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

• Published in: Clinical and experimental immunology 2018-05, Vol.192 (2), p.233-241
• Main Authors: Bigenzahn, S., Juergens, B., Mahr, B., Pratschke, J., Koenigsrainer, A., Becker, T., Fuchs, D., Brandacher, G., Kainz, A., Muehlbacher, F., Wekerle, T.
• Format: Article
• Language: English
• Subjects: Antigen-presenting cells; Antigens; B7 antigen; belatacept; CD28 antigen; Cytotoxicity; Dendritic cells; Dioxygenase; Fusion protein; Immunoglobulins; Immunosuppression; indoleamine 2,3‐dioxygenase (IDO); Kidney transplantation; Liver; Liver transplantation; Liver transplants; Lymphocytes T; Original; Patients; Serum levels; Tacrolimus; Transplantation; Transplants & implants; Tryptophan; tryptophan metabolism
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13093

Summary 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. The potential impact of belatacept on indoleamine 2,3‐dioxygenase (IDO) activity was investigated in liver transplant patients treated with either belatacept or tacrolimus and was tested in vitro in human DCs. No significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio was found, 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.