Elsevier

Human Immunology

Volume 78, Issue 2, February 2017, Pages 64-71
Human Immunology

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

https://doi.org/10.1016/j.humimm.2016.12.005Get rights and content

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 chainc). 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.

Introduction

Solid organ transplantation serves as a viable treatment option for patients suffering from end-stage organ diseases. In an analysis by Rana et al. [1] of the United Network for Organ Sharing (UNOS) database encompassing all solid organ transplant recipients, transplantation demonstrated a mean 4.3 year survival advantage per patient versus those remaining on the waiting list. Since the advent of cyclosporine in 1983, the calcineurin inhibitors (CNI) have remained the cornerstone of therapy in most immunosuppression regimens post-transplantation [2]. The CNIs, cyclosporine and tacrolimus, have dramatically improved short-term outcomes, including patient and allograft survival at one year, for all allografts post-transplantation. Today, patient and allograft survival remains very high at one year post-transplantation, but long-term survival has remained largely unchanged with current immunosuppression options [3], [4]. Furthermore, five-year patient survival remains relatively low in some allografts. Specifically, adult lung transplant recipients have a median survival of 5.6 years and only 53% of patients can be expected to survive five years post-transplant [5].

Numerous adverse events, including nephrotoxicity, bone marrow suppression, post-transplant diabetes, dyslipidemia, hypertension, and neurotoxicity are associated with currently available maintenance immunosuppression agents (Table 1) [6]. One of the largest drawbacks to modern immunosuppression regimens is their propensity to cause irreversible renal dysfunction. CNIs mediate both acute and chronic renal nephrotoxicity through interrelated processes. Causes of acute CNI nephrotoxicity include isometric tubular vacuolization, thrombotic microangiopathy, and hemodynamic changes due to of decreases in vasodilators, such as nitric oxide (NO), and increases in vasoconstrictors, like endothelin, leading to vasoconstriction of the afferent arteriole [7], [8], [9], [10]. Native kidney biopsies in heart transplant recipients provided initial evidence of cyclosporine-provoked interstitial fibrosis, tubular atrophy, and focal glomerular sclerosis [11]. Additionally, close to 80% of kidney transplant recipients have chronic kidney disease (CKD) stage 1 to 2 at one-year post transplantation [12]. Furthermore, over 50% of heart and lung transplant recipients will have renal dysfunction within 5 years post-transplantation [13], [14], [15]. A study by Ojo et al. [16] revealed that chronic renal failure in nonrenal transplant recipients also increases the risk of death in nonrenal transplant recipients versus those recipients not affected by chronic renal failure [relative risk 4.55; 95% CI 4.38–4.74, p < 0.001].

With the aforementioned drawbacks and irreversible nephropathy associated with CNI-based immunosuppression, the need for alternative immunosuppressive options remains high. Janus kinase (JAK) inhibitors have previously been trialed as maintenance immunosuppression in kidney transplantation. Due to the toxicities and infectious complications elucidated from these trials, development of the Janus kinase inhibitor, tofacitinib, in transplantation has been halted [17], [18], [19]. The purpose of this review is to describe the immunologic consequences of JAK inhibition and to propose complex immunologic scenarios where JAK inhibition may be useful.

T cell formation and maturation pathways are critically important in evaluating the immunosuppressive properties of JAK inhibition. Naïve T cells are initially presented with antigen via the T-cell receptor (TCR) by antigen presenting cells (APCs) such as dendritic cells, macrophages, and B cells. After encountering foreign allograft or antigen, naïve helper T (TH) cells undergo differentiation into effector T cells depending on the presence of specific cytokines or lymphokines [20]. Cytokines secreted from lymphocytes that play an integral role in the formation of T cell lineages can be referred to as lymphokines [21]. Although T cell differentiation is a complex process that involves a multitude of factors; lymphokine profiles are highlighted as being essential. T helper 1 (TH1), T helper 2 (TH2), T helper 17 (TH17), and T regulatory (Treg) can all be selected based on the types of lymphokines and cytokines that naïve T cells encounter in the milieu [20], [22], [23], [24], [25], [26], [27], [28], [29]. However, cytokine and lymphokine receptors located on T cells are intrinsically deficient of enzymatic activity and are therefore coupled with JAKs [30]. Thus, JAKs are essential lymphokine activity and ultimately for T cell differentiation.

TH2 cell differentiation was the first to be associated with the effects of a lymphokine [20]. TH2 cells are less commonly implicated in acute cellular rejection (ACR) versus their TH1 counterpart, but are important in extracellular protection mechanisms against parasites and also in the pathogenesis of asthma. TH2 differentiation occurs when naïve T cells are stimulated by antigen in the presence of IL-4, utilizing JAK1 and JAK3 [30], [31]. These JAKs then are able to turn on STAT6 and STAT5. Activation of STAT6 is primarily responsible for TH2 differentiation [20]. Further downstream, the GATA3 transcription factor is upregulated by the presence of IL-4. Additionally, IL-25 and IL-33 have also been shown to select for TH2 cells. The resultant GATA3 protein causes heritable remodeling of the IL-4 locus and is one of the primary characteristics of a fully differentiated TH2 cell. Within the TH2 cell, other regulators such as the nuclear factor of activated T cells (NFAT), c-MAF, and AP1 are responsible for further transcription of IL-4 [20], [22].

TH1 cell differentiation also occurs after APC presentation of antigen at the TCR. However, interferon-γ (IFN-γ) and IL-12, have been predominantly shown to regulate TH1 differentiation. IFN-γ acts to upregulate STAT1 through the activation of JAK1 at the cytokine receptor. IL-12 exerts it activity through JAK2 and TYK2 [20], [30]. Downstream, STAT1 induces T-bet, the Th1 transcription factor that remodels the IFN-γ locus. Activation of the IFN-γ locus also results in transcription and upregulation of IL-12 and IL-18 receptors on the surface of the TH1 cell. Thus, fully differentiated TH1 cells have numerous pathways to upregulate IFN-γ production that include the IL-12 and IL-18 receptors [20], [22].

Treg cells constitute approximately 5–10% of the peripheral CD4+ T cell population within an individual [29]. Treg cells maintain peripheral self-tolerance and have been shown to prevent autoimmune diseases or autoimmunity [26], [29]. IL-2 exerts its effect by acting at that IL-2 receptor that is associated with JAK1 and JAK3. These JAKs activate STAT5, STAT1, and STAT3 [30], [31]. TH17 cells are defined based on the production of the pro-inflammatory cytokine IL-17 [23]. Evidence suggests that inhibition of IL-17 may lead to improvement in certain autoimmune diseases such as psoriasis, rheumatoid arthritis (RA), and ankylosing spondylitis [26]. There have been various cytokines and lymphokines implicated in the differentiation of TH17 cells [23]. Of these, IL-21 acts at IL-21 receptor that is associated with JAK1 and JAK3. Additionally, IL-23 has been shown to activate TYK2 [30], [31]. The cytokine IL-17 that is produced by TH17 cells has been shown to exert its action via a pathway independent from JAK-STAT. However, IL-17 is not the only cytokine that is produced by TH17 cells. These cells are also capable of producing other cytokines such as IL-22 and IL-26 [23], [24], [25], [26]. A summary of the T cell subsets and their functions can be found in Table 2 [20], [22], [23], [24], [25], [26], [27], [28], [29].

Lymphokines and cytokines are a large family of secreted molecules that regulate numerous functions such as homeostasis, body growth, lactation, and cellular proliferation, differentiation, and survival [30], [31], [32]. Specifically, type I cytokines all have a similar structure in that they each contain four α-helical bundles. Type I cytokines include mostly interleukins, but also include some growth and hematopoietic factors. Within the type I cytokines classification, there are a family of cytokines that exert their action only on a receptor subunit referred to as the common cytokine receptor γ-chain (γc). γc is also referred to as IL-2Rγ and CD132 [30], [31], [32], [33]. The cytokines and lymphokines which signal through γc are IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These cytokines act on different IL receptors, however they all require γc for subsequent phosphorylation and activity. For instance, the IL-2 receptor is made up of three subunit chains (γc, IL-2Rα, and IL-2Rβ). If one of these subunits is not present in the receptor, IL-2 binds or signals less effectively [30], [31], [32], [34].

Evidence to support γc involvement in immune regulation comes from patients affected with X-linked severe combined immunodeficiency (XSCID) [30], [35]. XSCID is caused by a mutation in the IL2R gene which codes for γc and manifests as complete loss of T and natural killer (NK) cells. This mutation results in a loss of function of the IL-2 receptor [36]. As stated previously, IL-2 plays an integral role in T cell growth and homeostasis, but it also stimulates the cytolytic activity of NK cells and promotes immunoglobulin production by B cells [34]. XSCID is rapidly fatal unless the patient receives a hematopoietic cell transplant. Interestingly, loss of production of IL-2 in mice and humans does not produce the same severe consequences. This finding is what led to the discovery that γc is shared between multiple cytokine receptors [30], [35], [36], [37].

The cytokines that signal through the γ chainc are highly involved in immune processes as illustrated in Table 3 [30], [38], [39]. These cytokines have the capacity to regulate immunologic functions such as immunoglobulin class switching, T cell expansion, and B cell maturation thus making γc an appealing target for immunosuppression [30], [38], [39], [40], [41], [31]. However, as the deleterious effects of XSCID demonstrate, the level of inhibition of γc and therapeutic effect is a delicate balance.

As mentioned previously, JAKs are a small family of protein kinase enzymes that associate with cytokine receptors. After a cytokine binds to its respective receptor, the JAK molecules exert their action by auto and trans-phosphorylating the cytokine receptor. This phosphorylation creates a docking site for cellular substrates important in signaling and transcriptional regulation. One type of molecule that is able to dock to the cytokine receptor after phosphorylation is known as the signal transducer and activator of transcription (STAT) [30], [42], [43], [44].

The phosphorylation by JAKs is necessary because the cytokine receptors lack enzymatic activity [30]. The four molecules within the JAK family are JAK1, JAK2, JAK3, and TYK2. JAK1 is activated by type I interferon (IFN), all γc chain cytokines, βc cytokines, and gp130 cytokines. Furthermore, defects in JAK1 lead to XSCID and impaired bacterial and viral defenses due to impaired immune responses. JAK2 is primarily activated by erythropoietin (EPO), growth hormone (GH), IFN-γ, and IL-12. Logically, inhibitions and defects in JAK2 may lead to defective erythropoiesis. TYK2 is activated by numerous cytokines and defects and inhibition lead to increased host viral susceptibility, reduced IL-12 response, and resistance to arthritis induction. The last molecule in the family is JAK3, which is selective only for γc chain cytokines and defects also lead to XSCID. Due to its selectivity for a specific cytokine subunit, JAK3 is considered a highly appealing therapeutic target [42].

JAK3 is also desirable because its expression is unique to cells in the hematopoietic lineage and its inhibition is specific for TH and B cell responses. Thus, inhibition of JAK3 would be expected to have high specificity and a low amount of cross reactivity to other non-target cells. This would be a significant difference compared to currently available immunosuppression. This selectivity would potentially improve side effect profile of immunosuppression regimens since CNIs, steroids, and cell cycle inhibitors all act on ubiquitous targets [30], [42]. A problem with this immunosuppression strategy is that it has been highly difficult to develop a specific inhibitor of JAK3. There is a high degree of homology in the kinase domains between JAK family members and also other tyrosine kinase families. The consequences for inhibiting unintended JAK targets greatly hinder the therapeutic application of such a drug. For instance, if JAK2 is inhibited, a patient may experience profound anemia, thrombocytopenia, and leukopenia. Likewise, inhibiting JAK1 may result in an increased incidence of viral and bacterial infections [42].

An antagonist of JAK3 would be expected to have profound impact on aforementioned T cell subsets. The inhibition of IL-7 would provoke diminished proliferation of both naïve and memory T cells [31]. Meaning, there would be fewer naïve T cells available for activation. In combination, IL-21 and IL-15 promote survival of CD8 + T cells. It could also be postulated that through the inhibition of IL-4, there would be fewer naïve T cells that would transition into TH2. This shift away from TH2 would likely play little role in ACR, but it could impair extracellular protection mechanisms [20], [31]. IL-2 is one of the primary cytokine products produced by TH1 cells. Preventing IL-2’s action at the cytokine receptor would inhibit further T cell expansion and prevent ACR from occurring. Furthermore, there is some concern for the loss of self-tolerance and Treg function due to JAK3 and IL-2 inhibition [42], [43]. However, the issue of self-tolerance has not appeared for a currently marketed JAK inhibitor called tofacitinib [17], [18], [19], [43].

Section snippets

Marketed JAK inhibitors

Presently, there are two JAK inhibitors on the U.S. market that have FDA-approved indications and numerous other investigational agents in clinical trials. Tofacitinib citrate (XELJANZ®) is the salt form of tofacitinib, a relatively non-selective JAK inhibitor approved for the treatment of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate [45]. Ruxolitinib phosphate (Jakafi®) selectively inhibits JAK1 and JAK2 and

Clinical effectiveness of tofacitinib

Tofacitinib’s effectiveness as mono- or combo-therapy, with methotrexate, or in combination with other nonbiologic disease-modifying antirheumatic drugs (DMARDS) is well-documented in patients with active rheumatoid arthritis (RA) [58], [59], [60], [61], [62]. Apart from its success as a DMARD, tofacitinib has also been trialed as a part of a CNI-free maintenance immunosuppression regimen after kidney transplantation. In a phase 2A, multicenter, randomized, open-label study conducted by Busque

Potential roles given infection outcomes

We believe that tofacitinib may still provide value in the augmentation of immunosuppression regimens for various solid organ transplant recipients. Furthermore, we propose that tofacitinib may play a niche role in patients that have refractory rejection secondary to a memory T cell phenotype. Alemtuzumab, an anti-CD52 monoclonal antibody, is a powerful induction immunosuppression agent that is used to prevent ACR and reduce immunosuppression burden after transplantation [63]. CD52 + cells

Conflicts of interest

The authors have no potential or theoretical conflicts of interest.

Acknowledgment

We are grateful to Dr. Lorin Grieve at the University of Pittsburgh School of Pharmacy for his creative work on Fig. 1.

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