Background : The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia. Design and Methods : Leukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels. Results : We demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4+CD25+ Foxp3+ T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan. Purified CD4+CD25+ T cells obtained from co-culture with indoleamine 2,3-dioxygenase-positive leukemic dendritic cells act as regulatory T cells as they inhibit naive T-cell proliferation and impair the complete maturation of normal dendritic cells. Importantly, leukemic dendritic cell-induced regulatory T cells are capable of in vitro suppression of a leukemia-specific T cell-mediated immune response, directed against the leukemia-associated antigen, Wilms’ tumor protein. Conclusions : These data identify indoleamine 2,3-dioxygenase-mediated catabolism as a tolerogenic mechanism exerted by leukemic dendritic cells and have clinical implications for the use of these cells for active immunotherapy of leukemia.

Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells / Curti A; Trabanelli S; Onofri C; Aluigi M; Salvestrini V; Ocadlikova D; Evangelisti C; Rutella S; De Cristofaro R; Ottaviani E; Baccarani M; Lemoli RM.. - In: HAEMATOLOGICA. - ISSN 0390-6078. - ELETTRONICO. - 95:12(2010), pp. 2022-2030. [10.3324/haematol.2010.025924]

Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells.

CURTI, ANTONIO
;
SALVESTRINI, VALENTINA;OCADLIKOVA, DARINA;EVANGELISTI, CECILIA;BACCARANI, MICHELE;LEMOLI, ROBERTO MASSIMO
2010

Abstract

Background : The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia. Design and Methods : Leukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels. Results : We demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4+CD25+ Foxp3+ T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan. Purified CD4+CD25+ T cells obtained from co-culture with indoleamine 2,3-dioxygenase-positive leukemic dendritic cells act as regulatory T cells as they inhibit naive T-cell proliferation and impair the complete maturation of normal dendritic cells. Importantly, leukemic dendritic cell-induced regulatory T cells are capable of in vitro suppression of a leukemia-specific T cell-mediated immune response, directed against the leukemia-associated antigen, Wilms’ tumor protein. Conclusions : These data identify indoleamine 2,3-dioxygenase-mediated catabolism as a tolerogenic mechanism exerted by leukemic dendritic cells and have clinical implications for the use of these cells for active immunotherapy of leukemia.
2010
Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells / Curti A; Trabanelli S; Onofri C; Aluigi M; Salvestrini V; Ocadlikova D; Evangelisti C; Rutella S; De Cristofaro R; Ottaviani E; Baccarani M; Lemoli RM.. - In: HAEMATOLOGICA. - ISSN 0390-6078. - ELETTRONICO. - 95:12(2010), pp. 2022-2030. [10.3324/haematol.2010.025924]
Curti A; Trabanelli S; Onofri C; Aluigi M; Salvestrini V; Ocadlikova D; Evangelisti C; Rutella S; De Cristofaro R; Ottaviani E; Baccarani M; Lemoli RM.
File in questo prodotto:
File Dimensione Formato  
Indoleamine 2,3-Dioxygenase-Expressing Leukemic Dendritic Cells.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Altra tipologia di licenza compatibile con Open Access
Dimensione 1.06 MB
Formato Adobe PDF
1.06 MB Adobe PDF Visualizza/Apri
025924.Curti_suppl.pdf

accesso aperto

Descrizione: Data Supplement
Tipo: Versione (PDF) editoriale
Licenza: Licenza per accesso libero gratuito
Dimensione 104.98 kB
Formato Adobe PDF
104.98 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/100084
Citazioni
  • ???jsp.display-item.citation.pmc??? 36
  • Scopus 77
  • ???jsp.display-item.citation.isi??? 72
social impact