CTLA-4–Ig regulates tryptophan catabolism in vivo

Grohmann, Ursula; Orabona, Ciriana; Fallarino, Francesca; Vacca, Carmine; Calcinaro, Filippo; Falorni, Alberto; Candeloro, Paola; Belladonna, Maria Laura; Bianchi, Roberta; Fioretti, Maria Cristina; Puccetti, Paolo

doi:10.1038/ni846

Cited by 1,061 publications

(940 citation statements)

References 53 publications

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“…The direct effect of abatacept binding to CD80/86 on APCs remains a topic of controversy (37,38,(48)(49)(50). While some studies have demonstrated that CTLA-4Ig induced the up-regulation of IDO in DCs, which subsequently modulated T cell activation, our data and other transcriptional data have failed to confirm this (37,38).…”

Section: Discussioncontrasting

confidence: 60%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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Section: Discussioncontrasting

confidence: 60%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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“…Whatever the mechanisms involved in the control of IFN-a by IDO, which is in turn controlled by the former, the present observations by Manlapat et al [20], combined with the previous data on the role of pDC and IFN in the balance of inflammation and tolerance [4,5,9,10,21], call attention to the importance of the IDO-dependent effects of B7 ligands, including CTLA-4-Ig [11], as therapeutic agents. At the same time, these studies further establish IDO as a truly immunoregulatory enzyme.…”

Section: Cd19 + DC Exercise Self Controlsupporting

confidence: 61%

“…Similar to TLR9 ligation, cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) engagement of B7 on pDC activates tryptophan catabolism [11]. Because IDO contributes to the peripheral generation of Treg cells [12], not only may CTLA-4 + Treg cells expand their own population through pDC, but the pDC themselves could exploit TLR-dependent and -independent mechanisms to activate IDO and exert a regulatory control over an excessively inflammatory milieu dominated by IFN production [13].…”

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confidence: 99%

On watching the watchers: IDO and type I/II IFN

Puccetti

2007

Eur J Immunol

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A series of recent studies, including an article in this issue of the European Journal of Immunology, have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), not only represents an effector mechanism of peripheral tolerance, but is also a critical participant in the promotion of an optimally protective immune response balanced between inflammation and tolerance. Although subjected to transcriptional regulation by type I/II IFN, IDO is itself required for the production of type I IFN in response to B7 signaling in CD19 + DC. Such a bidirectional feedback loop could be part of an integrated response for preventing excessive inflammation and autoimmunity.

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“…As treatment of graft recipients with the competitive inhibitor 1-MT had no effect on allograft survival, we consider that this IDO mRNA up-regulation corresponds to increased cytokine activity in syngeneic and allogeneic transplanted tissue; although IDO may or may not be functionally active, it is not effective at blocking rejection. The possibility raised by a recent report that cross-linking of CD80/CD86 by the costimulatory molecule CTLA-4 induces IDO via IFN-c upregulation [30] can be discounted as a mechanism for IDO regulation in corneal endothelium, as we have found that MCEC do not express CD80 or CD86 molecules (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 81%

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

et al. 2006

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Indoleamine 2,3-dioxygenase (IDO) suppresses T cell responses by its action in catabolising tryptophan. It is important in maintenance of immune privilege in the placenta. We investigated the activity of IDO in the cornea, following corneal transplantation and the effect of IDO over-expression in donor corneal endothelium on the survival of corneal allografts. IDO expression was analysed and functional activity was quantified in normal murine cornea and in corneas following transplantation as allografts. Low levels of IDO, at both mRNA and protein levels, was detected in the normal cornea, up-regulated by IFN-c and TNF. Expression of IDO in cornea was significantly increased following corneal transplantation. However, inhibition of IDO activity in vivo had no effect on graft survival. Following IDO cDNA transfer, murine corneal endothelial cells expressed functional IDO, which was effective at inhibiting allogeneic T cell proliferation. Over-expression of IDO in donor corneal allografts resulted in prolonged graft survival. While, on one hand, our data indicate that IDO may augment corneal immune privilege, up-regulated IDO activity following cytokine stimulation may serve to inhibit inflammatory cellular responses. While increasing IDO mRNA expression was found in allogeneic corneas at rejection, over-expression in donor cornea was found to significantly extend survival of allografts.

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CTLA-4–Ig regulates tryptophan catabolism in vivo

Cited by 1,061 publications

References 53 publications

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

On watching the watchers: IDO and type I/II IFN

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

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