ABSTRACT
Background: Belatacept is a second generation CTLA4Ig fusion protein approved for immunosuppression in renal transplant recipients. It was intentionally designed to interrupt costimulation via CD28 by binding to its ligands B7.1 and B7.2. Experimental evidence suggests a potential additional mechanism for CTLA4Ig compounds through binding to B7 molecules expressed on antigen presenting cells (APCs) and upregulation of indoleamine 2,3-dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that downregulates T cell immunity. So far it remains unknown whether belatacept upregulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi-center, investigator-initiated substudy of the phase II trial of belatacept in liver transplantation (IM103-045).
Methods: Tryptophan and kynurenine serum levels were measured during the first six weeks post-transplant in liver transplant patients randomized to receive either belatacept or tacrolimus-based immunosuppression.
Results: 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.
Conclusion: These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus-treated patients. This article is protected by copyright. All rights reserved.
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