Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges?

• Published in: Human immunology Vol. 78; no. 2; pp. 64 - 71
• Main Authors: Moore, Cody A, Iasella PharmD, Carlo J, Venkataramanan, Raman, Lakkis, Fadi G, Smith, Randall B, McDyer, John F, Zeevi, Adriana, Ensor, Christopher R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017
• Subjects: Allergy and Immunology; Graft Rejection - prevention & control; Humans; Immunosuppression; Interleukin Receptor Common gamma Subunit - metabolism; JAK; Janus kinase; Janus Kinase 3 - immunology; Janus Kinase 3 - metabolism; Kidney Transplantation; Molecular Targeted Therapy; Monitoring, Physiologic; Piperidines - therapeutic use; Pyrimidines - therapeutic use; Pyrroles - therapeutic use; Signal Transduction - immunology; Tofacitinib; Transplantation; Janus kinase; Transplantation; Tofacitinib; JAK
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/j.humimm.2016.12.005

Abstract Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γc ). The γc is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family. Clinical outcomes have validated tofacitinib’s pan-JAK activity in kidney transplantation after demonstrating an increased risk of infection and malignancy as compared to CNI-based regimens. After these trials, tofacitinib investigation for use in transplantation has effectively ceased. However, a post-hoc analysis has shed new light on the monitoring of tofacitinib exposure in order to predict infection and oncologic events. With new methods to monitor tofacitinib exposure, clinicians may be able to effectively reduce toxicities while providing a high level of immunosuppression. The purpose of this review to identify when, and for whom, JAK inhibitors may provide benefit in solid organ transplantation.