Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine.

Graft-versus-host disease (GVHD) is a phenomenon almost unique to allogeneic bone marrow transplantation (BMT) whereby lymphocytes are introduced and permitted to engraft and proliferate within an immunocompromised host. In this setting, naive (i.e., those that have not previously encountered Ag) donor T cells are able to recognize host or recipient Ags as foreign, an effect that constitutes the therapeutic intent of BMT, allowing destruction of leukemic or other malignant cells through activation of pathways of the adaptive immune response. This beneficial effect is termed “graft-versus-leukemia” (GVL). The relative contributions of memory T cells to GVHD and GVL were discussed elsewhere (1). However, the effect is not specific to malignant cells, and simultaneous damage and destruction of healthy cells and tissues via the same or similar mechanisms give rise to GVHD. The morbidity and mortality of GVHD limit the clinical scenarios in which allogeneic hematopoietic stem cell transplantation may otherwise offer therapeutic benefit. Therefore, much research has focused on the separation of GVL and GVHD, although success has been limited because of the use of the same immune effector mechanisms. An example of this is T cell depletion of transplants: a reduction in GVHD is offset by attendant increases in the rates of relapse of primary malignancy (2, 3), in addition to more delayed immune reconstitution with increased morbidity and mortality due to opportunistic infection. An alternate focus has been to examine the influences on emerging innate and adaptive immune responses in an attempt to preserve beneficial GVL effects while eliminating the harmful “off-target” GVHD effects. In this setting, understanding the cytokine orchestration of the maturing immune response within allogeneic transplantation offers the opportunity to improve outcomes of this treatment through identification of rapidly translatable clinical therapeutic targets. Our understanding of events within the allogeneic transplantation landscape also informs our understanding of emerging innate and adaptive immune responses in scenarios other than BMT.

The initiation of GVHD is necessarily influenced by the cytokine milieu in which it arises, and three distinct phases have been described (4, 5). The initial phase is triggered by tissue damage and associated loss of mucosal barrier function, primarily in the gastrointestinal (GI) tract, which is caused by the conditioning regimens needed to bring malignant disease to a minimal residual level suitable for subsequent immune control and to ablate existing immune function, allowing engraftment of the naive donor inoculum. Myeloablative stem cell transplantation typically uses total body irradiation or busulphan-based chemotherapy to achieve these dual aims; however, they also result in damage to the GI tract mucosa and other cells contributing to the “cytokine storm,” which is characterized by the release of proinflammatory cytokines: classically TNF, IL-1, and IL-6 (4, 6). Although less well defined, there is an appreciation that a similar process occurs with reduced intensity–conditioning transplantation, although the dominant cytokines and temporal relationships may differ (7).

In addition to chemotherapy and radiation-induced tissue damage and inflammation, recognition of pathogen-associated molecular patterns, such as LPS, and danger-associated molecular patterns arising from GI microbiota have significant bearing on GVHD pathophysiology. The inflammatory signals generated in the emerging adaptive immune response are added to by recognition of molecular motifs from both pathogenic and commensal organisms and subsequent activation of innate lymphoid pathways. The diversity of the resident organisms can be affected by conditioning-associated inflammation and by GVHD itself; conversely, the microbiota present can influence the severity of GVHD (8). The quantitative and qualitative contributions of this microbiota-driven inflammatory signal are influenced by the variety and pathogenicity of organisms present, and has been demonstrated to affect the severity of GVHD (810). A reduction in the bacterial burden by use of antimicrobial decontamination in the posttransplant period also can reduce GVHD severity (10). Although our mechanistic understanding of this effect is not complete, it is apparent that GVHD mediates a loss of Paneth cell–derived antimicrobial peptides that play an important role in shaping the diversity of microbiota (11), in addition to the use of pharmaceutical antimicrobials (9). Understanding these mechanisms may offer manipulable targets to alter this primary, inflammation-mediated, initiation phase of GVHD.

Recognition of the range of triggers to the cytokine storm complements our knowledge of subsequent T cell and APC interactions that define the second phase of acute GVHD (aGVHD) pathophysiology and during which cytokines play a key role in driving naive T cell differentiation and expansion toward one maturation program or another. Type 1 or Tc1/Th1 maturation is recognized as the dominant pattern in aGVHD (12, 13), and is linked to severe GI tract pathology (14). Indeed, in animal models of aGVHD, Th2 and regulatory T cells (Tregs) are rare (15). T cells expressing IL-17 are also rare, although this may reflect the plasticity of this lineage (16). Increased quantities of Th1-associated cytokines, TNF and IFN-γ, in aGVHD are associated with earlier onset and more severe disease in preclinical models and clinical BMT (4, 14, 1719). Although the dominance of Th1 subsets is well established, Th2 and Th17 subsets are also involved in pathology, and the balance between subsets determines aGVHD severity (20), in addition to organ specificity (15, 20), and the pathogenic or protective effects of any subset cannot be viewed in isolation. Implicit in the known reciprocal regulation of T cell differentiation by these cytokines is the concept that inhibition of any one lineage may provoke unwanted and exaggerated differentiation down alternative differentiation pathways.

Th2 differentiation is often seen as opposing Th1 differentiation; however, this subset is also recognized to cause aGVHD but with predominant pathology in pulmonary, hepatic, and cutaneous tissues (21), in contrast to the strong GI association with Th1. Cutaneous pathology also may be generated by Th17 cells; although they are more commonly associated with chronic GVHD (cGVHD), they also have been associated with acute pathology (2224). Th17 differentiation is initiated by IL-6 (25), and RORγt is the defining transcription factor (26), whereas maintenance and amplification relies on IL-23 and IL-21, respectively (27). The use of RORC-deficient donor T cells results in attenuated aGVHD severity and lethality (26). Further studies are needed to better define the role of this subset in late aGVHD versus early cGVHD, as well as the relative contribution of IL-17 from CD4 and CD8 T cells to end-organ pathology.

The third and final effector phase of aGVHD is characterized by target tissue damage, with the hallmark histological finding being apoptosis, most commonly in the GI tract, liver, and skin. This tissue damage is mediated by more than one immunological mechanism. First, cognate T cell–MHC interactions are required for effector, usually CD8, T cells that are able to evoke cytolytic machinery, including perforins and granzymes that induce target cell death via apoptosis (5, 6, 28). Interestingly, granzyme B–deficient donor T cells mediate less severe GVHD but may still generate GVL (29), via reduced activation-induced death of CD8 T cells (30). In a complementary pathway in which cognate T cell–MHC interactions are not required, myeloid cells, in addition to lymphoid cells, are primed during aGVHD to release cytopathic quantities of inflammatory cytokines (e.g., TNF, IL-6) that directly invoke apoptosis (31). Importantly, TNF is also involved in GVL effects, and inhibition can compromise antitumor immunity (32). Damage to the primary target organs of GVHD is driven by chemokine expression that results in tissue homing of lymphocyte populations. LPAM-1 (α4β7 integrin) and L-selectin (CD62L) are associated with homing to GI and GALTs and cutaneous lymphoid Ag to skin (33) and are necessary for induction of GVHD tissue damage at these sites (34). Cytokines, including IFN-γ, are known to induce upregulation of chemokines and receptors (35), and these mechanisms were shown to be important in determining the severity of GVHD within an inflammatory environment (3638). The expression of molecules associated with lymphocyte exhaustion (e.g., PD1) and their ligands (e.g., PD-L1) on nonlymphoid tissue also was shown to be cytokine (IFN) dependent and contribute to the constraint of lymphocyte-mediated tissue damage late in the aGVHD setting (39, 40). Therefore, the inflammatory cytokines present in this setting participate in positive- and negative-feedback loops in both lymphocyte and nonlymphocyte populations.

cGVHD represents a distinct pathophysiological entity from aGVHD that traditionally is separated by time of onset; however, it is now recognized by its distinct end-organ pathology. Although the cardinal feature of aGVHD is apoptosis, fibrosis is the predominant mechanism of tissue damage in cGVHD. Additionally, primary target organs also differ, with lung and skin being the primary target organs in cGVHD, manifesting as bronchiolitis obliterans and scleroderma (41, 42). Sicca symptoms secondary to salivary and lacrimal gland destruction and oral lichenoid GVHD are also prominent. Despite these disparate pathophysiological manifestations, clear roles for cytokine control of this phase of disease also were demonstrated, unaccompanied by large-scale conditioning-related tissue damage and the “cytokine storm” that initiates aGVHD. IL-17 and subsequent T cell differentiation along the Th17 pathway are becoming more strongly associated with cGVHD. Initially identified with the use of G-CSF in stem cell mobilization of donors and prominent Th17 differentiation (43), IL-17 was shown more recently to result in CSF1-dependent macrophage accumulation in skin and lung, which drives tissue fibrosis (44). We demonstrated recently that, consistent with this, systemic IL-17 levels increase late after clinical BMT, at a time when cGVHD develops (45). It is also clear that T follicular helper (TFH) cells and IL-21 play important roles in the development of cGVHD via the stimulation of germinal center B cells and alloantibody generation (46). This is particularly relevant to bronchiolitis obliterans, because preliminary evidence suggests that Th17 differentiation and CSF1 dysregulation are also involved in this aberrant immunological pathway (44). Thus, inhibition of Th17 differentiation and CSF1 appear highly relevant to the prevention and treatment of cGVHD. Inhibition of terminal cytokines involved in fibrosis, such as TGF-β and IL-13, represent additional targets; however, TGF-β inhibition is problematic given its important role in Treg homeostasis (47).

The ability of cytokines to drive cellular differentiation is recognized in situations other than GVHD, with the acceptance that derivation of phenotypically distinct erythroid, myeloid, and lymphoid populations from a common long-term hematopoietic stem cell is dependent upon binding of cytokines to their cognate receptors (48, 49). Similarly, the maturation of the naive T cell population in the context of BMT and GVHD is also driven by cytokines and subsequent transcriptional pathways elicited thereafter (50). A summary of these effects is shown in Fig. 1 and outlined further below.

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 gut microbiota 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 monocyte and macrophage populations. End-organ damage in cGVHD classically follows aGVHD and is mediated by Th2/Th17 cells and monocyte/macrophage populations secreting TGF-β that result in tissue fibrosis. The influence of ILCs on GVHD requires further delineation but they may be regulatory, at least early after BMT.

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 gut microbiota 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 monocyte and macrophage populations. End-organ damage in cGVHD classically follows aGVHD and is mediated by Th2/Th17 cells and monocyte/macrophage populations secreting TGF-β that result in tissue fibrosis. The influence of ILCs on GVHD requires further delineation but they may be regulatory, at least early after BMT.

Close modal

Cytokines and Th1 differentiation.

IFN-γ, IL-2, and TNF are the key cytokines generated during Th1 differentiation (14), and phenotypic differentiation is initiated by IL-12 and controlled by the transcription factor T-bet (25, 48). IFN-γ in this setting participates in positive feedback to reinforce Th1 responses, in addition to exerting effects on nonlymphocytes, as well as on nonhematopoietic cells (18). Initial attempts to define the role of IFN-γ in determining aGVHD severity were hampered by conflicting data supporting the exacerbation and amelioration of pathology; however, subsequent work demonstrated this to be related to differing effects on donor and host tissues, in addition to tissue-specific effects on nonhematopoietic tissues. Donor lymphocyte IFN-γ signaling enhanced GVHD via the promotion of Th1 differentiation, and it also is directly cytotoxic to gut mucosa (18). Tissue-specific effects are also seen in pulmonary parenchyma in which a protective role for IFN-γ was demonstrated and these effects have also been described by other groups (15). IFN-γ provides evidence for a paradigm where cytokines may exert effects in nonhematopoietic tissue, in addition to specific effects on lymphocytes and other hematopoietic cells. Evidence of similar patterns for other cytokines is continually being defined and allows selection of appropriate targets for inhibition in the clinic.

With regard to other Th1-associated cytokines, a similarly complex effect is seen for IL-2, both mechanistically and in therapeutic outcomes (51). Initially used at a high dose in an attempt to augment proliferation of lymphocytes as “immunotherapy” for solid malignancies (52, 53), it was subsequently found, paradoxically, to have a critical role in supporting Treg populations and in controlling GVHD (51, 54). The promotion of regulatory pathways in GVHD was demonstrated in small numbers of patients when used in a “low dose” (55). These apparently dose-dependent effects are likely explained by competition for consumption of this cytokine by maturing Treg and T effector cell populations (56); in the clinical transplantation scenario, they are further complicated by the use of calcineurin inhibitors, which also target this pathway, when used as GVHD prophylaxis posttransplant.

Cytokines and Th2 differentiation.

The presence of IL-25 and, subsequently, IL-4 supports the development of T cells of the Th2 lineage that traditionally have been described as being involved in allergy and host defense against parasites and helminths. Th2 cells produce IL-4, IL-5, IL-10, and IL-13, with transcriptional control exerted by GATA3 (57). In aGVHD, the Th2 program appears to mediate skin and lung pathology (15, 18), as opposed to the strong association of Th1 cells with gut and liver damage. Recent work demonstrated a role for an IL-25–dependent immature non-B non-T cell innate immune effector cell population that is responsible for propagation of Th2 responses and production of IL-4, IL-5, and IL-13; where lacking, this results in an impaired ability to expel helminths (5860). This cytokine may be seen as having protective effects on GI tissues, an outcome that is clearly attractive in the context of aGVHD pathology.

Other Th2 cytokines were shown to have protective roles in GVHD, including IL-10. Despite mixed results when initially given as therapy to patients, its production by B lymphocytes in animal models of transplantation reduces the severity of GVHD (61). These outcomes were mediated by effects on donor T cell expansion; similarly, reductions in IL-4 and IL-10 were demonstrated in patients with cGVHD (62, 63).

Cytokines and Th17 differentiation.

Th17 cells are a more recent addition to the Th1/Th2 paradigm (25), and roles for IL-17–producing cells of both Th17 and Tc17 varieties are still being defined in the GVHD setting and in other immune pathologies (64). Initiation of Th17 development is triggered by IL-6 and TGF-β and is associated with transcriptional activation of RORγt after phosphorylation of STAT3, as well as with the secretion of IL-17, IL-21, and IL-22. There is an increasing appreciation for the role that Th17 cells play in determining the severity of GVHD (65), with a particular role for IL-6 becoming apparent (66, 67). Recently, our group demonstrated the importance of this effect in cohorts in which IL-6 inhibition represents a potentially effective therapeutic strategy to reduce the severity of aGVHD in clinical stem cell transplantation (45). IL-22 may be secreted by Th17 cells and, in this setting, it appears to be pathogenic (68); conversely, it may be secreted by innate lymphoid cells where, in the GI tract at least, it appears to be an important protective cytokine (69). IL-21 can be produced by both Th17 and TFH cells, and it promotes aGVHD by impairing Treg homeostasis (70). Given that it also has an important role in inducing aberrant, allospecific germinal center B cell responses and cGVHD, inhibition of this Th17-associated cytokine represents another attractive therapeutic target for GVHD control after BMT.

Increasingly, the effects mediated by a particular cytokine are being defined as dependent on the cells in which it transduces a signal and may be considered to regulate effector cell populations, as well as to confer susceptibility or protection to other inflammatory signals in target organs and tissues. Modes of signaling also influence these responses, with a recent appreciation for the differential pathology induced by the binding of cytokines by membrane-bound receptors as opposed to soluble receptors.

Hematopoietic and nonhematopoietic cells.

Cytokines may exert effects on cells of hematopoietic origin, in addition to nonhematopoietic target tissues directly. IFN-γ (18) and IL-22 (68, 69) are clear examples that were already discussed. Further examples are seen in cGVHD: IL-2, IL-10, and TGF-β may act directly on tissue fibroblasts in affected organs to mediate pathology (71), in addition to known effects of IL-2 in supporting Treg populations (51, 55) and B cell–derived IL-10 being protective in the initiation of aGVHD (61). A role for innate lymphoid cells as cytokine-responsive mediators of protection from GVHD is emerging (72), with ILC1, ILC2, and ILC3 subtypes demonstrating similar transcriptional control and cytokine profiles to Th1, Th2, and Th17 cells (73).

Donor and host cells.

The effect of a single cytokine can be dependent upon its roles in hematopoietic and nonhematopoietic tissue; however, in BMT, donor or host origin of the cell transducing the signal is as an additional factor influencing outcomes. Type I IFN is an example of a cytokine for which signaling through recipient APCs results in less severe class II–dependent GVHD in the colon, whereas signaling through donor APCs may amplify GVHD responses. The former is mediated through decreased donor CD4 proliferation, and the latter is mediated through more effective cross-presentation of alloantigens to CD8 T cells (19). IL-4 is another example. A subpopulation of recipient NKT cells secretes high levels of IL-4 and indirectly expands donor Treg populations to promote tolerance after BMT (74). In contrast, IL-4 may drive donor Th2 differentiation directly and enhance GVHD that likely usually represents chronic disease. Appreciation of these mechanisms is important, because treatment of a recipient or graft can be temporally separated and offers the opportunity to select desirable effects while avoiding potentially deleterious outcomes.

Receptor disposition.

Additional complicating factors exist when considering cytokine-mediated effects in immune-mediated and inflammatory conditions. IL-6 is an example of a cytokine for which signaling via “classical” or membrane-bound receptor–ligand interactions produces differing pathology than does signaling mediated through soluble or trans receptor binding. These effects were described originally in mouse models of rheumatoid arthritis, in which trans signaling (by the IL-6–soluble IL-6R complex) recapitulated inflammatory joint disease in IL-6–deficient mice, whereas injection of the native IL-6 cytokine itself did not (75). Subsequently, IL-6 signaling through the trans pathway has been thought to be more inflammatory in nature than classical signaling, in part relating to the ability of IL-6 to signal through cells that express the gp130 receptor complex but do not basally express IL-6R (76). A similar paradigm was demonstrated in allergic asthma: Th2 expansion appears to be driven by trans signaling whereby expansion of Tregs was limited by classical IL-6 signaling, and inhibition with anti–IL-6R mAb resulted in increased numbers of Tregs (77), and an increase in asthma risk was associated with a single nucleotide polymorphism that results in an increase in soluble IL-6R and trans signaling (78). Appreciation of the mechanisms by which a cytokine can mediate differential effects is critical to understanding both disease pathophysiology and effective clinical translation of therapeutics. The availability of mAbs to cytokine receptors, such as tocilizumab for IL-6R, which inhibits all IL-6 signaling, in addition to more specific inhibitors of signalling pathway components, such as soluble gp130:Fc, which inhibits IL-6 trans signaling only, is a clear example.

Accepted murine models of transplantation and rapid and reproducible multiplexed techniques to measure cytokines in serum or cell culture supernatants or intracellular cytokine production by flow cytometry have allowed identification of, and will continue to define, the key cytokines in aGVHD (45, 79), as well as facilitate clinical translation of findings. However, a number of factors must be considered when extrapolating laboratory observations into clinical cohorts. Variation exists in transplantation protocols, patient populations, modes of conditioning, and posttransplant immune-suppression strategies. The last factor is of particular importance when considering the translation of observations made in animal models to the clinical setting, where immune suppression with cyclosporin or tacrolimus, combined with methotrexate or mycophenolate, is considered standard of care to avoid life-threatening acute and severe GVHD. However, most animal models of transplantation rely solely on radiation-based conditioning. Therefore, effective translation will require validation of observations made in animal models with clinical cohorts, because standard immune-suppressing agents were shown to affect cytokine levels produced by T cells and NK cells, and profiles vary with stem cell source (80, 81). Importantly, IFN-γ, TNF, and IL-1 are not systemically dysregulated in clinical subjects after BMT who receive immune suppression in the same way as seen in rodent models (45). With this in mind, it should be noted that no cytokine-inhibition strategy or cytokine administration has proved efficacious in randomized studies. In general, encouraging results seen in preclinical studies and early-phase clinical trials have either not progressed into phase III studies, or effects have not been robust within this context [e.g., IL-1 (82) and TNF inhibition (83, 84)]. Table I provides a summary of cytokines and inhibitors that have been explored for efficacy in the treatment or prevention of GVHD, in addition to agents with potential efficacy in GVHD that are being explored in other disease settings. Importantly, most studies in GVHD examine the usefulness of cytokine antagonists as an adjunct to standard modalities of immune suppression rather than their efficacy in isolation, as is usually the case in preclinical testing. Thus, it will be important to follow some recently defined general principles, taking into consideration concurrent immune suppression, when planning to translate findings from mice to patients (28).

Table I.
Summary of relevant cytokine-targeted therapeutic studies
Cytokine InhibitorsPhase I and/or II Clinical Trial DataRandomized, Double-Blind Controlled and/or Phase III Clinical Trial Data
TNF-αR2 (etanercept)   
 Prophylaxis + (83) • 
 Treatment + (102–105) • 
TNF-α binding mAb (infliximab)   
 Prophylaxis − (84) • 
 Treatment + (99, 100) − (101) 
IL-1Ra (anakinra)   
 Prophylaxis  − (82) 
 Treatment + (106) • 
IL-2Ra/anti-CD25 (basiliximab/daclizumaba  
 Prophylaxis + (107) • 
 Treatment + (108–110) − (111, 112) 
IL-6R (tocilizumab)   
 Prophylaxis + (45) • 
 Treatment + (113, 114) • 
Keratinocyte growth factor (palifermin)   
 Prophylaxis − (115–119) − (120) 
   
Cytokines
IL-2 (aldesleukin)   
 Prophylaxis + (55) • 
 Treatment + (51) • 
IL-11 (oprelvekin)   
 Prophylaxis − (121) • 
   
Cytokines with Non-GVHD Benefits
IFN-α (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) 
   
Potential GVHD TherapiesPhase I and/or II Clinical Data Outside GVHDPhase III Clinical Trial Data Outside GVHD
IL-17   
 IL-17A mAb (secukinumab, ixekizumab, perakizumab) + Ixekizumab (129) + Secukinumab (131) 
 IL-17RA mAb (brodalumab) + (130) • 
 IL-17A/TNF (ABT122) Ongoing • 
IL-22 (fezakinumab) Ongoing • 
IL-12p40/23 mAb (ustekinumab) + (97, 132) • 
IL-23p19 (guselkumab, tildrakizumab) + Guselkumab (133)  
 + Tildrakizumab (134) Tildrakizumab (ongoing) 
IL-13 (lebrikizumab, tralokinumab) + Tralokinumab (135) + Lebrikizumab (136) 
  Tralokinumab (ongoing) 
Cytokine InhibitorsPhase I and/or II Clinical Trial DataRandomized, Double-Blind Controlled and/or Phase III Clinical Trial Data
TNF-αR2 (etanercept)   
 Prophylaxis + (83) • 
 Treatment + (102–105) • 
TNF-α binding mAb (infliximab)   
 Prophylaxis − (84) • 
 Treatment + (99, 100) − (101) 
IL-1Ra (anakinra)   
 Prophylaxis  − (82) 
 Treatment + (106) • 
IL-2Ra/anti-CD25 (basiliximab/daclizumaba  
 Prophylaxis + (107) • 
 Treatment + (108–110) − (111, 112) 
IL-6R (tocilizumab)   
 Prophylaxis + (45) • 
 Treatment + (113, 114) • 
Keratinocyte growth factor (palifermin)   
 Prophylaxis − (115–119) − (120) 
   
Cytokines
IL-2 (aldesleukin)   
 Prophylaxis + (55) • 
 Treatment + (51) • 
IL-11 (oprelvekin)   
 Prophylaxis − (121) • 
   
Cytokines with Non-GVHD Benefits
IFN-α (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) 
   
Potential GVHD TherapiesPhase I and/or II Clinical Data Outside GVHDPhase III Clinical Trial Data Outside GVHD
IL-17   
 IL-17A mAb (secukinumab, ixekizumab, perakizumab) + Ixekizumab (129) + Secukinumab (131) 
 IL-17RA mAb (brodalumab) + (130) • 
 IL-17A/TNF (ABT122) Ongoing • 
IL-22 (fezakinumab) Ongoing • 
IL-12p40/23 mAb (ustekinumab) + (97, 132) • 
IL-23p19 (guselkumab, tildrakizumab) + Guselkumab (133)  
 + Tildrakizumab (134) Tildrakizumab (ongoing) 
IL-13 (lebrikizumab, tralokinumab) + 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; −, negative data.

The effect of a particular cytokine in any one individual is also affected by human genetic heterogeneity, and data already demonstrated a clear impact of single nucleotide polymorphisms in cytokine loci on GVHD outcomes (85, 86). Despite these difficulties in directly translating laboratory observations to the clinic, cytokine therapy for GVHD remains fertile ground for new and effective therapeutics, because a number of agents that augment or antagonize cytokine pathways are already available, having been explored and validated in other autoimmune and inflammatory disease settings. Cytokine inhibition, initially with TNF and subsequently with IL-6, is considered routine care for rheumatoid arthritis patients whose disease is not controlled by more nonspecific immune suppression with corticosteroids, methotrexate, and calcineurin inhibitors (8790). Imperfect disease control, when used as monotherapy, has paved the way for the use of combination cytokine inhibition, and the rational combination of TNF and IL-17 showed efficacy in preclinical models of disease (91). Novel targets, such as IL-32, IL-34, and IL-35, are also being explored (92). The success of cytokine inhibition in rheumatoid arthritis is also paralleled in other inflammatory diseases, including psoriatic dermatitis and arthritis (93), with TNF inhibition having a demonstrated role, in addition to promising newer targets, such as IL-22 and IL-23 (94, 95). Evidence for the value of cytokine inhibition exists in diseases other than inflammatory arthropathies, with efficacy demonstrated for TNF (96), as well as IL-12/23 (97, 98), in inflammatory bowel disease. In this setting of proven efficacy for cytokine inhibition in other diseases of dysregulated immunity, further definition of the role of cytokines in the determination of GVHD severity is likely to translate rapidly into efficacious therapies for the transplant patient population.

Cytokines are a defining influence on evolving immune responses in BMT and in the generation of GVHD, the major pathology limiting the wider application of transplantation. The classical appreciation of a naive T cell being influenced by a cytokine to mature into a more differentiated phenotype is made more complex in the GVHD setting as the impact of cytokines acting in different tissue compartments (e.g., lymphoid and nonlymphoid or donor and host) and the use of classical and trans signaling pathways become better appreciated. Although these factors require further work to better define these complex interactions, they go some way in explaining the previously mixed and conflicting results associated with some cytokine therapies (99101). Appreciation of this complexity will allow for the development of more logical trials in this field, and early positive results are already being realized (45). The use of murine models of disease, in parallel with observations in clinical cohorts, will allow further refinement of our current understanding and result in more effective prevention and treatment for GVHD. In the future, cytokine therapies may become a standard component of transplantation protocols as we have seen in other inflammatory and autoimmune pathologies.

Abbreviations used in this article:

     
  • aGVHD

    acute GVHD

  •  
  • BMT

    bone marrow transplantation

  •  
  • cGVHD

    chronic GVHD

  •  
  • GI

    gastrointestinal

  •  
  • GVHD

    graft-versus-host disease

  •  
  • GVL

    graft-versus-leukemia

  •  
  • TFH

    T follicular helper

  •  
  • Treg

    regulatory T cell.

1
Anderson
B. E.
,
Zheng
H.
,
Taylor
P. A.
,
Matte-Martone
C.
,
McNiff
J. M.
,
Jain
D.
,
Demetris
A. J.
,
Panoskaltsis-Mortari
A.
,
Ager
A.
,
Blazar
B. R.
, et al
.
2008
.
Memory T cells in GVHD and GVL.
Biol. Blood Marrow Transplant.
14
(
1
,
Suppl. 1
)
19
20
.
2
Wagner
J. E.
,
Thompson
J. S.
,
Carter
S. L.
,
Kernan
N. A.
Unrelated Donor Marrow Transplantation Trial
.
2005
.
Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial.
Lancet
366
:
733
741
.
3
Horowitz
M. M.
,
Gale
R. P.
,
Sondel
P. M.
,
Goldman
J. M.
,
Kersey
J.
,
Kolb
H. J.
,
Rimm
A. A.
,
Ringdén
O.
,
Rozman
C.
,
Speck
B.
, et al
.
1990
.
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood
75
:
555
562
.
4
Hill
G. R.
,
Crawford
J. M.
,
Cooke
K. R.
,
Brinson
Y. S.
,
Pan
L.
,
Ferrara
J. L.
.
1997
.
Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines.
Blood
90
:
3204
3213
.
5
Ferrara
J. L.
,
Deeg
H. J.
.
1991
.
Graft-versus-host disease.
N. Engl. J. Med.
324
:
667
674
.
6
Hill
G. R.
2009
.
Inflammation and bone marrow transplantation.
Biol. Blood Marrow Transplant.
15
(
1
,
Suppl.
)
139
141
.
7
Mohty
M.
,
Blaise
D.
,
Faucher
C.
,
Vey
N.
,
Bouabdallah
R.
,
Stoppa
A. M.
,
Viret
F.
,
Gravis
G.
,
Olive
D.
,
Gaugler
B.
.
2005
.
Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation.
Blood
106
:
4407
4411
.
8
Jenq
R. R.
,
Ubeda
C.
,
Taur
Y.
,
Menezes
C. C.
,
Khanin
R.
,
Dudakov
J. A.
,
Liu
C.
,
West
M. L.
,
Singer
N. V.
,
Equinda
M. J.
, et al
.
2012
.
Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation.
J. Exp. Med.
209
:
903
911
.
9
Holler
E.
,
Butzhammer
P.
,
Schmid
K.
,
Hundsrucker
C.
,
Koestler
J.
,
Peter
K.
,
Zhu
W.
,
Sporrer
D.
,
Hehlgans
T.
,
Kreutz
M.
, et al
.
2014
.
Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease.
Biol. Blood Marrow Transplant.
20
:
640
645
.
10
Beelen
D. W.
,
Elmaagacli
A.
,
Müller
K. D.
,
Hirche
H.
,
Schaefer
U. W.
.
1999
.
Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial.
Blood
93
:
3267
3275
.
11
Eriguchi
Y.
,
Takashima
S.
,
Oka
H.
,
Shimoji
S.
,
Nakamura
K.
,
Uryu
H.
,
Shimoda
S.
,
Iwasaki
H.
,
Shimono
N.
,
Ayabe
T.
, et al
.
2012
.
Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins.
Blood
120
:
223
231
.
12
Teshima
T.
,
Maeda
Y.
,
Ozaki
K.
.
2011
.
Regulatory T cells and IL-17-producing cells in graft-versus-host disease.
Immunotherapy
3
:
833
852
.
13
Pan
B.
,
Zhang
Y.
,
Sun
Y.
,
Cheng
H.
,
Wu
Y.
,
Song
G.
,
Chen
W.
,
Zeng
L.
,
Xu
K.
.
2014
.
Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice.
Cytokine
68
:
69
75
.
14
Hill
G. R.
,
Ferrara
J. L.
.
2000
.
The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.
Blood
95
:
2754
2759
.
15
Yi
T.
,
Chen
Y.
,
Wang
L.
,
Du
G.
,
Huang
D.
,
Zhao
D.
,
Johnston
H.
,
Young
J.
,
Todorov
I.
,
Umetsu
D. T.
, et al
.
2009
.
Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease.
Blood
114
:
3101
3112
.
16
Hirota
K.
,
Duarte
J. H.
,
Veldhoen
M.
,
Hornsby
E.
,
Li
Y.
,
Cua
D. J.
,
Ahlfors
H.
,
Wilhelm
C.
,
Tolaini
M.
,
Menzel
U.
, et al
.
2011
.
Fate mapping of IL-17-producing T cells in inflammatory responses.
Nat. Immunol.
12
:
255
263
.
17
Xun
C. Q.
,
Thompson
J. S.
,
Jennings
C. D.
,
Brown
S. A.
,
Widmer
M. B.
.
1994
.
Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice.
Blood
83
:
2360
2367
.
18
Burman
A. C.
,
Banovic
T.
,
Kuns
R. D.
,
Clouston
A. D.
,
Stanley
A. C.
,
Morris
E. S.
,
Rowe
V.
,
Bofinger
H.
,
Skoczylas
R.
,
Raffelt
N.
, et al
.
2007
.
IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract.
Blood
110
:
1064
1072
.
19
Robb
R. J.
,
Kreijveld
E.
,
Kuns
R. D.
,
Wilson
Y. A.
,
Olver
S. D.
,
Don
A. L.
,
Raffelt
N. C.
,
De Weerd
N. A.
,
Lineburg
K. E.
,
Varelias
A.
, et al
.
2011
.
Type I-IFNs control GVHD and GVL responses after transplantation.
Blood
118
:
3399
3409
.
20
Yi
T.
,
Zhao
D.
,
Lin
C.-L.
,
Zhang
C.
,
Chen
Y.
,
Todorov
I.
,
LeBon
T.
,
Kandeel
F.
,
Forman
S.
,
Zeng
D.
.
2008
.
Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease.
Blood
112
:
2101
2110
.
21
Nikolic
B.
,
Lee
S.
,
Bronson
R. T.
,
Grusby
M. J.
,
Sykes
M.
.
2000
.
Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets.
J. Clin. Invest.
105
:
1289
1298
.
22
Carlson
M. J.
,
West
M. L.
,
Coghill
J. M.
,
Panoskaltsis-Mortari
A.
,
Blazar
B. R.
,
Serody
J. S.
.
2009
.
In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations.
Blood
113
:
1365
1374
.
23
Varelias, A., K. H. Gartlan, E. Kreijveld, S. D. Olver, M. Lor, R. D. Kuns, K. E. Lineburg, B. E. Teal, N. C. Raffelt, M. Cheong, et al. 2015. Lung parenchyma-derived IL-6 promotes IL-17A-dependent acute lung injury after allogeneic stem cell transplantation. Blood. DOI: 10.1182/blood-2014-07-590232.
24
Kappel
L. W.
,
Goldberg
G. L.
,
King
C. G.
,
Suh
D. Y.
,
Smith
O. M.
,
Ligh
C.
,
Holland
A. M.
,
Grubin
J.
,
Mark
N. M.
,
Liu
C.
, et al
.
2009
.
IL-17 contributes to CD4-mediated graft-versus-host disease.
Blood
113
:
945
952
.
25
Steinman
L.
2007
.
A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage.
Nat. Med.
13
:
139
145
.
26
Fulton
L. M.
,
Carlson
M. J.
,
Coghill
J. M.
,
Ott
L. E.
,
West
M. L.
,
Panoskaltsis-Mortari
A.
,
Littman
D. R.
,
Blazar
B. R.
,
Serody
J. S.
.
2012
.
Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.
J. Immunol.
189
:
1765
1772
.
27
Serody
J. S.
,
Hill
G. R.
.
2012
.
The IL-17 differentiation pathway and its role in transplant outcome.
Biol. Blood Marrow Transplant.
18
(
1
,
Suppl.
)
S56
S61
.
28
Markey
K. A.
,
MacDonald
K. P.
,
Hill
G. R.
.
2014
.
The biology of graft-versus-host disease: experimental systems instructing clinical practice.
Blood
124
:
354
362
.
29
Graubert
T. A.
,
DiPersio
J. F.
,
Russell
J. H.
,
Ley
T. J.
.
1997
.
Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation.
J. Clin. Invest.
100
:
904
911
.
30
Bian
G.
,
Ding
X.
,
Leigh
N. D.
,
Tang
Y.
,
Capitano
M. L.
,
Qiu
J.
,
McCarthy
P. L.
,
Liu
H.
,
Cao
X.
.
2013
.
Granzyme B-mediated damage of CD8+ T cells impairs graft-versus-tumor effect.
J. Immunol.
190
:
1341
1350
.
31
Mantovani
A.
,
Sica
A.
,
Sozzani
S.
,
Allavena
P.
,
Vecchi
A.
,
Locati
M.
.
2004
.
The chemokine system in diverse forms of macrophage activation and polarization.
Trends Immunol.
25
:
677
686
.
32
Hill
G. R.
,
Teshima
T.
,
Gerbitz
A.
,
Pan
L.
,
Cooke
K. R.
,
Brinson
Y. S.
,
Crawford
J. M.
,
Ferrara
J. L.
.
1999
.
Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia.
J. Clin. Invest.
104
:
459
467
.
33
Sackstein
R.
2006
.
A revision of Billingham’s tenets: the central role of lymphocyte migration in acute graft-versus-host disease.
Biol. Blood Marrow Transplant.
12
(
1
,
Suppl. 1
)
2
8
.
34
Dutt
S.
,
Ermann
J.
,
Tseng
D.
,
Liu
Y. P.
,
George
T. I.
,
Fathman
C. G.
,
Strober
S.
.
2005
.
L-selectin and beta7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease.
Blood
106
:
4009
4015
.
35
He
T.
,
Tang
C.
,
Xu
S.
,
Moyana
T.
,
Xiang
J.
.
2007
.
Interferon gamma stimulates cellular maturation of dendritic cell line DC2.4 leading to induction of efficient cytotoxic T cell responses and antitumor immunity.
Cell. Mol. Immunol.
4
:
105
111
.
36
Cooke
K. R.
,
Gerbitz
A.
,
Crawford
J. M.
,
Teshima
T.
,
Hill
G. R.
,
Tesolin
A.
,
Rossignol
D. P.
,
Ferrara
J. L.
.
2001
.
LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation.
J. Clin. Invest.
107
:
1581
1589
.
37
He
W.
,
Racine
J. J.
,
Johnston
H. F.
,
Li
X.
,
Li
N.
,
Cassady
K.
,
Liu
C.
,
Deng
R.
,
Martin
P.
,
Forman
S.
,
Zeng
D.
.
2014
.
Depletion of host CCR7(+) dendritic cells prevented donor T cell tissue tropism in anti-CD3-conditioned recipients.
Biol. Blood Marrow Transplant.
20
:
920
928
.
38
Li
N.
,
Chen
Y.
,
He
W.
,
Yi
T.
,
Zhao
D.
,
Zhang
C.
,
Lin
C.-L.
,
Todorov
I.
,
Kandeel
F.
,
Forman
S.
,
Zeng
D.
.
2009
.
Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI.
Blood
113
:
953
962
.
39
Blazar
B. R.
,
Carreno
B. M.
,
Panoskaltsis-Mortari
A.
,
Carter
L.
,
Iwai
Y.
,
Yagita
H.
,
Nishimura
H.
,
Taylor
P. A.
.
2003
.
Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism.
J. Immunol.
171
:
1272
1277
.
40
Li
X.
,
Deng
R.
,
He
W.
,
Liu
C.
,
Wang
M.
,
Young
J.
,
Meng
Z.
,
Du
C.
,
Huang
W.
,
Chen
L.
, et al
.
2012
.
Loss of B7-H1 expression by recipient parenchymal cells leads to expansion of infiltrating donor CD8+ T cells and persistence of graft-versus-host disease.
J. Immunol.
188
:
724
734
.
41
Filipovich
A. H.
,
Weisdorf
D.
,
Pavletic
S.
,
Socie
G.
,
Wingard
J. R.
,
Lee
S. J.
,
Martin
P.
,
Chien
J.
,
Przepiorka
D.
,
Couriel
D.
, et al
.
2005
.
National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.
Biol. Blood Marrow Transplant.
11
:
945
956
.
42
Afessa
B.
,
Litzow
M. R.
,
Tefferi
A.
.
2001
.
Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation.
Bone Marrow Transplant.
28
:
425
434
.
43
Hill
G. R.
,
Olver
S. D.
,
Kuns
R. D.
,
Varelias
A.
,
Raffelt
N. C.
,
Don
A. L.
,
Markey
K. A.
,
Wilson
Y. A.
,
Smyth
M. J.
,
Iwakura
Y.
, et al
.
2010
.
Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma.
Blood
116
:
819
828
.
44
Alexander
K. A.
,
Flynn
R.
,
Lineburg
K. E.
,
Kuns
R. D.
,
Teal
B. E.
,
Olver
S. D.
,
Lor
M.
,
Raffelt
N. C.
,
Koyama
M.
,
Leveque
L.
, et al
.
2014
.
CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease.
J. Clin. Invest.
124
:
4266
4280
.
45
Kennedy
G. A.
,
Varelias
A.
,
Vuckovic
S.
,
Le Texier
L.
,
Gartlan
K. H.
,
Zhang
P.
,
Thomas
G.
,
Anderson
L.
,
Boyle
G.
,
Cloonan
N.
, et al
.
2014
.
Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.
Lancet Oncol.
15
:
1451
1459
.
46
Flynn
R.
,
Du
J.
,
Veenstra
R. G.
,
Reichenbach
D. K.
,
Panoskaltsis-Mortari
A.
,
Taylor
P. A.
,
Freeman
G. J.
,
Serody
J. S.
,
Murphy
W. J.
,
Munn
D. H.
, et al
.
2014
.
Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.
Blood
123
:
3988
3998
.
47
Banovic
T.
,
MacDonald
K. P.
,
Morris
E. S.
,
Rowe
V.
,
Kuns
R.
,
Don
A.
,
Kelly
J.
,
Ledbetter
S.
,
Clouston
A. D.
,
Hill
G. R.
.
2005
.
TGF-beta in allogeneic stem cell transplantation: friend or foe?
Blood
106
:
2206
2214
.
48
Lotem
J.
,
Sachs
L.
.
2002
.
Cytokine control of developmental programs in normal hematopoiesis and leukemia.
Oncogene
21
:
3284
3294
.
49
Metcalf
D.
2008
.
Hematopoietic cytokines.
Blood
111
:
485
491
.
50
Weaver
C. T.
,
Hatton
R. D.
,
Mangan
P. R.
,
Harrington
L. E.
.
2007
.
IL-17 family cytokines and the expanding diversity of effector T cell lineages.
Annu. Rev. Immunol.
25
:
821
852
.
51
Koreth
J.
,
Matsuoka
K.
,
Kim
H. T.
,
McDonough
S. M.
,
Bindra
B.
,
Alyea
E. P.
 III
,
Armand
P.
,
Cutler
C.
,
Ho
V. T.
,
Treister
N. S.
, et al
.
2011
.
Interleukin-2 and regulatory T cells in graft-versus-host disease.
N. Engl. J. Med.
365
:
2055
2066
.
52
Dutcher
J.
2002
.
Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma.
Oncology (Huntington)
16
:
4
10
.
53
Murphy
W. J.
,
Ferrara
J. L. M.
,
Malek
T.
.
2012
.
A delicate balance: tweaking IL-2 immunotherapy.
Nat. Med.
18
:
208
209
.
54
Pérol
L.
,
Martin
G. H.
,
Maury
S.
,
Cohen
J. L.
,
Piaggio
E.
.
2014
.
Potential limitations of IL-2 administration for the treatment of experimental acute graft-versus-host disease.
Immunol. Lett.
162
(
2 Pt B
):
173
184
.
55
Kennedy-Nasser
A. A.
,
Ku
S.
,
Castillo-Caro
P.
,
Hazrat
Y.
,
Wu
M.-F.
,
Liu
H.
,
Melenhorst
J.
,
Barrett
A. J.
,
Ito
S.
,
Foster
A.
, et al
.
2014
.
Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity.
Clin. Cancer Res.
20
:
2215
2225
.
56
Höfer
T.
,
Krichevsky
O.
,
Altan-Bonnet
G.
.
2012
.
Competition for IL-2 between regulatory and effector T cells to chisel immune responses.
Front. Immunol.
3
:
268
.
57
Nurieva
R. I.
,
Chung
Y.
.
2010
.
Understanding the development and function of T follicular helper cells.
Cell. Mol. Immunol.
7
:
190
197
.
58
Fallon
P. G.
,
Ballantyne
S. J.
,
Mangan
N. E.
,
Barlow
J. L.
,
Dasvarma
A.
,
Hewett
D. R.
,
McIlgorm
A.
,
Jolin
H. E.
,
McKenzie
A. N.
.
2006
.
Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion.
J. Exp. Med.
203
:
1105
1116
.
59
Saenz
S. A.
,
Siracusa
M. C.
,
Perrigoue
J. G.
,
Spencer
S. P.
,
Urban
J. F.
 Jr.
,
Tocker
J. E.
,
Budelsky
A. L.
,
Kleinschek
M. A.
,
Kastelein
R. A.
,
Kambayashi
T.
, et al
.
2010
.
IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.
Nature
464
:
1362
1366
.
60
Neill
D. R.
,
Wong
S. H.
,
Bellosi
A.
,
Flynn
R. J.
,
Daly
M.
,
Langford
T. K.
,
Bucks
C.
,
Kane
C. M.
,
Fallon
P. G.
,
Pannell
R.
, et al
.
2010
.
Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.
Nature
464
:
1367
1370
.
61
Rowe
V.
,
Banovic
T.
,
MacDonald
K. P.
,
Kuns
R.
,
Don
A. L.
,
Morris
E. S.
,
Burman
A. C.
,
Bofinger
H. M.
,
Clouston
A. D.
,
Hill
G. R.
.
2006
.
Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation.
Blood
108
:
2485
2492
.
62
Tanaka
J.
,
Imamura
M.
,
Kasai
M.
,
Hashino
S.
,
Kobayashi
S.
,
Noto
S.
,
Higa
T.
,
Sakurada
K.
,
Asaka
M.
.
1996
.
Th2 cytokines (IL-4, IL-10 and IL-13) and IL-12 mRNA expression by concanavalin A-stimulated peripheral blood mononuclear cells during chronic graft-versus-host disease.
Eur. J. Haematol.
57
:
111
113
.
63
Rozmus
J.
,
Schultz
K. R.
,
Wynne
K.
,
Kariminia
A.
,
Satyanarayana
P.
,
Krailo
M.
,
Grupp
S. A.
,
Gilman
A. L.
,
Goldman
F. D.
.
2011
.
Early and late extensive chronic graft-versus-host disease in children is characterized by different Th1/Th2 cytokine profiles: findings of the Children’s Oncology Group Study ASCT0031.
Biol. Blood Marrow Transplant.
17
:
1804
1813
.
64
Gaffen
S. L.
,
Jain
R.
,
Garg
A. V.
,
Cua
D. J.
.
2014
.
The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing.
Nat. Rev. Immunol.
14
:
585
600
.
65
van der Waart
A. B.
,
van der Velden
W. J.
,
Blijlevens
N. M.
,
Dolstra
H.
.
2014
.
Targeting the IL17 pathway for the prevention of graft-versus-host disease.
Biol. Blood Marrow Transplant.
20
:
752
759
.
66
Tawara
I.
,
Koyama
M.
,
Liu
C.
,
Toubai
T.
,
Thomas
D.
,
Evers
R.
,
Chockley
P.
,
Nieves
E.
,
Sun
Y.
,
Lowler
K. P.
, et al
.
2011
.
Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation.
Clin. Cancer Res.
17
:
77
88
.
67
Chen
X.
,
Das
R.
,
Komorowski
R.
,
Beres
A.
,
Hessner
M. J.
,
Mihara
M.
,
Drobyski
W. R.
.
2009
.
Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease.
Blood
114
:
891
900
.
68
Couturier
M.
,
Lamarthée
B.
,
Arbez
J.
,
Renauld
J.-C.
,
Bossard
C.
,
Malard
F.
,
Bonnefoy
F.
,
Mohty
M.
,
Perruche
S.
,
Tiberghien
P.
, et al
.
2013
.
IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect.
Leukemia
27
:
1527
1537
.
69
Hanash
A. M.
,
Dudakov
J. A.
,
Hua
G.
,
O’Connor
M. H.
,
Young
L. F.
,
Singer
N. V.
,
West
M. L.
,
Jenq
R. R.
,
Holland
A. M.
,
Kappel
L. W.
, et al
.
2012
.
Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease.
Immunity
37
:
339
350
.
70
Bucher
C.
,
Koch
L.
,
Vogtenhuber
C.
,
Goren
E.
,
Munger
M.
,
Panoskaltsis-Mortari
A.
,
Sivakumar
P.
,
Blazar
B.R.
.
2009
.
IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation.
Blood
114
:
5375
5384
.
71
Blazar
B. R.
,
Murphy
W. J.
,
Abedi
M.
.
2012
.
Advances in graft-versus-host disease biology and therapy.
Nat. Rev. Immunol.
12
:
443
458
.
72
Munneke
J. M.
,
Björklund
A. T.
,
Mjösberg
J. M.
,
Garming-Legert
K.
,
Bernink
J. H.
,
Blom
B.
,
Huisman
C.
,
van Oers
M. H.
,
Spits
H.
,
Malmberg
K.-J.
,
Hazenberg
M. D.
.
2014
.
Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease.
Blood
124
:
812
821
.
73
Spits
H.
,
Cupedo
T.
.
2012
.
Innate lymphoid cells: emerging insights in development, lineage relationships, and function.
Annu. Rev. Immunol.
30
:
647
675
.
74
Pillai
A. B.
,
George
T. I.
,
Dutt
S.
,
Strober
S.
.
2009
.
Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease.
Blood
113
:
4458
4467
.
75
Nowell
M. A.
,
Richards
P. J.
,
Horiuchi
S.
,
Yamamoto
N.
,
Rose-John
S.
,
Topley
N.
,
Williams
A. S.
,
Jones
S. A.
.
2003
.
Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130.
J. Immunol.
171
:
3202
3209
.
76
Scheller
J.
,
Ohnesorge
N.
,
Rose-John
S.
.
2006
.
Interleukin-6 trans-signalling in chronic inflammation and cancer.
Scand. J. Immunol.
63
:
321
329
.
77
Doganci
A.
,
Eigenbrod
T.
,
Krug
N.
,
De Sanctis
G. T.
,
Hausding
M.
,
Erpenbeck
V. J.
,
Haddad
B.
,
Lehr
H. A.
,
Schmitt
E.
,
Bopp
T.
, et al
.
2005
.
The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.
J. Clin. Invest.
115
:
313
325
.
78
Revez
J. A.
,
Bain
L.
,
Chapman
B.
,
Powell
J. E.
,
Jansen
R.
,
Duffy
D. L.
,
Tung
J. Y.
AAGC Collaborators
Penninx
P. M.
,
Visscher
P. M.
,
De Geus
E. J.
, et al
.
2013
.
A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk.
Genes Immun.
14
:
441
446
.
79
DiCarlo
J.
,
Agarwal-Hashmi
R.
,
Shah
A.
,
Kim
P.
,
Craveiro
L.
,
Killen
R.
,
Rosenberg-Hasson
Y.
,
Maecker
H.
.
2014
.
Cytokine and chemokine patterns across 100 days after hematopoietic stem cell transplantation in children.
Biol. Blood Marrow Transplant.
20
:
361
369
.
80
Derniame
S.
,
Perazzo
J.
,
Lee
F.
,
Domogala
A.
,
Escobedo-Cousin
M.
,
Alnabhan
R.
,
Luevano
M.
,
Pedroza-Pacheco
I.
,
Cooper
N.
,
Madrigal
A.
,
Saudemont
A.
.
2014
.
Differential effects of mycophenolate mofetil and cyclosporine A on peripheral blood and cord blood natural killer cells activated with interleukin-2.
Cytotherapy
16
:
1409
1418
.
81
Derniame
S.
,
Lee
F.
,
Domogala
A.
,
Madrigal
A.
,
Saudemont
A.
.
2014
.
Unique effects of mycophenolate mofetil on cord blood T cells: implications for GVHD prophylaxis.
Transplantation
97
:
870
878
.
82
Antin
J. H.
,
Weisdorf
D.
,
Neuberg
D.
,
Nicklow
R.
,
Clouthier
S.
,
Lee
S. J.
,
Alyea
E.
,
McGarigle
C.
,
Blazar
B. R.
,
Sonis
S.
, et al
.
2002
.
Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation.
Blood
100
:
3479
3482
.
83
Choi
S. W.
,
Stiff
P.
,
Cooke
K.
,
Ferrara
J. L.
,
Braun
T.
,
Kitko
C.
,
Reddy
P.
,
Yanik
G.
,
Mineishi
S.
,
Paczesny
S.
, et al
.
2012
.
TNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes.
Biol. Blood Marrow Transplant.
18
:
1525
1532
.
84
Hamadani
M.
,
Hofmeister
C. C.
,
Jansak
B.
,
Phillips
G.
,
Elder
P.
,
Blum
W.
,
Penza
S.
,
Lin
T. S.
,
Klisovic
R.
,
Marcucci
G.
, et al
.
2008
.
Addition of infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation.
Biol. Blood Marrow Transplant.
14
:
783
789
.
85
Karimi
M. H.
,
Salek
S.
,
Yaghobi
R.
,
Ramzi
M.
,
Geramizadeh
B.
,
Hejr
S.
.
2014
.
Association of IL-17 gene polymorphisms and serum level with graft versus host disease after allogeneic hematopoietic stem cell transplantation.
Cytokine
69
:
120
124
.
86
Resende
R. G.
,
Correia-Silva
J. d. F.
,
Silva
T. A.
,
Salomão
U. E.
,
Marques-Silva
L.
,
Vieira
É. L. M.
,
Dutra
W. O.
,
Gomez
R. S.
.
2014
.
IL-17 genetic and immunophenotypic evaluation in chronic graft-versus-host disease.
Mediators Inflamm.
DOI:
87
Buch
M. H.
,
Emery
P.
.
2011
.
New therapies in the management of rheumatoid arthritis.
Curr. Opin. Rheumatol.
23
:
245
251
.
88
Monaco
C.
,
Nanchahal
J.
,
Taylor
P.
,
Feldmann
M.
.
2015
.
Anti-TNF therapy: past, present and future.
Int. Immunol.
27
:
55
62
.
89
Singh
J. A.
,
Beg
S.
,
Lopez-Olivo
M. A.
.
2011
.
Tocilizumab for rheumatoid arthritis: a Cochrane systematic review.
J. Rheumatol.
38
:
10
20
.
90
Gabay
C.
,
Emery
P.
,
van Vollenhoven
R.
,
Dikranian
A.
,
Alten
R.
,
Pavelka
K.
,
Klearman
M.
,
Musselman
D.
,
Agarwal
S.
,
Green
J.
,
Kavanaugh
A.
ADACTA Study Investigators
.
2013
.
Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial.
Lancet
381
:
1541
1550
.
91
Fischer
J. A.
,
Hueber
A. J.
,
Wilson
S.
,
Galm
M.
,
Baum
W.
,
Kitson
C.
,
Auer
J.
,
Lorenz
S. H.
,
Moelleken
J.
,
Bader
M.
, et al
.
2015
.
Combined inhibition of tumor necrosis factor α and interleukin-17 as a therapeutic opportunity in rheumatoid arthritis: development and characterization of a novel bispecific antibody.
Arthritis Rheumatol.
67
:
51
62
.
92
Venkatesha
S. H.
,
Dudics
S.
,
Acharya
B.
,
Moudgil
K. D.
.
2015
.
Cytokine-modulating strategies and newer cytokine targets for arthritis therapy.
Int. J. Mol. Sci.
16
:
887
906
.
93
Mandell
B. F.
,
Sobell
J. M.
.
2014
.
The role of TNF inhibitors in psoriatic disease.
Semin. Cutan. Med. Surg.
33
(
4
,
Suppl.
)
S64
S68
.
94
Mitra
A.
,
Raychaudhuri
S. K.
,
Raychaudhuri
S. P.
.
2012
.
Functional role of IL-22 in psoriatic arthritis.
Arthritis Res. Ther.
14
:
R65
.
95
Tonel
G.
,
Conrad
C.
,
Laggner
U.
,
Di Meglio
P.
,
Grys
K.
,
McClanahan
T. K.
,
Blumenschein
W. M.
,
Qin
J.-Z.
,
Xin
H.
,
Oldham
E.
, et al
.
2010
.
Cutting edge: A critical functional role for IL-23 in psoriasis.
J. Immunol.
185
:
5688
5691
.
96
Colombel
J. F.
,
Sandborn
W. J.
,
Reinisch
W.
,
Mantzaris
G. J.
,
Kornbluth
A.
,
Rachmilewitz
D.
,
Lichtiger
S.
,
D’Haens
G.
,
Diamond
R. H.
,
Broussard
D. L.
, et al
.
2010
.
Infliximab, azathioprine, or combination therapy for Crohn’s disease.
N. Engl. J. Med.
362
:
1383
1395
.
97
Burakoff
R.
,
Barish
C. F.
,
Riff
D.
,
Pruitt
R.
,
Chey
W. Y.
,
Farraye
F. A.
,
Shafran
I.
,
Katz
S.
,
Krone
C. L.
,
Vander Vliet
M.
, et al
.
2006
.
A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn’s disease.
Inflamm. Bowel Dis.
12
:
558
565
.
98
Sandborn
W. J.
,
Feagan
B. G.
,
Fedorak
R. N.
,
Scherl
E.
,
Fleisher
M. R.
,
Katz
S.
,
Johanns
J.
,
Blank
M.
,
Rutgeerts
P.
Ustekinumab Crohn’s Disease Study Group
.
2008
.
A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease.
Gastroenterology
135
:
1130
1141
.
99
Patriarca
F.
,
Sperotto
A.
,
Damiani
D.
,
Morreale
G.
,
Bonifazi
F.
,
Olivieri
A.
,
Ciceri
F.
,
Milone
G.
,
Cesaro
S.
,
Bandini
G.
, et al
.
2004
.
Infliximab treatment for steroid-refractory acute graft-versus-host disease.
Haematologica
89
:
1352
1359
.
100
Couriel
D.
,
Saliba
R.
,
Hicks
K.
,
Ippoliti
C.
,
de Lima
M.
,
Hosing
C.
,
Khouri
I.
,
Andersson
B.
,
Gajewski
J.
,
Donato
M.
, et al
.
2004
.
Tumor necrosis factor-alpha blockade for the treatment of acute GVHD.
Blood
104
:
649
654
.
101
Couriel
D. R.
,
Saliba
R.
,
de Lima
M.
,
Giralt
S.
,
Andersson
B.
,
Khouri
I.
,
Hosing
C.
,
Ippoliti
C.
,
Shpall
E. J.
,
Champlin
R.
,
Alousi
A.
.
2009
.
A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease.
Biol. Blood Marrow Transplant.
15
:
1555
1562
.
102
Levine
J. E.
,
Paczesny
S.
,
Mineishi
S.
,
Braun
T.
,
Choi
S. W.
,
Hutchinson
R. J.
,
Jones
D.
,
Khaled
Y.
,
Kitko
C. L.
,
Bickley
D.
, et al
.
2008
.
Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease.
Blood
111
:
2470
2475
.
103
Alousi
A. M.
,
Weisdorf
D. J.
,
Logan
B. R.
,
Bolaños-Meade
J.
,
Carter
S.
,
Difronzo
N.
,
Pasquini
M.
,
Goldstein
S. C.
,
Ho
V. T.
,
Hayes-Lattin
B.
, et al
.
2009
.
Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network.
Blood
114
:
511
517
.
104
Busca
A.
,
Locatelli
F.
,
Marmont
F.
,
Ceretto
C.
,
Falda
M.
.
2007
.
Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.
Am. J. Hematol.
82
:
45
52
.
105
Wolff
D.
,
Roessler
V.
,
Steiner
B.
,
Wilhelm
S.
,
Weirich
V.
,
Brenmoehl
J.
,
Leithaeuser
M.
,
Hofmeister
N.
,
Junghanss
C.
,
Casper
J.
, et al
.
2005
.
Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept.
Bone Marrow Transplant.
35
:
1003
1010
.
106
Antin
J. H.
,
Weinstein
H. J.
,
Guinan
E. C.
,
McCarthy
P.
,
Bierer
B. E.
,
Gilliland
D. G.
,
Parsons
S. K.
,
Ballen
K. K.
,
Rimm
I. J.
,
Falzarano
G.
, et al
.
1994
.
Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease.
Blood
84
:
1342
1348
.
107
Fang
J.
,
Hu
C.
,
Hong
M.
,
Wu
Q.
,
You
Y.
,
Zhong
Z.
,
Li
W.
,
Zou
P.
,
Hu
Y.
,
Xia
L.
.
2012
.
Prophylactic effects of interleukin-2 receptor antagonists against graft-versus-host disease following unrelated donor peripheral blood stem cell transplantation.
Biol. Blood Marrow Transplant.
18
:
754
762
.
108
Schmidt-Hieber
M.
,
Fietz
T.
,
Knauf
W.
,
Uharek
L.
,
Hopfenmüller
W.
,
Thiel
E.
,
Blau
I. W.
.
2005
.
Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease.
Br. J. Haematol.
130
:
568
574
.
109
Przepiorka
D.
,
Kernan
N. A.
,
Ippoliti
C.
,
Papadopoulos
E. B.
,
Giralt
S.
,
Khouri
I.
,
Lu
J. G.
,
Gajewski
J.
,
Durett
A.
,
Cleary
K.
, et al
.
2000
.
Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease.
Blood
95
:
83
89
.
110
Willenbacher
W.
,
Basara
N.
,
Blau
I. W.
,
Fauser
A. A.
,
Kiehl
M. G.
.
2001
.
Treatment of steroid refractory acute and chronic graft-versus-host disease with daclizumab.
Br. J. Haematol.
112
:
820
823
.
111
Cahn
J. Y.
,
Bordigoni
P.
,
Tiberghien
P.
,
Milpied
N.
,
Brion
A.
,
Widjenes
J.
,
Lioure
B.
,
Michel
G.
,
Burdach
S.
,
Kolb
H. J.
, et al
.
1995
.
Treatment of acute graft-versus-host disease with methylprednisolone and cyclosporine with or without an anti-interleukin-2 receptor monoclonal antibody. A multicenter phase III study.
Transplantation
60
:
939
942
.
112
Lee
S. J.
,
Zahrieh
D.
,
Agura
E.
,
MacMillan
M. L.
,
Maziarz
R. T.
,
McCarthy
P. L.
 Jr.
,
Ho
V. T.
,
Cutler
C.
,
Alyea
E. P.
,
Antin
J. H.
,
Soiffer
R. J.
.
2004
.
Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial.
Blood
104
:
1559
1564
.
113
Gergis
U.
,
Arnason
J.
,
Yantiss
R.
,
Shore
T.
,
Wissa
U.
,
Feldman
E.
,
Woodworth
T.
.
2010
.
Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease.
J. Clin. Oncol.
28
:
e602
e604
.
114
Drobyski
W. R.
,
Pasquini
M.
,
Kovatovic
K.
,
Palmer
J.
,
Douglas Rizzo
J.
,
Saad
A.
,
Saber
W.
,
Hari
P.
.
2011
.
Tocilizumab for the treatment of steroid refractory graft-versus-host disease.
Biol. Blood Marrow Transplant.
17
:
1862
1868
.
115
Blazar
B. R.
,
Weisdorf
D. J.
,
Defor
T.
,
Goldman
A.
,
Braun
T.
,
Silver
S.
,
Ferrara
J. L.
.
2006
.
Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).
Blood
108
:
3216
3222
.
116
Nasilowska-Adamska
B.
,
Rzepecki
P.
,
Manko
J.
,
Czyz
A.
,
Markiewicz
M.
,
Federowicz
I.
,
Tomaszewska
A.
,
Piatkowska-Jakubas
B.
,
Wrzesien-Kus
A.
,
Bieniaszewska
M.
, et al
.
2007
.
The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant.
Bone Marrow Transplant.
40
:
983
988
.
117
Langner
S.
,
Staber
P.
,
Schub
N.
,
Gramatzki
M.
,
Grothe
W.
,
Behre
G.
,
Rabitsch
W.
,
Urban
C.
,
Linkesch
W.
,
Neumeister
P.
.
2008
.
Palifermin reduces incidence and severity of oral mucositis in allogeneic stem-cell transplant recipients.
Bone Marrow Transplant.
42
:
275
279
.
118
Levine
J. E.
,
Blazar
B. R.
,
DeFor
T.
,
Ferrara
J. L.
,
Weisdorf
D. J.
.
2008
.
Long-term follow-up of a phase I/II randomized, placebo-controlled trial of palifermin to prevent graft-versus-host disease (GVHD) after related donor allogeneic hematopoietic cell transplantation (HCT).
Biol. Blood Marrow Transplant.
14
:
1017
1021
.
119
Nasilowska-Adamska
B.
,
Szydlo
R.
,
Rzepecki
P.
,
Czyz
A.
,
Tomaszewska
A.
,
Markiewicz
M.
,
Torosian
T.
,
Bieniaszewska
M.
,
Hellman
A.
,
Jedrzejczak
W. W.
, et al
.
2011
.
Palifermin does not influence the incidence and severity of GvHD nor long-term survival of patients with hematological diseases undergoing HSCT.
Ann. Transplant.
16
:
47
54
.
120
Jagasia
M. H.
,
Abonour
R.
,
Long
G. D.
,
Bolwell
B. J.
,
Laport
G. G.
,
Shore
T. B.
,
Durrant
S.
,
Szer
J.
,
Chen
M.-G.
,
Lizambri
R.
,
Waller
E. K.
.
2012
.
Palifermin for the reduction of acute GVHD: a randomized, double-blind, placebo-controlled trial.
Bone Marrow Transplant.
47
:
1350
1355
.
121
Antin
J. H.
,
Lee
S. J.
,
Neuberg
D.
,
Alyea
E.
,
Soiffer
R. J.
,
Sonis
S.
,
Ferrara
J. L.
.
2002
.
A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation.
Bone Marrow Transplant.
29
:
373
377
.
122
Porter
D. L.
,
Roth
M. S.
,
McGarigle
C.
,
Ferrara
J. L.
,
Antin
J. H.
.
1994
.
Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia.
N. Engl. J. Med.
330
:
100
106
.
123
Samson
D.
,
Volin
L.
,
Schanz
U.
,
Bosi
A.
,
Gahrtron
G.
.
1996
.
Feasibility and toxicity of interferon maintenance therapy after allogeneic BMT for multiple myeloma: a pilot study of the EBMT.
Bone Marrow Transplant.
17
:
759
762
.
124
Ratanatharathorn
V.
,
Uberti
J.
,
Karanes
C.
,
Lum
L. G.
,
Abella
E.
,
Dan
M. E.
,
Hussein
M.
,
Sensenbrenner
L. L.
.
1994
.
Phase I study of alpha-interferon augmentation of cyclosporine-induced graft versus host disease in recipients of autologous bone marrow transplantation.
Bone Marrow Transplant.
13
:
625
630
.
125
Streetly
M.
,
Kazmi
M.
,
Radia
D.
,
Hoyle
C.
,
Schey
S. A.
.
2004
.
Second autologous transplant with cyclosporin/interferon alpha-induced graft versus host disease for patients who have failed first-line consolidation.
Bone Marrow Transplant.
33
:
1131
1135
.
126
Kolb
H. J.
,
Mittermüller
J.
,
Clemm
C.
,
Holler
E.
,
Ledderose
G.
,
Brehm
G.
,
Heim
M.
,
Wilmanns
W.
.
1990
.
Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.
Blood
76
:
2462
2465
.
127
Lim
S. H.
,
Coleman
S.
,
Bull
A.
,
O’Callaghan
U.
,
Evely
R.
,
Booth
M.
.
1997
.
Cyclosporin A/alpha interferon-induced autologous graft-versus-host disease following peripheral blood stem cell transplant for chronic myeloid leukaemia: a clinico-pathological study.
Bone Marrow Transplant.
20
:
83
85
.
128
Klingemann
H. G.
,
Grigg
A. P.
,
Wilkie-Boyd
K.
,
Barnett
M. J.
,
Eaves
A. C.
,
Reece
D. E.
,
Shepherd
J. D.
,
Phillips
G. L.
.
1991
.
Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected].
Blood
78
:
3306
3311
.
129
Gordon
K. B.
,
Leonardi
C. L.
,
Lebwohl
M.
,
Blauvelt
A.
,
Cameron
G. S.
,
Braun
D.
,
Erickson
J.
,
Heffernan
M.
.
2014
.
A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis.
J. Am. Acad. Dermatol.
71
:
1176
1182
.
130
Papp
K.
,
Leonardi
C.
,
Menter
A.
,
Thompson
E. H. Z.
,
Milmont
C. E.
,
Kricorian
G.
,
Nirula
A.
,
Klekotka
P.
.
2014
.
Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment.
J. Am. Acad. Dermatol.
71
:
1183
1190.e3
.
131
Langley
R. G.
,
Elewski
B. E.
,
Lebwohl
M.
,
Reich
K.
,
Griffiths
C. E.
,
Papp
K.
,
Puig
L.
,
Nakagawa
H.
,
Spelman
L.
,
Sigurgeirsson
B.
, et al
.
2014
.
Secukinumab in plaque psoriasis—results of two phase 3 trials.
N. Engl. J. Med.
371
:
326
338
.
132
Krueger
G. G.
,
Langley
R. G.
,
Leonardi
C.
,
Yeilding
N.
,
Guzzo
C.
,
Wang
Y.
,
Dooley
L. T.
,
Lebwohl
M.
CNTO 1275 Psoriasis Study Group
.
2007
.
A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis.
N. Engl. J. Med.
356
:
580
592
.
133
Sofen
H.
,
Smith
S.
,
Matheson
R. T.
,
Leonardi
C. L.
,
Calderon
C.
,
Brodmerkel
C.
,
Li
K.
,
Campbell
K.
,
Marciniak
S. J.
 Jr.
,
Wasfi
Y.
, et al
.
2014
.
Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis.
J. Allergy Clin. Immunol.
133
:
1032
1040
.
134
Zandvliet
A.
,
Glasgow
S.
,
Horowitz
A.
,
Montgomery
D.
,
Marjason
J.
,
Mehta
A.
,
Xu
C.
,
van Vugt
M.
,
Khalilieh
S.
.
2015
.
Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects.
Int. J. Clin. Pharmacol. Ther.
53
:
139
146
.
135
Piper
E.
,
Brightling
C.
,
Niven
R.
,
Oh
C.
,
Faggioni
R.
,
Poon
K.
,
She
D.
,
Kell
C.
,
May
R. D.
,
Geba
G. P.
,
Molfino
N. A.
.
2013
.
A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma.
Eur. Respir. J.
41
:
330
338
.
136
Corren
J.
,
Lemanske
R. F.
,
Hanania
N. A.
,
Korenblat
P. E.
,
Parsey
M. V.
,
Arron
J. R.
,
Harris
J. M.
,
Scheerens
H.
,
Wu
L. C.
,
Su
Z.
, et al
.
2011
.
Lebrikizumab treatment in adults with asthma.
N. Engl. J. Med.
365
:
1088
1098
.

The authors have no financial conflicts of interest.