Amico, Cui Hong Yang, Walter Luini, Annunciata Vecchi, Alberto Mantovani, Paola Allavena, Lorenzo Piemonti

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

BACKGROUND. Appropriate recruitment of dendritic cells (DC) at sites of inflammation and migration to secondary lymphoid organs is of critical importance for the initiation of Ag-specific immune responses. The proper localization of DC in selected tissues is guided primarily by the coordinated expression of chemokine receptors (CKR). Here we show that immunosuppressive drugs have divergent effects on the modulation of CKR in maturing DC. METHODS AND RESULTS. Dexamethazone (DEX) and IL-10 inhibited human DC migration to CCL19 in vitro and mouse DC migration to lymph nodes (LN) in vivo, by impairing CCR7 expression. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) were characterized by the inability to modulate CKR expression and migratory activity. Rapamycin (RAPA) increased DC migration to CCL19 in vitro and to LN in vivo by enhancing CCR7 expression. This effect could be mediated, in LPS-maturing DC, by the inhibition of autocrine IL-10 production. The in vivo data obtained with ex vivo RAPA treated DC were confirmed in a model of in vivo drug administration in mice, suggesting a potential clinical relevance. CONCLUSIONS. These findings demonstrate that immunosuppressive agents differently modulate the CKR switch associated with maturing DC; in particular, RAPA selectively up-regulates CCR7 and enhances the migration of differentiated DC to regional LN. This study contributes to a better understanding of the role of immunosuppressive therapy on DC migration, a potentially relevant check point of immunosuppressive treatment.

Original languageEnglish
Pages (from-to)826-834
Number of pages9
JournalTransplantation
Volume82
Issue number6
DOIs
Publication statusPublished - Sep 2006

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Chemokine Receptors
Sirolimus
Immunosuppressive Agents
Dendritic Cells
Monocytes
Up-Regulation
Pharmaceutical Preparations
Cell Movement
Lymph Nodes
Tacrolimus
Interleukin-10
Cyclosporine
Inflammation

Keywords

  • Dendritic cell
  • Immunosuppression
  • Migration

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Differential effects of immunosuppressive drugs on chemokine receptor CCR7 in human monocyte-derived dendritic cells : Selective upregulation by rapamycin. / Sordi, Valeria; Bianchi, Giancarlo; Buracchi, Chiara; Mercalli, Alessia; Marchesi, Federica; D'Amico, Giovanna; Yang, Cui Hong; Luini, Walter; Vecchi, Annunciata; Mantovani, Alberto; Allavena, Paola; Piemonti, Lorenzo.

In: Transplantation, Vol. 82, No. 6, 09.2006, p. 826-834.

Research output: Contribution to journalArticle

Sordi, Valeria ; Bianchi, Giancarlo ; Buracchi, Chiara ; Mercalli, Alessia ; Marchesi, Federica ; D'Amico, Giovanna ; Yang, Cui Hong ; Luini, Walter ; Vecchi, Annunciata ; Mantovani, Alberto ; Allavena, Paola ; Piemonti, Lorenzo. / Differential effects of immunosuppressive drugs on chemokine receptor CCR7 in human monocyte-derived dendritic cells : Selective upregulation by rapamycin. In: Transplantation. 2006 ; Vol. 82, No. 6. pp. 826-834.
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AU - Yang, Cui Hong

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AB - BACKGROUND. Appropriate recruitment of dendritic cells (DC) at sites of inflammation and migration to secondary lymphoid organs is of critical importance for the initiation of Ag-specific immune responses. The proper localization of DC in selected tissues is guided primarily by the coordinated expression of chemokine receptors (CKR). Here we show that immunosuppressive drugs have divergent effects on the modulation of CKR in maturing DC. METHODS AND RESULTS. Dexamethazone (DEX) and IL-10 inhibited human DC migration to CCL19 in vitro and mouse DC migration to lymph nodes (LN) in vivo, by impairing CCR7 expression. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) were characterized by the inability to modulate CKR expression and migratory activity. Rapamycin (RAPA) increased DC migration to CCL19 in vitro and to LN in vivo by enhancing CCR7 expression. This effect could be mediated, in LPS-maturing DC, by the inhibition of autocrine IL-10 production. The in vivo data obtained with ex vivo RAPA treated DC were confirmed in a model of in vivo drug administration in mice, suggesting a potential clinical relevance. CONCLUSIONS. These findings demonstrate that immunosuppressive agents differently modulate the CKR switch associated with maturing DC; in particular, RAPA selectively up-regulates CCR7 and enhances the migration of differentiated DC to regional LN. This study contributes to a better understanding of the role of immunosuppressive therapy on DC migration, a potentially relevant check point of immunosuppressive treatment.

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