No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients

S. Bigenzahn, B. Juergens, B. Mahr, J. Pratschke, A. Koenigsrainer, T. Becker, D. Fuchs, Gerald Brandacher, A. Kainz, F. Muehlbacher, T. Wekerle

Research output: Contribution to journalArticle

Abstract

Belatacept is a second-generation cytotoxic T lymphocyte antigen (CTLA)-4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co-stimulation via CD28 by binding to its ligands B7·1 and B7·2. Experimental evidence suggests a potential additional mechanism for CTLA-4 Ig compounds through binding to B7 molecules expressed on antigen-presenting cells (APCs) and up-regulation of indoleamine 2,3-dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down-regulates T cell immunity. So far it remains unknown whether belatacept up-regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi-centre, investigator-initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103-045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post-transplant in liver transplant patients randomized to receive either belatacept or tacrolimus-based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus-treated patients in per-protocol and in intent-to-treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus-treated patients.

Original languageEnglish (US)
JournalClinical and Experimental Immunology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Liver
Kynurenine
Tacrolimus
Tryptophan
CTLA-4 Antigen
Therapeutics
Transplants
Immunosuppression
Immunoglobulins
Up-Regulation
B7 Antigens
Abatacept
Transplant Recipients
Antigen-Presenting Cells
Liver Transplantation
Dendritic Cells
Immunity
Down-Regulation
Research Personnel

Keywords

  • Belatacept
  • Indoleamine 2,3-dioxygenase (IDO)
  • Liver transplantation
  • Tryptophan metabolism

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients. / Bigenzahn, S.; Juergens, B.; Mahr, B.; Pratschke, J.; Koenigsrainer, A.; Becker, T.; Fuchs, D.; Brandacher, Gerald; Kainz, A.; Muehlbacher, F.; Wekerle, T.

In: Clinical and Experimental Immunology, 01.01.2018.

Research output: Contribution to journalArticle

Bigenzahn, S, Juergens, B, Mahr, B, Pratschke, J, Koenigsrainer, A, Becker, T, Fuchs, D, Brandacher, G, Kainz, A, Muehlbacher, F & Wekerle, T 2018, 'No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients', Clinical and Experimental Immunology. https://doi.org/10.1111/cei.13093
Bigenzahn, S. ; Juergens, B. ; Mahr, B. ; Pratschke, J. ; Koenigsrainer, A. ; Becker, T. ; Fuchs, D. ; Brandacher, Gerald ; Kainz, A. ; Muehlbacher, F. ; Wekerle, T. / No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients. In: Clinical and Experimental Immunology. 2018.
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abstract = "Belatacept is a second-generation cytotoxic T lymphocyte antigen (CTLA)-4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co-stimulation via CD28 by binding to its ligands B7·1 and B7·2. Experimental evidence suggests a potential additional mechanism for CTLA-4 Ig compounds through binding to B7 molecules expressed on antigen-presenting cells (APCs) and up-regulation of indoleamine 2,3-dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down-regulates T cell immunity. So far it remains unknown whether belatacept up-regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi-centre, investigator-initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103-045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post-transplant in liver transplant patients randomized to receive either belatacept or tacrolimus-based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus-treated patients in per-protocol and in intent-to-treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus-treated patients.",
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AU - Fuchs, D.

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AU - Wekerle, T.

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