title: Janus kinase inhibition for immunosuppression in solid organ transplantation: Is there a role in complex immunologic challenges?
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 γcis 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.
authors.affiliation: Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: cam158@pitt.edu.
authors.forename: Cody A
authors.initials: CA
authors.lastname: Moore
authors.affiliation: Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Carlo J
authors.initials: CJ
authors.lastname: Iasella
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States; Thomas E. Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Lakkis
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Randall B
authors.initials: RB
authors.lastname: Smith
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.affiliation: Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States; Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Ensor
mesh_terms: D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism; D053616:Janus Kinase 3 / Q000276:immunology / Q000378:metabolism*; D016030:Kidney Transplantation; D058990:Molecular Targeted Therapy; D008991:Monitoring, Physiologic; D010880:Piperidines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D015398:Signal Transduction / Q000276:immunology
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3
keywords: JAK; Janus kinase; Tofacitinib; Transplantation