Abstract

With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor–mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β–high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.

Introduction

Chronic graft-versus-host disease (cGVHD) remains the major cause of morbidity and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation (SCT).1-3  Progress in improving cGVHD prevention and therapy has been hindered by complexities in cGVHD diagnosis and staging,4,5  lack of uniform treatment response criteria,6  paucity of controlled trials,7  and access to new therapies with an established proof-of-concept or strong pathophysiological basis in preclinical models. Such progress has been supported by analysis of human materials acquired from cGVHD patients.

This review draws from animal model and clinical studies to provide an overview; we combined interpretation of our current understanding of the cellular and molecular mediators of cGVHD. In turn, we highlight promising new therapeutic approaches. Additionally, we will provide our perspective on the gaps in cGVHD basic biology that deserve more attention as the prevalence of clinical cGVHD grows. Finally, we will review translation of current and possible future cGVHD therapies that have evolved from cGVHD basic biological insights.

Because no individual review can cover all aspects of cGVHD pathogenesis and preclinical studies leading to clinical applications, the reader is referred to several excellent reviews on this subject.8-13  Mouse models have served as a mainstay for recent advances in cGVHD therapies, and hence, will be a focus of this review. As virtually all patients receive some form of conditioning, nonconditioned murine cGVHD models will not be discussed in this review; instead, we refer the reader to Chu et al.9 

cGVHD manifestations and initiating factors in the clinic

cGVHD typically manifests with multiorgan pathology and historically has been defined temporally as GVHD that occurred later than 100 days post-SCT. The commonly seen diagnostic features, as outlined by the National Institutes of Health (NIH) consensus criteria,14  include skin pathology varying from lichen planus–like lesions to full sclerosis, bronchiolitis obliterans (BO), and oral lichen planus–like lesions (ie, skin, lung, and mouth involvement). Esophageal webs and strictures and muscle or joint fasciitis are also diagnostic. Importantly, these diagnostic features can be seen before day 100 and may occur simultaneously with features commonly seen in acute GVHD (aGVHD) (eg, macular-papular rashes, weight loss, diarrhea, and hepatitis). Thus, cGVHD occurs as a continuum in time with clinical features that are distinct from, but not mutually exclusive with, those seen in aGVHD.

Over the last decade granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (G-PBSC) grafts have been rapidly adopted as an increasingly used stem cell source for SCT. From its inception, it was clear that G-CSF exerts immunomodulatory effects on the graft,15-17  resulting in altered transplant outcomes in patients receiving G-PBSC grafts as compared with unmanipulated bone marrow (BM) grafts, with the primary advantage of G-PBSC grafts being accelerated engraftment. A randomized trial of BM vs G-PBSC revealed similar overall survival with secondary end points showing that G-PBSC grafts provided decreased graft failure but increased cGVHD incidence.18,19  Consistent with G-CSF immune-regulatory effects on PBSCs, aGVHD incidence was similar despite the higher T-cell dose that accompanied G-PBSC grafts. Risk factors for cGVHD development include preceding aGVHD, use of PBSCs,18  use of mismatched or unrelated donors (as opposed to matched siblings), transplant of female donors to male recipients, absence of antithymocyte globulin in conditioning, and older recipients.20  Given the expanding allogeneic SCT and G-PBSC graft use as well as the treatment of older recipients who historically were not candidates for allogeneic SCT, it is not surprising that the prevalence of cGVHD has reached new heights.

Overview of mouse models and cGVHD pathogenesis

With clinical cGVHD heterogeneity and frequent preceding aGVHD manifestations, it is somewhat surprising that GVHD models in mice have been described in the literature with such a clear demarcation as representing aGVHD or cGVHD. Similar to patients, it is now clear that transplanted mice receiving pre-SCT conditioning regimens, typically radiation-containing, can progress through a continuum of aGVHD to cGVHD which can evolve over time.21  In fact, autoreactive T cells can coexist with or emerge from alloreactive T cells.22-24  Indeed, many aGVHD model systems have been adapted to infuse lower donor T-cell numbers25-27  or use G-CSF treatment of donors,28  permitting mice to escape uniform aGVHD lethality and donor T cells to chronically receive T-cell receptor (TCR) signals from host or donor alloantigen/peptide-expressing cells. Features of cGVHD can be seen in most “aGVHD” models if T-cell doses are lowered and histopathology is later post-SCT (eg, at 4-8 weeks), the latter time favoring both escape from aGVHD lethality and a period of chronic TCR signaling.28 

A noteworthy distinction between the pathology of aGVHD and cGVHD is the typical tissue inflammatory T-cell infiltrate and destructive features of aGVHD and the relatively acellular, fibroproliferative findings in cGVHD. In particular, scleroderma,15,16,22,23  BO,25  and fibrosis in liver, gastrointestinal tract, salivary glands, and tongue can be seen in cGVHD mouse models.26,27,29  Intriguingly, many, but not all, cGVHD appear to have either scleroderma (reviewed in Reddy et al30 ) or multiorgan system involvement without scleroderma as their predominant manifestations, further highlighting the fact that no single model can replicate the wide spectrum of clinical manifestations which themselves are not all seen in an individual patient. There are no unique strain combinations that only cause cGVHD and are incapable of experiencing aGVHD if conditions are modified to favor aGVHD. Because aGVHD can attack the thymus, BM, and secondary lymphoid organs (SLOs), preceding aGVHD, even at a subclinical level in mice and patients, may have profound immunological manifestations resulting in T-cell or especially B-cell depletion31-33  or loss of thymic function34,35  that results in failed negative selection and loss of regulatory T-cell (Treg) production (see “Immune regulators of cGVHD”).23,36-38  Conversely, strategies that prevent or treat cGVHD may be efficacious if they inhibit aGVHD, whereas in settings in which aGVHD is no longer present, successful cGVHD therapy approaches must focus on reversing fibrosis, if debilitating, and any ongoing immune mechanisms that continue to propagate the cGVHD injury response.

Further complicating the analysis of cGVHD pathogenesis using preclinical models are the specifics of cGVHD generation. As in patients, variables that can contribute to differences in cGVHD pathogenesis and its manifestations between laboratories include radiation dose/source/dose rate, use of chemotherapy, subset and numbers of infused donor T cells, and hematopoietic stem cell (HSC) source and manipulations, if any. Other key variables may include mouse vendors39  and distinct microbiome colonization as well as antibiotic usage in each mouse colony that has been shown to affect immune responses,40,41  including aGVHD in mouse42,43  and humans.44  Recipient age may be a factor as older mice have augmented allostimulatory function.45  Although in most cGVHD models, donor and host strains are sex-matched, if this is not the case, anti-HY responses could occur with female-into-male transplants potentially resulting in aGVHD in rodents46  and cGVHD in patients.47,48  In our opinion, there is no inherent predilection for cGVHD per se or scleroderma generation in minor histocompatibility antigen (miH)-only disparate models, though such strain combinations are frequently used for analysis of cGVHD pathogenesis. Rather, we favor the explanation that the intensity of the GVHD response and responding T-cell type (CD4 vs CD8 subset and differentiation stage, cytokine profile, chemokine/integrin expression levels) are the major determining factors for aGVHD vs cGVHD independent of the type (major histocompatibility complex [MHC] and/or miH) of antigenic disparities between donor and host. This hypothesis is supported by the fact that miH only as well as models in which MHC antigen disparities are present each have been reported to induce aGVHD and cGVHD, dependent upon transplant conditions. Therefore, our collective recommendation is for the field to focus on discussing the immunological and pathophysiological mechanisms that result in cGVHD, not the system used. As such, we have chosen not to summarize particular strain combinations and SCT conditions that have been reported to cause cGVHD that is typically a part of such reviews.

Relationship between aGVHD and cGVHD pathogenesis

The initiation of and resultant target organ injury observed in both aGVHD and cGVHD is a consequence of the coordinated interplay between multiple cellular and molecular immune mediators that is dependent on the presence and function of donor graft T cells.49  Following SCT, tissue injury and inflammation characterized by proinflammatory cytokine release (eg, tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-1) is initiated by the conditioning regimen that would be common for both aGVHD and cGVHD, especially in the clinic, as both diseases can emanate in patients who receive the transplantation procedure. These cytokines, together with luminal damage-associated molecular patterns and pathogen-associated molecular patterns released from damaged gut tissue and the microbial luminal contents, result in the activation of antigen-presenting cells (APCs). Activated APCs then prime naive donor T cells and preferentially drive T-helper 1 (Th1)/T-cytotoxic 1 (Tc1) and Th17/Tc17 differentiation and expand T-effector cells, which can mediate target tissue GVHD, including the thymus and SLO, as well as the skin, liver, gastrointestinal tract, and lung, likely predisposing to cGVHD later after SCT.

Whereas aGVHD is generally defined as a Th1/Th17 paradigm, which results in extensive tissue destruction characterized by apoptosis, cGVHD and aGVHD in fact may share initiating mechanisms. For example, Th17/Tc17 cells have been shown, in some but not all systems, to cause either aGVHD50-52  or sclerodermatous cGVHD.28,53  Although donor natural killer (NK) cells, Tregs, regulatory B cells (Bregs), and macrophages play important roles in dampening both aGVHD and cGVHD (see “Immune regulators of cGVHD”), the role of B cells in controlling aGVHD pathogenesis in murine models is more controversial.54-56  In cGVHD, there is a preponderance of evidence for an interplay between donor T cells and donor B cells for disease pathogenesis (see “Immune regulators of cGVHD”). In this section, we define the contribution of each of these mediators to cGVHD pathology as instructed by preclinical studies with confirmation in the clinical setting where applicable.

Thymic and peripheral T-cell selection defects resulting in cGVHD

The donor graft T-cell compartment is composed of antigen-inexperienced naive and antigen-experienced T-effector and memory subsets. In both preclinical and clinical studies, naive T-cell–depleted grafts have a significantly reduced cGVHD incidence, while allowing transferred memory T cells to contribute to immune reconstitution and protective immunity.57,58  As briefly mentioned above, failed intrathymic deletion of “autoreactive” donor T cells can also contribute to cGVHD as evidenced by cGVHD induced by reconstitution of murine recipients with T-cell–depleted BM from allogeneic MHC class II–deficient donors that precludes thymic DC-mediated negative selection of maturing T cells.38  Intriguingly, thymectomy can prevent cGVHD pathology, suggesting that thymic dysfunction in cGVHD recipients favors selection of autoreactive and alloreactive T cells. Moreover, cGVHD and/or its therapy themselves are highly detrimental to thymic function.59  The possibility of shared mechanisms in the thymus and periphery is suggested by the finding of defective APC function in aGVHD mice.60  Collectively, these mechanisms can facilitate the emergence of self-reactive thymic emigrants and cGVHD induction caused by the de novo generation of both autoreactive and alloreactive donor CD4+ T cells as indicated by their capacity to induce cGVHD pathology upon their adoptive transfer in both syngeneic and allogeneic secondary recipients.24  Conversely, keratinocyte growth factor administration, by reducing aGVHD-induced thymic injury, can improve thymopoiesis and restore thymic DC, resulting in amelioration of cGVHD.24  In summary, both mature T cells contained within the graft and precursor-derived thymic T cells mediate cGVHD pathology; however, their relative contribution to distinct cGVHD pathology and mechanism of action remain to be elucidated and is likely to vary between cGVHD models and between patients.

T-cell effector mechanisms driving cGVHD pathology

Conventional T cells can be broadly divided into Th1/Tc1 (interferon γ [IFNγ]), Th17/Tc17 (IL-17), and Th2 (IL-4/IL-10) subsets. Until recently, aGVHD was largely considered Th1-dominated, whereas cGVHD was considered to represent a Th2-mediated disease.12,61  This notion had its support in studies showing differential cytokine expression in aGVHD and cGVHD mice,62  Th2 cell accumulation in cGVHD mice,63  the relationship between G-PBSC, Th2/plasmacytoid dendritic cell (DC) skewing, and the higher incidence of cGVHD in patients.15,16,18  However, in both mice64  and humans,65  there is not a clear paradigm demonstrating that Th1 cells are required for aGVHD, whereas Th2 cells cause cGVHD.

Recently, the Th/Tc17 pathway has been shown to promote pathogenic autoimmune-mediated organ damage in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis.66  In systemic sclerosis, a condition closely resembling sclerodermatous cGVHD, fibrosis, is mediated by Th17 cells infiltrating the skin and serum IL-17 levels positively correlate with disease severity.67,68  Preclinical and clinical data support a role for IL-17 as a predictor69  and central mediator of pathology, especially the skin.28,53,70,71  In a preclinical study, high G-CSF doses were shown to invoke type 17 rather than type 1 or type 2 T-cell differentiation, and amplification of IL-17 production occurred in both CD4 and CD8 T cells.28  Donor IL-17A, predominantly Tc17 derived, promoted skin pathology (dermal thickening, loss of subcutaneous fat and hair follicles, and increased cellular infiltrate) and cutaneous fibrosis, manifesting as scleroderma, providing a logical explanation for the propensity of G-PBSCs to invoke sclerodermatous cGVHD and highlighting Tc17 as an important cGVHD effector population. In clinical cGVHD studies, increased IL-17 messenger RNA transcripts and significant Tc17 infiltration were demonstrated in skin,72  whereas in the oral mucosa, Th17 infiltration dominated. Cytokines (IL-6, IL-21) known to support Th17 generation in GVHD are elevated in GVHD,73-76  and STAT3, which drives Th17 development and Th17-dependent autoimmunity,77  is essential for CD4+ T-cell–mediated sclerodermatous cGVHD.78  Lichenoid cGVHD in patients has coexisting Th1 and Th17 cells with increased CD8+ T cells producing IL-17 and IFNγ,72,79  and IL-17 is systemically elevated late after SCT as cGVHD develops.76  In multiple disease models including GVHD, both Th17 and Tc17 cells coexpress multiple proinflammatory cytokines (eg, IL-22, IFNγ, granulocyte-macrophage colony-stimulating factor [GM-CSF]) and exhibit significant functional plasticity.50,80-83  Just how these IL-17–producing T cells generate fibrosis remains to be elucidated but some clear pathways have been highlighted and are outlined in the following list.

Burgeoning areas of investigation include analysis of:

  1. TCR repertoires in the blood and organs of cGVHD mice and patients to determine whether there are dominant TCR clones that cause cGVHD;

  2. Chemokine-facilitated migratory properties of T-effector cells in cGVHD84,85 ; and

  3. The metabolic state of cGVHD T-effector cells that may suggest interventional approaches to prevent or treat cGVHD, as has been shown in preclinical aGVHD models.86-90 

B cells and antibodies in cGVHD pathogenesis

Emerging evidence supports an important role for donor B cells in both the initiation and perpetuation of cGVHD. In both mice and humans, B-cell homeostasis and tolerance mechanisms are disrupted after SCT, resulting in reduced memory B-cell formation and enrichment of activated transitional B cells in the reconstituting donor B-cell pool.91-93  A correlation between reduced IL-10–producing Bregs (B10 cells94 ) and cGVHD severity is increasingly reported.95-97  B-cell–activating factor (BAFF), a cytokine critical for B-cell survival and maturation, is found in excess levels in patients with active cGVHD, resulting in increased BAFF-to-B-cell ratios.98,99  In the setting of elevated BAFF levels, B cells reactive against polymorphic recipient (allo) or nonpolymorphic antigens shared by donor and host (auto)antigens, normally targeted for apoptotic death through negative selection, are protected and persist. Indeed, the association of BAFF and autoantibody production in cGVHD patients has been reported.99  Recent preclinical studies in a multiorgan nonsclerodermatous cGVHD model have demonstrated the requirement for increased T-follicular helper cells (Tfh), germinal center (GC) B cells, and antibody which accumulates in target tissues, resulting in the development of some, although not all, manifestations of cGVHD.26,29,100,101  Tfh cells produce IL-21, a cytokine known to be critical for GC formation and the cutaneous and pulmonary manifestations of cGVHD.28,29  Alloantibodies (predominantly to HY antigen) have been well described in cGVHD and correlate with disease activity.47,48,102,103  Autoantibodies are widely detected in patients with cGVHD. Although initial reports suggested that antibodies to the platelet-derived growth factor receptor may be pathogenic,104  this finding has been debated.105  Mechanistically, the aberrant GC B-cell reaction seen in cGVHD results in antibody formation.29  Elegant serum transfer experiments have now shown that antibody can be directly pathogenic and initiate disease.106  Increasing BAFF concentrations have been associated with pre-GC B cells and post-GC plasma-like cells in patients,107  which may be the result of either GC or extrafollicular B-cell responses, mechanisms yet to be determined in patients. Although peripheral blood Tfh cell frequency has been reported to be reduced in patients with cGVHD,108,109  Tfh cells were skewed toward a highly activated profile with a predominance of Th2 and Th17 (IL-17, IL-21 producing) subsets, increased functional ability to promote B-cell immunoglobulin secretion and maturation, and an activation signature highly correlated with increased B-cell activation and plasmablast maturation.108  Because in rodents GC B cells were quantified in the spleen, a plausible explanation for the reduced peripheral blood Tfh frequency in cGVHD is that the Tfh cells are localized in GCs within SLOs. However, cGVHD therapy or GVHD-induced injury to lymphoid organs resulting in decreased Tfh production cannot be excluded. Consistent with that hypothesis, high plasma CXCL3 levels, which are chemoattractant for T and B cells into SLOs, have been detected in cGVHD patients.108  Because cGVHD is also characterized by autoantibody formation, it remains to be established whether the pathogeneic antibodies in question are directed solely to allogeneic polymorphic antigens or also to nonpolymorphic “autologous” antigens shared by donor and recipient. Moreover, it is unclear whether antibody-dependent mechanisms are operative in all recipients with cGVHD, or only a subset; also unclear is the mechanism by which antibody initiates fibrosis and the cellular mediators involved remain to be elucidated.

Role of macrophages in cGVHD pathogenesis

Fibrotic injury is characterized by excessive accumulation of extracellular matrix (predominantly collagen) and fibroblasts, which replace parenchymal cells and impair normal tissue function. Macrophages play a crucial role in the tissue-repair response, are found in close proximity with collagen-producing fibroblasts and as demonstrated in multiple disease models, contribute to fibrosis.110,111  In both preclinical and clinical cGVHD, macrophages have been shown to accumulate in fibrotic lesions.28,72,112  However, the factors promoting macrophage tissue sequestration, and their mechanistic contribution to pathology have only recently been examined. In preclinical cGVHD models characterized by scleroderma or BO with multiorgan system fibrosis but without scleroderma, the sequestration of macrophages within skin and lung, and the subsequent development of cGVHD pathology, was shown to be both IL-17 and colony-stimulating factor 1 (CSF-1) dependent.28,112  Tissue-infiltrating macrophages were of donor origin, alternatively activated (skewed toward anti-inflammatory responses) as indicated by their expression of CD206 rather than inducible NO synthase, and promoted pathology through their production of transforming growth factor β (TGFβ), a key cytokine for myofibroblast activation and collagen production. Importantly, the attenuation of CSF-1 receptor (CSF-1R) signaling using an anti-CSF-1R–blocking antibody depleted circulating and tissue-associated Ly6Clo monocytes, ablated tissue-infiltrating macrophages, and markedly attenuated both cutaneous and preexisting pulmonary cGVHD.112  The mechanism by which IL-17 contributes to pathogenic macrophage migration and differentiation in cGVHD target organs remains undefined. However, IL-17 has been reported to function as a monocyte chemokine, to promote monocyte adhesion and elicit a proinflammatory transcriptome in macrophages, suggesting direct signaling of this lineage may be involved.113  Other proinflammatory cytokines coproduced by Tc17/Th17 such as GM-CSF50  may contribute synergistically to macrophage differentiation/polarization at localized sites.

Macrophages express very high levels of Fc-γ receptors and are highly efficient at opsonization of antibody-coated targets which in turn can generate very high levels of TGFβ.114,115  Consistent with a link between antibody secretion and fibrosis, mice incapable of producing B cells or that produce B cells incapable of immunoglobulin isotype switching,26  or that receive agents that either preclude GC formation29,73,116  or deplete B cells29,117-119  are unable to induce fibrosis or cGVHD. Thus, although unproven at this point, the interaction of allo-(and/or auto) antibody with tissue macrophages would appear an attractive unifying mechanism driving the aberrant macrophage differentiation and function that culminates in tissue fibrosis during cGVHD.

Immune regulators of cGVHD

Immune populations contained within the graft or that emerge from graft progeny can exhibit immune-modulatory capacity.120  Tregs, defined by their coexpression of CD4, CD25, and the master transcription factor FoxP3, are critical for the control of innate and adaptive immune responses and can mediate tissue regeneration via amphiregulin release.121  GC migratory Tregs, known as T-follicular regulatory cells, suppress GC responses.122  Treg number or function perturbations lead to the development of autoimmune diseases and are thought to contribute to aGVHD and cGVHD pathology.8,10,123  Both preclinical and clinical studies demonstrate that donor graft Treg number inversely correlates with aGVHD,124-128  and cGVHD is associated with decreased numbers of circulating Tregs.21,129-131  Factors contributing to diminished Treg numbers in cGVHD recipients remain to be fully elucidated although there are multiple candidates including diminished thymic production, reduced proliferative capacity of naive Tregs,132  and a failure in memory Treg survival due to their increased susceptibility to apoptosis.131,133  DCs play an important role in the maintenance of Tregs in steady state and following SCT,88,134,135  including cGVHD.88,134-136  However, in recent preclinical studies, donor DC MHC class II antigen presentation was shown to be impaired during aGVHD, and this resulted in a failure of Treg homeostasis that promoted cGVHD pathology.60,136 

Although less well studied, altered Breg and NK development after SCT is thought to contribute to cGVHD. Breg function to suppress immune responses through multiple IL-10 and cell-cell contact-dependent mechanisms, including suppression of CD4 T-cell proliferation and IFNγ production, and monocyte TNF production.137,138  In patients with cGVHD, recent studies show that Breg numbers, including immunoglobulin M memory and transitional subsets, are reduced and exhibit a diminished capacity to produce IL-10.95,97  Enhanced NK reconstitution has also been shown to correlate with reduced incidence of cGVHD in the clinical setting,139  although not all studies show an inverse correlation between alloreactive NK cells and cGVHD.140  Mechanistically, in preclinical studies, NK cells contribute to the regulation of CD4 and CD8 T-cell expansion through Fas-mediated killing and competition for IL-15, respectively.141,142  Additionally, NK cells also produce cytokines that promote tissue regeneration, although whether this represents a functioning cGVHD mechanism remains to be investigated.143  Together, these studies highlight the potential clinical utility of therapeutic strategies, which promote the expansion of Bregs and NK cells after transplant.

New therapeutic strategies based on recent insights to pathophysiology

Treatment of cGVHD is currently based on steroid administration and although many other approaches, including additional immune suppressants, UVB phototherapy, and extracorporeal photophoresis are commonly used, none have proven clearly effective.144,145  Thus, well-designed prospective studies based on NIH response criteria and our new understanding of cGVHD pathophysiology are needed. We now know that cGVHD develops via a complex cellular and molecular network involving thymic damage and aberrant antigen presentation leading to aberrant T- and B-cell reaction characterized by Th17/Tc17 differentiation, macrophage sequestration in tissue, alloantibody formation, and TGFβ-dependent fibrosis (Figure 1). Collectively, these studies highlight a number of therapeutic options. From a preventative aspect, the direct removal of naive αβ T cells from the graft (eg, using in vitro magnetic-based antibody approaches of T-cell removal or CD34+ stem cell selection)58,146  or depletion of differentiating T cells early after transplant (eg, by administering posttransplant cyclophosphamide to preferentially deplete alloreactive T cells while sparing Tregs)147  appears highly effective at eliminating cGVHD. Approaches to inhibit the more terminal stages of aberrant (Th17/Tfh) T-cell development in cGVHD include small-molecule RORγt148  or STAT3 inhibitors and antibody-based therapeutics targeting IL-17 or IL-21 and their receptors.28,29 

Figure 1.

Schematic overview of the cellular and molecular mediators, known and implicated, contributing to the continuum of aGVHD and cGVHD pathology. Both naive T cells (TN) and their precursors (HSCs, common lymphoid progenitor [CLP]) contained within the stem cell graft contribute to cGVHD pathology. Mature donor T cells within the graft contribute to thymic destruction resulting in disrupted immune reconstitution. Thymic dysfunction favors the selection of autoreactive and alloreactive T cells polarized toward Th17/Tc17 lineages. Donor-derived DC APC function is corrupted during aGVHD, reducing their capacity to expand and maintain Tregs in the periphery. T-follicular helper cell (TFH)-derived IL-21, together with elevated levels of BAFF, result in aberrant B-cell reconstitution favoring GC B-cell (GBC) expansion. Polyfunctional Th17/Tc17 cells migrate to target organs where secreted IL-17 may function as a chemokine for Ly6Clo monocytes. CSF-1 derived in part from Th17/Tc17 promotes the differentiation of Ly6Clo monocytes into tissue-resident macrophages (MΦ), which are polarized toward an M2 phenotype under the influence of multiple proinflammatory cytokines (GM-CSF, IL-22, IL-13, and IFNγ) produced by Th17/Tc17. Plasma cell–derived allo/autoantibodies (Ab) can bind to Fc receptors on macrophages, contributing to their polarization and promotion of TGFβ secretion, which promotes fibroblast activation and collagen production. Fc, receptor for immunoglobulins; Tallo, alloreactive T cell; TEFF, effector T cell.

Figure 1.

Schematic overview of the cellular and molecular mediators, known and implicated, contributing to the continuum of aGVHD and cGVHD pathology. Both naive T cells (TN) and their precursors (HSCs, common lymphoid progenitor [CLP]) contained within the stem cell graft contribute to cGVHD pathology. Mature donor T cells within the graft contribute to thymic destruction resulting in disrupted immune reconstitution. Thymic dysfunction favors the selection of autoreactive and alloreactive T cells polarized toward Th17/Tc17 lineages. Donor-derived DC APC function is corrupted during aGVHD, reducing their capacity to expand and maintain Tregs in the periphery. T-follicular helper cell (TFH)-derived IL-21, together with elevated levels of BAFF, result in aberrant B-cell reconstitution favoring GC B-cell (GBC) expansion. Polyfunctional Th17/Tc17 cells migrate to target organs where secreted IL-17 may function as a chemokine for Ly6Clo monocytes. CSF-1 derived in part from Th17/Tc17 promotes the differentiation of Ly6Clo monocytes into tissue-resident macrophages (MΦ), which are polarized toward an M2 phenotype under the influence of multiple proinflammatory cytokines (GM-CSF, IL-22, IL-13, and IFNγ) produced by Th17/Tc17. Plasma cell–derived allo/autoantibodies (Ab) can bind to Fc receptors on macrophages, contributing to their polarization and promotion of TGFβ secretion, which promotes fibroblast activation and collagen production. Fc, receptor for immunoglobulins; Tallo, alloreactive T cell; TEFF, effector T cell.

Strategies to enhance Treg numbers after SCT including Treg adoptive therapy to reconstitute the Treg pool have been adopted from rodent studies and are showing potential in the clinic.127,128,146,149-152  Recent preclinical studies show that Treg adoptive transfer can both prevent and treat cGVHD in mice with multiorgan system disease.136,153  Given the failure of Tregs during cGVHD and the challenges of generating sufficient Tregs for adoptive transfer to treat cGVHD patients, restorative approaches to date have focused on low-dose IL-2 administration to expand Tregs in vivo with ∼50% of patients showing Treg expansion and some clinical response as long as therapy is continued.154,155  Recently, the adoptive transfer of Tregs with or without IL-2 and/or rapamycin has begun to be tested in clinical trials in an effort to increase the proportion and depth of patient response.

Approaches targeting B cells involve the prevention of aberrant B-cell development by administration of CD20 monoclonal antibody which appears effective in reducing disease severity in cGVHD patients when used as a preventative but not treatment strategy, likely due to the more effective B-cell depletion than that of antibody-secreting plasmablasts and plasma cells formed after cGVHD is established.156,157  Pursuing pharmacological agents that inhibit B- (with or without T-) cell activation, differentiation, and GC integrity by kinase inhibition (eg, Syk kinase, fostamatinib118 ; Bruton kinase; ibrutinib117 ; Rho-associated kinase, KD025,73  and Janus kinase-1, ruxolitinib158 ) has a strong biological foundation, as confirmed in part by promising early clinical results already achieved with ruxolitinib159  and ibrutinib. At the most final stage of aberrant B-cell response, depletion of alloantibody-producing plasma cells by proteosome inhibition (eg, bortezomib) is supported by evidence of efficacy in animal systems and early clinical studies.160  Finally, targeting macrophages by preventing differentiation and survival in tissue through the inhibition of CSF-1R has proven highly effective in animal systems,112  as has the inhibition of TGFβ.112,161 

Acknowledgments

The authors thank members of their laboratories, their collaborators, and the scientific community for providing the foundation for this review. The authors apologize to those investigators whose work they were unable to cite here. Lastly, the authors thank the patients who have participated in clinical studies that have fostered the advancement of the new therapies for this devastating disease.

This work was supported by grants from the Australian National Health and Medical Research Council (NH&MRC) APP1031728 (K.P.A.M.), National Institutes of Health, National Cancer Institute grants P01 CA142106-06A1 and P01 CA047741-20, National Institutes of Health, National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI11879, and Leukemia & Lymphoma Society Translational Research grant 6458-15 and 6462-15 (B.R.B.). G.R.H. is a NH&MRC Senior Principal Research Fellow and Queensland Health Senior Clinical Research Fellow. K.P.A.M. is a Cancer Council Queensland Senior Research Fellow.

Authorship

Contribution: K.P.A.M., G.R.H., and B.R.B. wrote the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Kelli P. A. MacDonald, Antigen Presentation and Immunoregulation Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia; e-mail: kelli.macdonald@qimrberghofer.edu.au; Geoffrey R. Hill, Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia; e-mail: geoff.hill@qimrberghofer.edu.au; and Bruce R. Blazar, Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, MMC 109, 420 SE Delaware St, Minneapolis, MN 55455; e-mail: blaza001@umn.edu.

References

References
1.
Flowers
ME
,
Martin
PJ
.
How we treat chronic graft-versus-host disease
.
Blood
.
2015
;
125
(
4
):
606
-
615
.
2.
Martin
PJ
,
Counts
GW
Jr
,
Appelbaum
FR
, et al
.
Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation
.
J Clin Oncol
.
2010
;
28
(
6
):
1011
-
1016
.
3.
Wingard
JR
,
Majhail
NS
,
Brazauskas
R
, et al
.
Long-term survival and late deaths after allogeneic hematopoietic cell transplantation
.
J Clin Oncol
.
2011
;
29
(
16
):
2230
-
2239
.
4.
Arai
S
,
Jagasia
M
,
Storer
B
, et al
.
Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH consensus criteria
.
Blood
.
2011
;
118
(
15
):
4242
-
4249
.
5.
Jacobsohn
DA
,
Kurland
BF
,
Pidala
J
, et al
.
Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium
.
Blood
.
2012
;
120
(
13
):
2545
-
2552
.
6.
Shulman
HM
,
Cardona
DM
,
Greenson
JK
, et al
.
NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. The 2014 Pathology Working Group Report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
4
):
589
-
603
.
7.
Martin
PJ
,
Lee
SJ
,
Przepiorka
D
, et al
.
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
8
):
1343
-
1359
.
8.
Blazar
BR
,
Murphy
WJ
,
Abedi
M
.
Advances in graft-versus-host disease biology and therapy
.
Nat Rev Immunol
.
2012
;
12
(
6
):
443
-
458
.
9.
Chu
YW
,
Gress
RE
.
Murine models of chronic graft-versus-host disease: insights and unresolved issues
.
Biol Blood Marrow Transplant
.
2008
;
14
(
4
):
365
-
378
.
10.
McDonald-Hyman
C
,
Turka
LA
,
Blazar
BR
.
Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation
.
Sci Transl Med
.
2015
;
7
(
280
):
280rv2
.
11.
Schroeder
MA
,
DiPersio
JF
.
Mouse models of graft-versus-host disease: advances and limitations
.
Dis Model Mech
.
2011
;
4
(
3
):
318
-
333
.
12.
Shlomchik
WD
,
Lee
SJ
,
Couriel
D
,
Pavletic
SZ
.
Transplantation’s greatest challenges: advances in chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2007
;
13
(
1 suppl 1
):
2
-
10
.
13.
Socié
G
,
Ritz
J
.
Current issues in chronic graft-versus-host disease
.
Blood
.
2014
;
124
(
3
):
374
-
384
.
14.
Jagasia
MH
,
Greinix
HT
,
Arora
M
, et al
.
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
3
):
389
-
401
.
15.
Arpinati
M
,
Green
CL
,
Heimfeld
S
,
Heuser
JE
,
Anasetti
C
.
Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells
.
Blood
.
2000
;
95
(
8
):
2484
-
2490
.
16.
Morris
ES
,
MacDonald
KP
,
Rowe
V
, et al
.
Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance
.
Blood
.
2004
;
103
(
9
):
3573
-
3581
.
17.
Pan
L
,
Delmonte
J
Jr
,
Jalonen
CK
,
Ferrara
JL
.
Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease
.
Blood
.
1995
;
86
(
12
):
4422
-
4429
.
18.
Anasetti
C
,
Logan
BR
,
Lee
SJ
, et al
;
Blood and Marrow Transplant Clinical Trials Network
.
Peripheral-blood stem cells versus bone marrow from unrelated donors
.
N Engl J Med
.
2012
;
367
(
16
):
1487
-
1496
.
19.
Stem Cell Trialists’ Collaborative Group
.
Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials
.
J Clin Oncol
.
2005
;
23
(
22
):
5074
-
5087
.
20.
Flowers
ME
,
Inamoto
Y
,
Carpenter
PA
, et al
.
Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria
.
Blood
.
2011
;
117
(
11
):
3214
-
3219
.
21.
Chen
X
,
Vodanovic-Jankovic
S
,
Johnson
B
,
Keller
M
,
Komorowski
R
,
Drobyski
WR
.
Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease
.
Blood
.
2007
;
110
(
10
):
3804
-
3813
.
22.
Anderson
BE
,
McNiff
JM
,
Matte
C
,
Athanasiadis
I
,
Shlomchik
WD
,
Shlomchik
MJ
.
Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease
.
Blood
.
2004
;
104
(
5
):
1565
-
1573
.
23.
Tivol
E
,
Komorowski
R
,
Drobyski
WR
.
Emergent autoimmunity in graft-versus-host disease
.
Blood
.
2005
;
105
(
12
):
4885
-
4891
.
24.
Zhang
Y
,
Hexner
E
,
Frank
D
,
Emerson
SG
.
CD4+ T cells generated de novo from donor hemopoietic stem cells mediate the evolution from acute to chronic graft-versus-host disease
.
J Immunol
.
2007
;
179
(
5
):
3305
-
3314
.
25.
Panoskaltsis-Mortari
A
,
Tram
KV
,
Price
AP
,
Wendt
CH
,
Blazar
BR
.
A new murine model for bronchiolitis obliterans post-bone marrow transplant
.
Am J Respir Crit Care Med
.
2007
;
176
(
7
):
713
-
723
.
26.
Srinivasan
M
,
Flynn
R
,
Price
A
, et al
.
Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans
.
Blood
.
2012
;
119
(
6
):
1570
-
1580
.
27.
Wu
T
,
Young
JS
,
Johnston
H
, et al
.
Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells
.
J Immunol
.
2013
;
191
(
1
):
488
-
499
.
28.
Hill
GR
,
Olver
SD
,
Kuns
RD
, et al
.
Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma
.
Blood
.
2010
;
116
(
5
):
819
-
828
.
29.
Flynn
R
,
Du
J
,
Veenstra
RG
, et al
.
Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans
.
Blood
.
2014
;
123
(
25
):
3988
-
3998
.
30.
Reddy
P
,
Negrin
R
,
Hill
GR
.
Mouse models of bone marrow transplantation
.
Biol Blood Marrow Transplant
.
2008
;
14
(
1 suppl 1
):
129
-
135
.
31.
Baker
MB
,
Riley
RL
,
Podack
ER
,
Levy
RB
.
Graft-versus-host-disease-associated lymphoid hypoplasia and B cell dysfunction is dependent upon donor T cell-mediated Fas-ligand function, but not perforin function
.
Proc Natl Acad Sci USA
.
1997
;
94
(
4
):
1366
-
1371
.
32.
Garvy
BA
,
Elia
JM
,
Hamilton
BL
,
Riley
RL
.
Suppression of B-cell development as a result of selective expansion of donor T cells during the minor H antigen graft-versus-host reaction
.
Blood
.
1993
;
82
(
9
):
2758
-
2766
.
33.
Storek
J
,
Wells
D
,
Dawson
MA
,
Storer
B
,
Maloney
DG
.
Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation
.
Blood
.
2001
;
98
(
2
):
489
-
491
.
34.
Krenger
W
,
Holländer
GA
.
The immunopathology of thymic GVHD
.
Semin Immunopathol
.
2008
;
30
(
4
):
439
-
456
.
35.
van den Brink
MR
,
Moore
E
,
Ferrara
JL
,
Burakoff
SJ
.
Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with anti-host reactivity
.
Transplantation
.
2000
;
69
(
3
):
446
-
449
.
36.
Dertschnig
S
,
Hauri-Hohl
MM
,
Vollmer
M
,
Holländer
GA
,
Krenger
W
.
Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD
.
Blood
.
2015
;
125
(
17
):
2720
-
2723
.
37.
Holländer
GA
,
Widmer
B
,
Burakoff
SJ
.
Loss of normal thymic repertoire selection and persistence of autoreactive T cells in graft vs host disease
.
J Immunol
.
1994
;
152
(
4
):
1609
-
1617
.
38.
Sakoda
Y
,
Hashimoto
D
,
Asakura
S
, et al
.
Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease
.
Blood
.
2007
;
109
(
4
):
1756
-
1764
.
39.
Ivanov
II
,
Atarashi
K
,
Manel
N
, et al
.
Induction of intestinal Th17 cells by segmented filamentous bacteria
.
Cell
.
2009
;
139
(
3
):
485
-
498
.
40.
Bennett
M
,
Taylor
PA
,
Austin
M
, et al
.
Cytokine and cytotoxic pathways of NK cell rejection of class I-deficient bone marrow grafts: influence of mouse colony environment
.
Int Immunol
.
1998
;
10
(
6
):
785
-
790
.
41.
Beura
LK
,
Hamilton
SE
,
Bi
K
, et al
.
Normalizing the environment recapitulates adult human immune traits in laboratory mice
.
Nature
.
2016
;
532
(
7600
):
512
-
516
.
42.
Jenq
RR
,
Ubeda
C
,
Taur
Y
, et al
.
Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation
.
J Exp Med
.
2012
;
209
(
5
):
903
-
911
.
43.
Mathewson
ND
,
Jenq
R
,
Mathew
AV
, et al
.
Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease
.
Nat Immunol
.
2016
;
17
(
5
):
505
-
513
.
44.
Shono
Y
,
Docampo
MD
,
Peled
JU
, et al
.
Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice
.
Sci Transl Med
.
2016
;
8
(
339
):
339ra71
.
45.
Ordemann
R
,
Hutchinson
R
,
Friedman
J
, et al
.
Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease
.
J Clin Invest
.
2002
;
109
(
9
):
1249
-
1256
.
46.
Toubai
T
,
Tawara
I
,
Sun
Y
, et al
.
Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic-derived antigen-presenting cells
.
Blood
.
2012
;
119
(
16
):
3844
-
3853
.
47.
Miklos
DB
,
Kim
HT
,
Miller
KH
, et al
.
Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission
.
Blood
.
2005
;
105
(
7
):
2973
-
2978
.
48.
Zorn
E
,
Miklos
DB
,
Floyd
BH
, et al
.
Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation
.
J Exp Med
.
2004
;
199
(
8
):
1133
-
1142
.
49.
Hill
GR
,
Ferrara
JL
.
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
.
2000
;
95
(
9
):
2754
-
2759
.
50.
Gartlan
KH
,
Markey
KA
,
Varelias
A
, et al
.
Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects
.
Blood
.
2015
;
126
(
13
):
1609
-
1620
.
51.
Kappel
LW
,
Goldberg
GL
,
King
CG
, et al
.
IL-17 contributes to CD4-mediated graft-versus-host disease
.
Blood
.
2009
;
113
(
4
):
945
-
952
.
52.
Yi
T
,
Chen
Y
,
Wang
L
, et al
.
Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease
.
Blood
.
2009
;
114
(
14
):
3101
-
3112
.
53.
Carlson
MJ
,
West
ML
,
Coghill
JM
,
Panoskaltsis-Mortari
A
,
Blazar
BR
,
Serody
JS
.
In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations
.
Blood
.
2009
;
113
(
6
):
1365
-
1374
.
54.
Matte-Martone
C
,
Wang
X
,
Anderson
B
, et al
.
Recipient B cells are not required for graft-versus-host disease induction
.
Biol Blood Marrow Transplant
.
2010
;
16
(
9
):
1222
-
1230
.
55.
Rowe
V
,
Banovic
T
,
MacDonald
KP
, et al
.
Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation
.
Blood
.
2006
;
108
(
7
):
2485
-
2492
.
56.
Weber
M
,
Stein
P
,
Prüfer
S
, et al
.
Donor and host B cell-derived IL-10 contributes to suppression of graft-versus-host disease
.
Eur J Immunol
.
2014
;
44
(
6
):
1857
-
1865
.
57.
Anderson
BE
,
McNiff
J
,
Yan
J
, et al
.
Memory CD4+ T cells do not induce graft-versus-host disease
.
J Clin Invest
.
2003
;
112
(
1
):
101
-
108
.
58.
Bleakley
M
,
Heimfeld
S
,
Loeb
KR
, et al
.
Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts
.
J Clin Invest
.
2015
;
125
(
7
):
2677
-
2689
.
59.
Weinberg
K
,
Blazar
BR
,
Wagner
JE
, et al
.
Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation
.
Blood
.
2001
;
97
(
5
):
1458
-
1466
.
60.
Markey
KA
,
Koyama
M
,
Kuns
RD
, et al
.
Immune insufficiency during GVHD is due to defective antigen presentation within dendritic cell subsets
.
Blood
.
2012
;
119
(
24
):
5918
-
5930
.
61.
Coghill
JM
,
Sarantopoulos
S
,
Moran
TP
,
Murphy
WJ
,
Blazar
BR
,
Serody
JS
.
Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new
.
Blood
.
2011
;
117
(
12
):
3268
-
3276
.
62.
Allen
RD
,
Staley
TA
,
Sidman
CL
.
Differential cytokine expression in acute and chronic murine graft-versus-host-disease
.
Eur J Immunol
.
1993
;
23
(
2
):
333
-
337
.
63.
Via
CS
,
Rus
V
,
Gately
MK
,
Finkelman
FD
.
IL-12 stimulates the development of acute graft-versus-host disease in mice that normally would develop chronic, autoimmune graft-versus-host disease
.
J Immunol
.
1994
;
153
(
9
):
4040
-
4047
.
64.
Murphy
WJ
,
Welniak
LA
,
Taub
DD
, et al
.
Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice
.
J Clin Invest
.
1998
;
102
(
9
):
1742
-
1748
.
65.
Ochs
LA
,
Blazar
BR
,
Roy
J
,
Rest
EB
,
Weisdorf
DJ
.
Cytokine expression in human cutaneous chronic graft-versus-host disease
.
Bone Marrow Transplant
.
1996
;
17
(
6
):
1085
-
1092
.
66.
Steinman
L
.
A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage
.
Nat Med
.
2007
;
13
(
2
):
139
-
145
.
67.
Murata
M
,
Fujimoto
M
,
Matsushita
T
, et al
.
Clinical association of serum interleukin-17 levels in systemic sclerosis: is systemic sclerosis a Th17 disease?
J Dermatol Sci
.
2008
;
50
(
3
):
240
-
242
.
68.
Yoshizaki
A
,
Yanaba
K
,
Iwata
Y
, et al
.
Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model
.
J Immunol
.
2010
;
185
(
4
):
2502
-
2515
.
69.
Li
W
,
Liu
L
,
Gomez
A
, et al
.
Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease
.
JCI Insight
.
2016
;
1
(
6
).
70.
Dander
E
,
Balduzzi
A
,
Zappa
G
, et al
.
Interleukin-17-producing T-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation
.
Transplantation
.
2009
;
88
(
11
):
1261
-
1272
.
71.
Serody
JS
,
Hill
GR
.
The IL-17 differentiation pathway and its role in transplant outcome
.
Biol Blood Marrow Transplant
.
2012
;
18
(
1 suppl
):
S56
-
S61
.
72.
Brüggen
MC
,
Klein
I
,
Greinix
H
, et al
.
Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease
.
Blood
.
2014
;
123
(
2
):
290
-
299
.
73.
Flynn
R
,
Paz
K
,
Du
J
, et al
.
Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism
.
Blood
.
2016
;
127
(
17
):
2144
-
2154
.
74.
Lu
L
,
Lan
Q
,
Li
Z
, et al
.
Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions
.
Proc Natl Acad Sci USA
.
2014
;
111
(
33
):
E3432
-
E3440
.
75.
Varelias
A
,
Gartlan
KH
,
Kreijveld
E
, et al
.
Lung parenchyma-derived IL-6 promotes IL-17A-dependent acute lung injury after allogeneic stem cell transplantation
.
Blood
.
2015
;
125
(
15
):
2435
-
2444
.
76.
Kennedy
GA
,
Varelias
A
,
Vuckovic
S
, et al
.
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
.
2014
;
15
(
13
):
1451
-
1459
.
77.
Harris
TJ
,
Grosso
JF
,
Yen
HR
, et al
.
Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity
.
J Immunol
.
2007
;
179
(
7
):
4313
-
4317
.
78.
Radojcic
V
,
Pletneva
MA
,
Yen
HR
, et al
.
STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model
.
J Immunol
.
2010
;
184
(
2
):
764
-
774
.
79.
Broady
R
,
Yu
J
,
Chow
V
, et al
.
Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells
.
Blood
.
2010
;
116
(
25
):
5748
-
5751
.
80.
Kara
EE
,
McKenzie
DR
,
Bastow
CR
, et al
.
CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells
.
Nat Commun
.
2015
;
6
:
8644
.
81.
Muranski
P
,
Restifo
NP
.
Essentials of Th17 cell commitment and plasticity
.
Blood
.
2013
;
121
(
13
):
2402
-
2414
.
82.
Yeh
N
,
Glosson
NL
,
Wang
N
, et al
.
Tc17 cells are capable of mediating immunity to vaccinia virus by acquisition of a cytotoxic phenotype
.
J Immunol
.
2010
;
185
(
4
):
2089
-
2098
.
83.
Yen
HR
,
Harris
TJ
,
Wada
S
, et al
.
Tc17 CD8 T cells: functional plasticity and subset diversity
.
J Immunol
.
2009
;
183
(
11
):
7161
-
7168
.
84.
Croudace
JE
,
Inman
CF
,
Abbotts
BE
, et al
.
Chemokine-mediated tissue recruitment of CXCR3+ CD4+ T cells plays a major role in the pathogenesis of chronic GVHD
.
Blood
.
2012
;
120
(
20
):
4246
-
4255
.
85.
Kitko
CL
,
Levine
JE
,
Storer
BE
, et al
.
Plasma CXCL9 elevations correlate with chronic GVHD diagnosis
.
Blood
.
2014
;
123
(
5
):
786
-
793
.
86.
Byersdorfer
CA
,
Tkachev
V
,
Opipari
AW
, et al
.
Effector T cells require fatty acid metabolism during murine graft-versus-host disease
.
Blood
.
2013
;
122
(
18
):
3230
-
3237
.
87.
Gatza
E
,
Wahl
DR
,
Opipari
AW
, et al
.
Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease
.
Sci Transl Med
.
2011
;
3
(
67
):
67ra8
.
88.
Marcondes
AM
,
Karoopongse
E
,
Lesnikova
M
, et al
.
α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics
.
Blood
.
2014
;
124
(
18
):
2881
-
2891
.
89.
Nguyen
HD
,
Chatterjee
S
,
Haarberg
KM
, et al
.
Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation
.
J Clin Invest
.
2016
;
126
(
4
):
1337
-
1352
.
90.
Saha
A
,
Aoyama
K
,
Taylor
PA
, et al
.
Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality
.
Blood
.
2013
;
122
(
17
):
3062
-
3073
.
91.
Greinix
HT
,
Pohlreich
D
,
Kouba
M
, et al
.
Elevated numbers of immature/transitional CD21- B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2008
;
14
(
2
):
208
-
219
.
92.
Corre
E
,
Carmagnat
M
,
Busson
M
, et al
.
Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections
.
Haematologica
.
2010
;
95
(
6
):
1025
-
1029
.
93.
Allen
JL
,
Fore
MS
,
Wooten
J
, et al
.
B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways
.
Blood
.
2012
;
120
(
12
):
2529
-
2536
.
94.
Tedder
TF
.
B10 cells: a functionally defined regulatory B cell subset
.
J Immunol
.
2015
;
194
(
4
):
1395
-
1401
.
95.
Khoder
A
,
Sarvaria
A
,
Alsuliman
A
, et al
.
Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD
.
Blood
.
2014
;
124
(
13
):
2034
-
2045
.
96.
Le Huu
D
,
Matsushita
T
,
Jin
G
, et al
.
Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease
.
Blood
.
2013
;
121
(
16
):
3274
-
3283
.
97.
de Masson
A
,
Bouaziz
JD
,
Le Buanec
H
, et al
.
CD24(hi)CD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease
.
Blood
.
2015
;
125
(
11
):
1830
-
1839
.
98.
Fujii
H
,
Cuvelier
G
,
She
K
, et al
.
Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children’s Oncology Group
.
Blood
.
2008
;
111
(
6
):
3276
-
3285
.
99.
Sarantopoulos
S
,
Stevenson
KE
,
Kim
HT
, et al
.
High levels of B-cell activating factor in patients with active chronic graft-versus-host disease
.
Clin Cancer Res
.
2007
;
13
(
20
):
6107
-
6114
.
100.
Patriarca
F
,
Skert
C
,
Sperotto
A
, et al
.
The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery
.
Exp Hematol
.
2006
;
34
(
3
):
389
-
396
.
101.
Young
JS
,
Wu
T
,
Chen
Y
, et al
.
Donor B cells in transplants augment clonal expansion and survival of pathogenic CD4+ T cells that mediate autoimmune-like chronic graft-versus-host disease
.
J Immunol
.
2012
;
189
(
1
):
222
-
233
.
102.
Miklos
DB
,
Kim
HT
,
Zorn
E
, et al
.
Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors
.
Blood
.
2004
;
103
(
1
):
353
-
359
.
103.
Sahaf
B
,
Yang
Y
,
Arai
S
,
Herzenberg
LA
,
Herzenberg
LA
,
Miklos
DB
.
H-Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease
.
Proc Natl Acad Sci USA
.
2013
;
110
(
8
):
3005
-
3010
.
104.
Svegliati
S
,
Olivieri
A
,
Campelli
N
, et al
.
Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease
.
Blood
.
2007
;
110
(
1
):
237
-
241
.
105.
Spies-Weisshart
B
,
Schilling
K
,
Böhmer
F
,
Hochhaus
A
,
Sayer
HG
,
Scholl
S
.
Lack of association of platelet-derived growth factor (PDGF) receptor autoantibodies and severity of chronic graft-versus-host disease (GvHD)
.
J Cancer Res Clin Oncol
.
2013
;
139
(
8
):
1397
-
1404
.
106.
Jin
H
,
Ni
X
,
Deng
R
, et al
.
Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice
.
Blood
.
2016
;
127
(
18
):
2249
-
2260
.
107.
Sarantopoulos
S
,
Stevenson
KE
,
Kim
HT
, et al
.
Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease
.
Blood
.
2009
;
113
(
16
):
3865
-
3874
.
108.
Forcade
E
,
Kim
HT
,
Cutler
C
, et al
.
Circulating T follicular helper cells with increased function during chronic graft-versus-host disease
.
Blood
.
2016
;
127
(
20
):
2489
-
2497
.
109.
Knorr
DA
,
Wang
H
,
Aurora
M
, et al
.
Loss of T follicular helper cells in the peripheral blood of patients with chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2016
;
22
(
5
):
825
-
833
.
110.
Duffield
JS
,
Forbes
SJ
,
Constandinou
CM
, et al
.
Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair
.
J Clin Invest
.
2005
;
115
(
1
):
56
-
65
.
111.
Gangadharan
B
,
Hoeve
MA
,
Allen
JE
, et al
.
Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages
.
J Leukoc Biol
.
2008
;
84
(
1
):
50
-
58
.
112.
Alexander
KA
,
Flynn
R
,
Lineburg
KE
, et al
.
CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease
.
J Clin Invest
.
2014
;
124
(
10
):
4266
-
4280
.
113.
Erbel
C
,
Akhavanpoor
M
,
Okuyucu
D
, et al
.
IL-17A influences essential functions of the monocyte/macrophage lineage and is involved in advanced murine and human atherosclerosis
.
J Immunol
.
2014
;
193
(
9
):
4344
-
4355
.
114.
Clancy
RM
,
Buyon
JP
.
Clearance of apoptotic cells: TGF-beta in the balance between inflammation and fibrosis
.
J Leukoc Biol
.
2003
;
74
(
6
):
959
-
960
.
115.
Clancy
J
Jr
,
Tonder
O
,
Boettcher
CE
.
The effect of neonatal rat graft-vs-host disease (GVHD) on Fc receptor lymphocytes
.
J Immunol
.
1976
;
116
(
1
):
210
-
217
.
116.
Hechinger
AK
,
Smith
BA
,
Flynn
R
, et al
.
Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD
.
Blood
.
2015
;
125
(
3
):
570
-
580
.
117.
Dubovsky
JA
,
Flynn
R
,
Du
J
, et al
.
Ibrutinib treatment ameliorates murine chronic graft-versus-host disease
.
J Clin Invest
.
2014
;
124
(
11
):
4867
-
4876
.
118.
Flynn
R
,
Allen
JL
,
Luznik
L
, et al
.
Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease
.
Blood
.
2015
;
125
(
26
):
4085
-
4094
.
119.
Johnston
HF
,
Xu
Y
,
Racine
JJ
, et al
.
Administration of anti-CD20 mAb is highly effective in preventing but ineffective in treating chronic graft-versus-host disease while preserving strong graft-versus-leukemia effects
.
Biol Blood Marrow Transplant
.
2014
;
20
(
8
):
1089
-
1103
.
120.
Ohkura
N
,
Kitagawa
Y
,
Sakaguchi
S
.
Development and maintenance of regulatory T cells
.
Immunity
.
2013
;
38
(
3
):
414
-
423
.
121.
Arpaia
N
,
Green
JA
,
Moltedo
B
, et al
.
A distinct function of regulatory T cells in tissue protection
.
Cell
.
2015
;
162
(
5
):
1078
-
1089
.
122.
Sage
PT
,
Sharpe
AH
.
T follicular regulatory cells
.
Immunol Rev
.
2016
;
271
(
1
):
246
-
259
.
123.
Sakaguchi
S
,
Sakaguchi
N
,
Asano
M
,
Itoh
M
,
Toda
M
.
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases
.
J Immunol
.
1995
;
155
(
3
):
1151
-
1164
.
124.
Rezvani
K
,
Mielke
S
,
Ahmadzadeh
M
, et al
.
High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT
.
Blood
.
2006
;
108
(
4
):
1291
-
1297
.
125.
Robb
RJ
,
Lineburg
KE
,
Kuns
RD
, et al
.
Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation
.
Blood
.
2012
;
119
(
24
):
5898
-
5908
.
126.
Zhang
P
,
Tey
SK
,
Koyama
M
, et al
.
Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo
.
J Immunol
.
2013
;
191
(
10
):
5291
-
5303
.
127.
Edinger
M
,
Hoffmann
P
,
Ermann
J
, et al
.
CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation
.
Nat Med
.
2003
;
9
(
9
):
1144
-
1150
.
128.
Taylor
PA
,
Lees
CJ
,
Blazar
BR
.
The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality
.
Blood
.
2002
;
99
(
10
):
3493
-
3499
.
129.
Zorn
E
,
Kim
HT
,
Lee
SJ
, et al
.
Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease
.
Blood
.
2005
;
106
(
8
):
2903
-
2911
.
130.
Rieger
K
,
Loddenkemper
C
,
Maul
J
, et al
.
Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD
.
Blood
.
2006
;
107
(
4
):
1717
-
1723
.
131.
Matsuoka
K
,
Kim
HT
,
McDonough
S
, et al
.
Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation
.
J Clin Invest
.
2010
;
120
(
5
):
1479
-
1493
.
132.
Alho
AC
,
Kim
HT
,
Chammas
MJ
, et al
.
Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD
.
Blood
.
2016
;
127
(
5
):
646
-
657
.
133.
Kawano
Y
,
Kim
HT
,
Matsuoka
K
, et al
.
Low telomerase activity in CD4+ regulatory T cells in patients with severe chronic GVHD after hematopoietic stem cell transplantation
.
Blood
.
2011
;
118
(
18
):
5021
-
5030
.
134.
Suffner
J
,
Hochweller
K
,
Kühnle
MC
, et al
.
Dendritic cells support homeostatic expansion of Foxp3+ regulatory T cells in Foxp3.LuciDTR mice
.
J Immunol
.
2010
;
184
(
4
):
1810
-
1820
.
135.
Coghill
JM
,
Fowler
KA
,
West
ML
, et al
.
CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease
.
Blood
.
2013
;
122
(
5
):
825
-
836
.
136.
Leveque-El Mouttie
L
,
Koyama
M
,
Le Texier
L
, et al
.
Corruption of dendritic cell antigen presentation during acute GVHD leads to a failure of regulatory T-cell homeostasis and chronic GVHD
.
Blood
.
2016
;
128
(
6
):
794
-
804
.
137.
Blair
PA
,
Noreña
LY
,
Flores-Borja
F
, et al
.
CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients
.
Immunity
.
2010
;
32
(
1
):
129
-
140
.
138.
Iwata
Y
,
Matsushita
T
,
Horikawa
M
, et al
.
Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells
.
Blood
.
2011
;
117
(
2
):
530
-
541
.
139.
Kheav
VD
,
Busson
M
,
Scieux
C
, et al
.
Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation
.
Haematologica
.
2014
;
99
(
12
):
1860
-
1867
.
140.
Cooley
S
,
Trachtenberg
E
,
Bergemann
TL
, et al
.
Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia
.
Blood
.
2009
;
113
(
3
):
726
-
732
.
141.
Noval Rivas
M
,
Hazzan
M
,
Weatherly
K
,
Gaudray
F
,
Salmon
I
,
Braun
MY
.
NK cell regulation of CD4 T cell-mediated graft-versus-host disease
.
J Immunol
.
2010
;
184
(
12
):
6790
-
6798
.
142.
Zecher
D
,
Li
Q
,
Oberbarnscheidt
MH
, et al
.
NK cells delay allograft rejection in lymphopenic hosts by downregulating the homeostatic proliferation of CD8+ T cells
.
J Immunol
.
2010
;
184
(
12
):
6649
-
6657
.
143.
Palmer
JM
,
Rajasekaran
K
,
Thakar
MS
,
Malarkannan
S
.
Clinical relevance of natural killer cells following hematopoietic stem cell transplantation
.
J Cancer
.
2013
;
4
(
1
):
25
-
35
.
144.
Inamoto
Y
,
Flowers
ME
.
Treatment of chronic graft-versus-host disease in 2011
.
Curr Opin Hematol
.
2011
;
18
(
6
):
414
-
420
.
145.
Flowers
ME
,
Apperley
JF
,
van Besien
K
, et al
.
A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease
.
Blood
.
2008
;
112
(
7
):
2667
-
2674
.
146.
Martelli
MF
,
Di Ianni
M
,
Ruggeri
L
, et al
.
HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse
.
Blood
.
2014
;
124
(
4
):
638
-
644
.
147.
Robinson
TM
,
O’Donnell
PV
,
Fuchs
EJ
,
Luznik
L
.
Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide
.
Semin Hematol
.
2016
;
53
(
2
):
90
-
97
.
148.
Yu
Y
,
Wang
D
,
Liu
C
, et al
.
Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice
.
Blood
.
2011
;
118
(
18
):
5011
-
5020
.
149.
Cohen
JL
,
Trenado
A
,
Vasey
D
,
Klatzmann
D
,
Salomon
BL
.
CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease
.
J Exp Med
.
2002
;
196
(
3
):
401
-
406
.
150.
Hoffmann
P
,
Ermann
J
,
Edinger
M
,
Fathman
CG
,
Strober
S
.
Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation
.
J Exp Med
.
2002
;
196
(
3
):
389
-
399
.
151.
Di Ianni
M
,
Falzetti
F
,
Carotti
A
, et al
.
Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation
.
Blood
.
2011
;
117
(
14
):
3921
-
3928
.
152.
Brunstein
CG
,
Miller
JS
,
McKenna
DH
, et al
.
Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect
.
Blood
.
2016
;
127
(
8
):
1044
-
1051
.
153.
McDonald-Hyman
C
,
Flynn
R
,
Panoskaltsis-Mortari
A
, et al
.
Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner
.
Blood
.
2016
;
128
(
7
):
1013
-
1017
.
154.
Koreth
J
,
Kim
HT
,
Jones
KT
, et al
.
Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease
.
Blood
.
2016
;
128
(
1
):
130
-
137
.
155.
Koreth
J
,
Matsuoka
K
,
Kim
HT
, et al
.
Interleukin-2 and regulatory T cells in graft-versus-host disease
.
N Engl J Med
.
2011
;
365
(
22
):
2055
-
2066
.
156.
Cutler
C
,
Kim
HT
,
Bindra
B
, et al
.
Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial
.
Blood
.
2013
;
122
(
8
):
1510
-
1517
.
157.
Arai
S
,
Pidala
J
,
Pusic
I
, et al
.
A randomized phase II crossover study of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell transplantation
.
Clin Cancer Res
.
2016
;
22
(
2
):
319
-
327
.
158.
Spoerl
S
,
Mathew
NR
,
Bscheider
M
, et al
.
Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease
.
Blood
.
2014
;
123
(
24
):
3832
-
3842
.
159.
Zeiser
R
,
Burchert
A
,
Lengerke
C
, et al
.
Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey
.
Leukemia
.
2015
;
29
(
10
):
2062
-
2068
.
160.
Pai
CC
,
Chen
M
,
Mirsoian
A
, et al
.
Treatment of chronic graft-versus-host disease with bortezomib
.
Blood
.
2014
;
124
(
10
):
1677
-
1688
.
161.
Banovic
T
,
MacDonald
KP
,
Morris
ES
, et al
.
TGF-beta in allogeneic stem cell transplantation: friend or foe?
Blood
.
2005
;
106
(
6
):
2206
-
2214
.

Author notes

*

G.R.H. and B.R.B. contributed equally.