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in Graft-versus- Andrea S. Henden and Geoffrey R. Hill J Immunol 2015; 194:4604-4612; ; This information is current as doi: 10.4049/jimmunol.1500117 of September 25, 2021. http://www.jimmunol.org/content/194/10/4604 Downloaded from References This article cites 134 articles, 49 of which you can access for free at: http://www.jimmunol.org/content/194/10/4604.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Cytokines in Graft-versus-Host Disease Andrea S. Henden and Geoffrey R. Hill Graft-versus-host disease (GVHD) is a complication of mechanisms. An example of this is depletion of trans- allogeneic bone marrow transplantation whereby trans- plants: a reduction in GVHD is offset by attendant increases in planted naive and marrow-derived T cells damage recip- the rates of relapse of primary malignancy (2, 3), in addition to ient tissue through similar mechanisms to those that allow more delayed immune reconstitution with increased morbidity destruction of malignant cells, the therapeutic intent of and mortality due to opportunistic . An alternate focus bone marrow transplantation. The manifestations and has been to examine the influences on emerging innate and severity of GVHD are highly variable and are influenced adaptive immune responses in an attempt to preserve beneficial by the proportions of naive cells maturing along regula- GVL effects while eliminating the harmful “off-target” GVHD effects. In this setting, understanding the orchestration

tory T cell, Th1, Th2, or Th17 phenotypes. This matu- Downloaded from ration is largely influenced by local cytokines, which, in of the maturing within allogeneic transplan- turn, activate transcription factors and drive development tation offers the opportunity to improve outcomes of this treatment through identification of rapidly translatable clinical toward a dominant phenotype. In addition, proinflamma- therapeutic targets. Our understanding of events within the al- tory cytokines exert direct effects on GVHD target tissues. logeneic transplantation landscape also informs our under- Our knowledge of the role that cytokines play in orches- standing of emerging innate and adaptive immune responses in trating GVHD is expanding rapidly and parallels other scenarios other than BMT. http://www.jimmunol.org/ infective and inflammatory conditions in which a predom- inant T cell signature is causative of . Because Cytokines and acute GVHD a broad spectrum of cytokine is now routinely The initiation of GVHD is necessarily influenced by the cy- used in clinical practice, they are increasingly relevant to tokine milieu in which it arises, and three distinct phases have transplant . The Journal of Immunology, 2015, been described (4, 5). The initial phase is triggered by tissue 194: 4604–4612. damage and associated loss of mucosal barrier function, pri- marily in the gastrointestinal (GI) tract, which is caused by the

conditioning regimens needed to bring malignant disease to by guest on September 25, 2021 raft-versus-host disease (GVHD) is a phenomenon a minimal residual level suitable for subsequent immune control almost unique to allogeneic bone marrow trans- and to ablate existing immune function, allowing engraftment of G plantation (BMT) whereby are intro- the naive donor inoculum. Myeloablative stem cell transplan- duced and permitted to engraft and proliferate within an tation typically uses total body irradiation or busulphan-based immunocompromised host. In this setting, naive (i.e., those that to achieve these dual aims; however, they also have not previously encountered Ag) donor T cells are able to result in damage to the GI tract mucosa and other cells con- recognize host or recipient Ags as foreign, an effect that constitutes tributing to the “cytokine storm,” which is characterized by the the therapeutic intent of BMT, allowing destruction of leukemic release of proinflammatory cytokines: classically TNF, IL-1, and or other malignant cells through activation of pathways of the IL-6 (4, 6). Although less well defined, there is an appreciation adaptive immune response. This beneficial effect is termed “graft- that a similar process occurs with reduced intensity–condition- versus-leukemia” (GVL). The relative contributions of memory ing transplantation, although the dominant cytokines and T cells to GVHD and GVL were discussed elsewhere (1). temporal relationships may differ (7). However, the effect is not specific to malignant cells, and si- In addition to chemotherapy and radiation-induced tissue multaneous damage and destruction of healthy cells and tissues damage and inflammation, recognition of pathogen-associated via the same or similar mechanisms give rise to GVHD. The molecular patterns, such as LPS, and danger-associated mo- morbidity and mortality of GVHD limit the clinical scenarios in lecular patterns arising from GI microbiota have significant which allogeneic hematopoietic stem cell transplantation may bearing on GVHD pathophysiology. The inflammatory sig- otherwise offer therapeutic benefit. Therefore, much research has nals generated in the emerging adaptive immune response are focused on the separation of GVL and GVHD, although success added to by recognition of molecular motifs from both has been limited because of the use of the same immune effector pathogenic and commensal organisms and subsequent acti-

Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Abbreviations used in this article: aGVHD, acute GVHD; BMT, bone marrow trans- Brisbane 4006, Queensland, Australia; and The Royal Brisbane and Women’s , plantation; cGVHD, chronic GVHD; GI, gastrointestinal; GVHD, graft-versus-host Brisbane 4029, Queensland, Australia disease; GVL, graft-versus-leukemia; TFH, T follicular helper; Treg, . Received for publication January 20, 2015. Accepted for publication March 19, 2015. Copyright 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 Address correspondence and reprint requests to Prof. Geoffrey R. Hill, QIMR Berghofer Medical Research Institute, 300 Herston , Herston, Brisbane 4006, QLD, Australia. E-mail address: [email protected]

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500117 The Journal of Immunology 4605 vation of innate lymphoid pathways. The diversity of the and . This tissue damage is mediated by more than one resident organisms can be affected by conditioning-associated immunological mechanism. First, cognate T cell–MHC inflammation and by GVHD itself; conversely, the microbiota interactions are required for effector, usually CD8, T cells that present can influence the severity of GVHD (8). The quan- are able to evoke cytolytic machinery, including perforins and titative and qualitative contributions of this microbiota-driven granzymes that induce target cell via apoptosis (5, 6, inflammatory signal are influenced by the variety and path- 28). Interestingly, granzyme B–deficient donor T cells me- ogenicity of organisms present, and has been demonstrated to diate less severe GVHD but may still generate GVL (29), via affect the severity of GVHD (8–10). A reduction in the reduced activation-induced death of CD8 T cells (30). In bacterial burden by use of antimicrobial decontamination in a complementary pathway in which cognate T cell–MHC the posttransplant period also can reduce GVHD severity interactions are not required, myeloid cells, in addition to (10). Although our mechanistic understanding of this effect is lymphoid cells, are primed during aGVHD to release cyto- not complete, it is apparent that GVHD mediates a loss of pathic quantities of inflammatory cytokines (e.g., TNF, IL-6) Paneth cell–derived antimicrobial peptides that play an im- that directly invoke apoptosis (31). Importantly, TNF is also portant role in shaping the diversity of microbiota (11), in involved in GVL effects, and inhibition can compromise addition to the use of pharmaceutical antimicrobials (9). antitumor (32). Damage to the primary target Understanding these mechanisms may offer manipulable organs of GVHD is driven by chemokine expression that targets to alter this primary, inflammation-mediated, initia- results in tissue homing of populations. LPAM-1 tion phase of GVHD. (a4b7 ) and L-selectin (CD62L) are associated with Downloaded from Recognition of the range of triggers to the cytokine storm homing to GI and GALTs and cutaneous lymphoid Ag to complements our knowledge of subsequent T cell and APC skin (33) and are necessary for induction of GVHD tissue interactions that define the second phase of acute GVHD damage at these sites (34). Cytokines, including IFN-g, are (aGVHD) pathophysiology and during which cytokines play known to induce upregulation of chemokines and recep- a key role in driving naive T cell differentiation and expansion tors (35), and these mechanisms were shown to be important toward one maturation program or another. Type 1 or Tc1/ in determining the severity of GVHD within an inflam- http://www.jimmunol.org/ Th1 maturation is recognized as the dominant pattern in matory environment (36–38). The expression of mole- aGVHD (12, 13), and is linked to severe GI tract pathology cules associated with lymphocyte exhaustion (e.g., PD1) and (14). Indeed, in animal models of aGVHD, Th2 and regu- their ligands (e.g., PD-L1) on nonlymphoid tissue also was latory T cells (Tregs) are rare (15). T cells expressing IL-17 are shown to be cytokine (IFN) dependent and contribute to the also rare, although this may reflect the plasticity of this lineage constraint of lymphocyte-mediated tissue damage late in (16). Increased quantities of Th1-associated cytokines, TNF the aGVHD setting (39, 40). Therefore, the inflamma- and IFN-g, in aGVHD are associated with earlier onset and tory cytokines present in this setting participate in positive-

more severe disease in preclinical models and clinical BMT (4, and negative-feedback loops in both lymphocyte and non- by guest on September 25, 2021 14, 17–19). Although the dominance of Th1 subsets is well lymphocyte populations. established, Th2 and Th17 subsets are also involved in pa- thology, and the balance between subsets determines aGVHD Cytokines and cGVHD severity (20), in addition to organ specificity (15, 20), and the cGVHD represents a distinct pathophysiological entity from pathogenic or protective effects of any subset cannot be aGVHD that traditionally is separated by time of onset; how- viewed in isolation. Implicit in the known reciprocal regula- ever, it is now recognized by its distinct end-organ pathology. tion of T cell differentiation by these cytokines is the concept Although the cardinal feature of aGVHD is apoptosis, fibrosis that inhibition of any one lineage may provoke unwanted and is the predominant mechanism of tissue damage in cGVHD. exaggerated differentiation down alternative differentiation Additionally, primary target organs also differ, with and pathways. skin being the primary target organs in cGVHD, manifesting Th2 differentiation is often seen as opposing Th1 differ- as obliterans and (41, 42). Sicca entiation; however, this subset is also recognized to cause symptoms secondary to salivary and lacrimal gland destruc- aGVHD but with predominant pathology in pulmonary, tion and oral lichenoid GVHD are also prominent. Despite hepatic, and cutaneous tissues (21), in contrast to the strong these disparate pathophysiological manifestations, clear roles GI association with Th1. Cutaneous pathology also may be for cytokine control of this phase of disease also were dem- generated by Th17 cells; although they are more commonly onstrated, unaccompanied by large-scale conditioning-related associated with chronic GVHD (cGVHD), they also have tissue damage and the “cytokine storm” that initiates aGVHD. been associated with acute pathology (22–24). Th17 differ- IL-17 and subsequent T cell differentiation along the Th17 entiation is initiated by IL-6 (25), and RORgt is the defining pathway are becoming more strongly associated with cGVHD. transcription factor (26), whereas maintenance and amplifi- Initially identified with the use of G-CSF in stem cell mo- cation relies on IL-23 and IL-21, respectively (27). The use of bilization of donors and prominent Th17 differentiation (43), RORC-deficient donor T cells results in attenuated aGVHD IL-17 was shown more recently to result in CSF1-dependent severity and lethality (26). Further studies are needed to better accumulation in skin and lung, which drives tis- define the role of this subset in late aGVHD versus early sue fibrosis (44). We demonstrated recently that, consistent cGVHD, as well as the relative contribution of IL-17 from with this, systemic IL-17 levels increase late after clinical CD4 and CD8 T cells to end-organ pathology. BMT, at a time when cGVHD develops (45). It is also clear The third and final effector phase of aGVHD is charac- that T follicular helper (TFH) cells and IL-21 play important terized by target tissue damage, with the hallmark histological roles in the development of cGVHD via the stimulation of finding being apoptosis, most commonly in the GI tract, liver, germinal center B cells and alloantibody generation (46). 4606 BRIEF REVIEWS: CYTOKINES IN GVHD

This is particularly relevant to bronchiolitis obliterans, be- on nonhematopoietic tissues. Donor lymphocyte IFN-g cause preliminary evidence suggests that Th17 differentia- signaling enhanced GVHD via the promotion of Th1 dif- tion and CSF1 dysregulation are also involved in this ferentiation, and it also is directly cytotoxic to gut mucosa aberrant immunological pathway (44). Thus, inhibition of (18). Tissue-specific effects are also seen in pulmonary pa- Th17 differentiation and CSF1 appear highly relevant to renchyma in which a protective role for IFN-g was dem- the prevention and treatment of cGVHD. Inhibition of ter- onstrated and these effects have also been described by minal cytokines involved in fibrosis, such as TGF-b and other groups (15). IFN-g provides evidence for a paradigm IL-13, represent additional targets; however, TGF-b inhi- where cytokines may exert effects in nonhematopoietic tissue, bition is problematic given its important role in Treg ho- in addition to specific effects on lymphocytes and other he- meostasis (47). matopoietic cells. Evidence of similar patterns for other cy- tokines is continually being defined and allows selection of Cytokines and T cell–differentiation programs appropriate targets for inhibition in the . With regard to other Th1-associated cytokines, a similarly The ability of cytokines to drive cellular differentiation is complex effect is seen for IL-2, both mechanistically and in recognized in situations other than GVHD, with the accep- therapeutic outcomes (51). Initially used at a high dose in an tance that derivation of phenotypically distinct erythroid, attempt to augment proliferation of lymphocytes as “immu- myeloid, and lymphoid populations from a common long- term hematopoietic stem cell is dependent upon binding of notherapy” for solid malignancies (52, 53), it was subse- cytokines to their cognate receptors (48, 49). Similarly, the quently found, paradoxically, to have a critical role in sup- Downloaded from maturation of the naive T cell population in the context of porting Treg populations and in controlling GVHD (51, BMT and GVHD is also driven by cytokines and subsequent 54). The promotion of regulatory pathways in GVHD was transcriptional pathways elicited thereafter (50). A summary demonstrated in small numbers of patients when used in of these effects is shown in Fig. 1 and outlined further below. a “low dose” (55). These apparently dose-dependent effects g are likely explained by competition for consumption of this Cytokines and Th1 differentiation. IFN- , IL-2, and TNF are http://www.jimmunol.org/ the key cytokines generated during Th1 differentiation (14), cytokine by maturing Treg and T effector cell populations and phenotypic differentiation is initiated by IL-12 and (56); in the clinical transplantation scenario, they are further controlled by the transcription factor T-bet (25, 48). IFN-g complicated by the use of inhibitors, which also in this setting participates in positive feedback to reinforce Th1 target this pathway, when used as GVHD prophylaxis post- responses, in addition to exerting effects on nonlymphocytes, transplant. as well as on nonhematopoietic cells (18). Initial attempts Cytokines and Th2 differentiation. The presence of IL-25 and, to define the role of IFN-g in determining aGVHD severity subsequently, IL-4 supports the development of T cells of were hampered by conflicting data supporting the exacerba- the Th2 lineage that traditionally have been described as tion and amelioration of pathology; however, subsequent being involved in allergy and host defense against parasites by guest on September 25, 2021 work demonstrated this to be related to differing effects on and helminths. Th2 cells produce IL-4, IL-5, IL-10, and donor and host tissues, in addition to tissue-specific effects IL-13, with transcriptional control exerted by GATA3 (57).

FIGURE 1. Cytokine drivers in the three phases of aGVHD initiation and end-organ pathology. Initial inflammatory signals are elicited by cellular damage from chemo- and radiotherapy, in addition to those derived from following GI tract damage and loss of integrity. Cytokines act on naive T cell, ILC, and myeloid cell populations, resulting in differentiation to Th1, Th2, and Th17 cell subsets, activated ILC subsets, and activated myeloid cells. End-organ tissue damage in aGVHD is caused by apoptosis elicited by Th1/Tc1 cytokines and cytolytic machinery, including perforin and granzyme, following cognate TCR–MHC interactions. Additional inflammatory pathways that are not dependent on cognate T cell pathways, including IL-6– and TNF–mediated apoptosis, following release of these cytokines from activated and macrophage populations. End-organ damage in cGVHD classically follows aGVHD and is mediated by Th2/Th17 cells and monocyte/macrophage populations secreting TGF-b that result in tissue fibrosis. The influence of ILCs on GVHD requires further de- lineation but they may be regulatory, at least early after BMT. The Journal of Immunology 4607

In aGVHD, the Th2 program appears to mediate skin and –derived IL-10 being protective in the initiation of lung pathology (15, 18), as opposed to the strong association aGVHD (61). A role for innate lymphoid cells as cytokine- of Th1 cells with gut and liver damage. Recent work dem- responsive mediators of protection from GVHD is emerging onstrated a role for an IL-25–dependent immature non-B (72), with ILC1, ILC2, and ILC3 subtypes demonstrating non-T cell innate immune effector cell population that is re- similar transcriptional control and cytokine profiles to Th1, sponsible for propagation of Th2 responses and production Th2, and Th17 cells (73). of IL-4, IL-5, and IL-13; where lacking, this results in an Donor and host cells. The effect of a single cytokine can impaired ability to expel helminths (58–60). This cytokine be dependent upon its roles in hematopoietic and non- may be seen as having protective effects on GI tissues, an hematopoietic tissue; however, in BMT, donor or host origin of outcome that is clearly attractive in the context of aGVHD the cell transducing the signal is as an additional factor influ- pathology. encing outcomes. Type I IFN is an example of a cytokine for Other Th2 cytokines were shown to have protective roles in which signaling through recipient APCs results in less severe class GVHD, including IL-10. Despite mixed results when initially II–dependent GVHD in the colon, whereas signaling through given as to patients, its production by B lymphocytes donor APCs may amplify GVHD responses. The former is in animal models of transplantation reduces the severity of mediated through decreased donor CD4 proliferation, and the GVHD (61). These outcomes were mediated by effects on latter is mediated through more effective cross-presentation of donor T cell expansion; similarly, reductions in IL-4 and IL- alloantigens to CD8 T cells (19). IL-4 is another example. A

10 were demonstrated in patients with cGVHD (62, 63). subpopulation of recipient NKT cells secretes high levels of IL-4 Downloaded from Cytokines and Th17 differentiation. Th17 cells are a more recent and indirectly expands donor Treg populations to promote addition to the Th1/Th2 paradigm (25), and roles for IL-17– tolerance after BMT (74). In contrast, IL-4 may drive donor producing cells of both Th17 and Tc17 varieties are still being Th2 differentiation directly and enhance GVHD that likely defined in the GVHD setting and in other immune usually represents chronic disease. Appreciation of these (64). Initiation of Th17 development is triggered by IL-6 and mechanisms is important, because treatment of a recipient or TGF-b and is associated with transcriptional activation of graft can be temporally separated and offers the opportunity to http://www.jimmunol.org/ RORgt after phosphorylation of STAT3, as well as with the select desirable effects while avoiding potentially deleterious secretion of IL-17, IL-21, and IL-22. There is an increasing outcomes. appreciation for the role that Th17 cells play in determining disposition. Additional complicating factors exist when the severity of GVHD (65), with a particular role for IL-6 considering cytokine-mediated effects in immune-mediated and becoming apparent (66, 67). Recently, our group demonstrated inflammatory conditions. IL-6 is an example of a cytokine for the importance of this effect in cohorts in which IL-6 inhibition which signaling via “classical” or membrane-bound receptor– represents a potentially effective therapeutic strategy to reduce the ligand interactions produces differing pathology than does severity of aGVHD in clinical stem cell transplantation (45). IL- signaling mediated through soluble or trans receptor binding. by guest on September 25, 2021 22maybesecretedbyTh17cellsand, in this setting, it appears to These effects were described originally in mouse models of be pathogenic (68); conversely, it may be secreted by innate , in which trans signaling (by the IL-6– lymphoid cells where, in the GI tract at least, it appears to be soluble IL-6R complex) recapitulated inflammatory joint an important protective cytokine (69). IL-21 can be produced by disease in IL-6–deficient mice, whereas injection of the both Th17 and TFH cells, and it promotes aGVHD by impairing native IL-6 cytokine itself did not (75). Subsequently, IL-6 Treg homeostasis (70). Given that it also has an important role in signaling through the trans pathway has been thought to be inducing aberrant, allospecific germinal center B cell responses more inflammatory in nature than classical signaling, in part and cGVHD, inhibition of this Th17-associated cytokine rep- relating to the ability of IL-6 to signal through cells that ex- resents another attractive therapeutic target for GVHD control press the gp130 receptor complex but do not basally express after BMT. IL-6R (76). A similar paradigm was demonstrated in al- lergic : Th2 expansion appears to be driven by trans Heterogeneity of effect conferred by cellular target signaling whereby expansion of Tregs was limited by classical Increasingly, the effects mediated by a particular cytokine are IL-6 signaling, and inhibition with anti–IL-6R mAb resulted being defined as dependent on the cells in which it transduces in increased numbers of Tregs (77), and an increase in asthma a signal and may be considered to regulate effector cell pop- risk was associated with a single nucleotide polymorphism ulations, as well as to confer susceptibility or protection to other that results in an increase in soluble IL-6R and trans signaling inflammatory signals in target organs and tissues. Modes of (78). Appreciation of the mechanisms by which a cytokine can signaling also influence these responses, with a recent appreci- mediate differential effects is critical to understanding both ation for the differential pathology induced by the binding of disease pathophysiology and effective clinical translation of cytokines by membrane-bound receptors as opposed to soluble therapeutics. The availability of mAbs to cytokine receptors, receptors. such as for IL-6R, which inhibits all IL-6 signaling, Hematopoietic and nonhematopoietic cells. Cytokines may exert in addition to more specific inhibitors of signalling pathway effects on cells of hematopoietic origin, in addition to non- components, such as soluble gp130:Fc, which inhibits IL-6 hematopoietic target tissues directly. IFN-g (18) and IL-22 trans signaling only, is a clear example. (68, 69) are clear examples that were already discussed. Further examples are seen in cGVHD: IL-2, IL-10, and Translational application TGF-b may act directly on tissue fibroblasts in affected Accepted murine models of transplantation and rapid and organs to mediate pathology (71), in addition to known reproducible multiplexed techniques to measure cytokines in effects of IL-2 in supporting Treg populations (51, 55) and serum or cell culture supernatants or intracellular cytokine 4608 BRIEF REVIEWS: CYTOKINES IN GVHD production by flow cytometry have allowed identification of, tion will require validation ofobservationsmadeinanimal and will continue to define, the key cytokines in aGVHD models with clinical cohorts, because standard immune- (45, 79), as well as facilitate clinical translation of findings. suppressing agents were shown to affect cytokine levels pro- However, a number of factors must be considered when ex- duced by T cells and NK cells, and profiles vary with stem cell trapolating laboratory observations into clinical cohorts. source (80, 81). Importantly, IFN-g, TNF, and IL-1 are not Variation exists in transplantation protocols, patient pop- systemically dysregulated in clinical subjects after BMT who ulations, modes of conditioning, and posttransplant immune- receive immune suppression in the same way as seen in rodent suppression strategies. The last factor is of particular im- models (45). With this in mind, it should be noted that no portance when considering the translation of observations cytokine-inhibition strategy or cytokine administration has made in animal models to the clinical setting, where immune proved efficacious in randomized studies. In general, en- suppression with cyclosporin or , combined with couraging results seen in preclinical studies and early-phase or mycophenolate,isconsideredstandardof clinical trials have either not progressed into phase III studies, care to avoid life-threatening acute and severe GVHD. How- or effects have not been robust within this context [e.g., IL-1 ever, most animal models of transplantation rely solely on (82) and TNF inhibition (83, 84)]. Table I provides a sum- radiation-based conditioning. Therefore, effective transla- mary of cytokines and inhibitors that have been explored for

Table I. Summary of relevant cytokine-targeted therapeutic studies Downloaded from

Randomized, Double-Blind Controlled and/or Phase III Cytokine Inhibitors Phase I and/or II Clinical Trial Data Clinical Trial Data TNF-aR2 () Prophylaxis + (83) •

Treatment + (102–105) • http://www.jimmunol.org/ TNF-a binding mAb (infliximab) Prophylaxis 2 (84) • Treatment + (99, 100) 2 (101) IL-1Ra () Prophylaxis 2 (82) Treatment + (106) • IL-2Ra/anti-CD25 (/daclizumaba) Prophylaxis + (107) • Treatment + (108–110) 2 (111, 112) IL-6R (tocilizumab) Prophylaxis + (45) • by guest on September 25, 2021 Treatment + (113, 114) • Keratinocyte growth factor (palifermin) Prophylaxis 2 (115–119) 2 (120)

Cytokines IL-2 (aldesleukin) Prophylaxis + (55) • Treatment + (51) • IL-11 () Prophylaxis 2 (121) •

Cytokines with Non-GVHD Benefits IFN-a (INTRON A, Roferon-A)—promotion of GVL with concomitant promotion of GVHD Prophylaxis + (122–126) • Treatment + (127, 128) • Keratinocyte growth factor (palifermin)—for reduction of oral mucositis Prophylaxis + (116–118) + (120)

Phase I and/or II Clinical Phase III Clinical Trial Potential GVHD Therapies Data Outside GVHD Data Outside GVHD IL-17 IL-17A mAb (, , perakizumab) + Ixekizumab (129) + Secukinumab (131) IL-17RA mAb () + (130) • IL-17A/TNF (ABT122) Ongoing • IL-22 () Ongoing • IL-12p40/23 mAb () + (97, 132) • IL-23p19 (, ) + Guselkumab (133) + Tildrakizumab (134) Tildrakizumab (ongoing) IL-13 (, ) + Tralokinumab (135) + Lebrikizumab (136) Tralokinumab (ongoing) Cytokines and their antagonists are included that have been tested within a trial setting to prevent or treat GVHD or other complications of allogeneic BMT. Also included is a list of newer therapeutics with potential application to GVHD that are undergoing testing in other disease settings. +, positive data; •, lack of data in this setting; 2, negative data. The Journal of Immunology 4609 efficacy in the treatment or prevention of GVHD, in addition effective prevention and treatment for GVHD. In the future, to agents with potential efficacy in GVHD that are being cytokine therapies may become a standard component of explored in other disease settings. Importantly, most studies transplantation protocols as we have seen in other inflam- in GVHD examine the usefulness of cytokine antagonists as matory and autoimmune pathologies. an adjunct to standard modalities of immune suppression rather than their efficacy in isolation, as is usually the case in Disclosures preclinical testing. Thus, it will be important to follow some recently defined general principles, taking into consideration The authors have no financial conflicts of interest. concurrent immune suppression, when planning to translate findings from mice to patients (28). References The effect of a particular cytokine in any one individual is 1. Anderson, B. E., H. Zheng, P. A. Taylor, C. Matte-Martone, J. M. McNiff, also affected by human genetic heterogeneity, and data already D. Jain, A. J. Demetris, A. 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