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Review Series

CHRONIC GRAFT-VERSUS-HOST DISEASE

Chronic graft-versus-host disease: biological insights from preclinical

and clinical studies
Kelli P. A. MacDonald,1 Geoffrey R. Hill,2,3,* and Bruce R. Blazar4,*
1
The Antigen Presentation and Immunoregulation Laboratory and 2Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute,
Brisbane, Australia; 3The Royal Brisbane and Women’s Hospital, Brisbane, Australia; and 4Masonic Cancer Center and the Division of Blood and Marrow
Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN

With the increasing use of mismatched, combination of mouse models and correl- can, in concert with colony-stimulating
unrelated, and granulocyte colony- ative clinical studies, has radically im- factor 1 (CSF-1)-dependent donor macro-
stimulating factor–mobilized peripheral proved. We now understand that cGVHD phages, induce a transforming growth
blood stem cell donor grafts and success- is initiated by naive T cells, differentiating factor b–high environment locally within
ful treatment of older recipients, chronic predominantly within highly inflammatory target tissue that results in scleroderma
graft-versus-host disease (cGVHD) has T-helper 17/T-cytotoxic 17 and T-follicular and bronchiolitis obliterans, diagnostic
emerged as the major cause of nonrelapse helper paradigms with consequent thymic features of cGVHD. These findings have
mortality and morbidity. cGVHD is char- damage and impaired donor antigen pre- yielded a raft of potential new therapeu-
acterized by lichenoid changes and fibro- sentation in the periphery. This leads to tics, centered on naive T-cell depletion,
sis that affects a multitude of tissues, aberrant T- and B-cell activation and interleukin-17/21 inhibition, kinase inhibi-
compromising organ function. Beyond differentiation, which cooperate to gener- tion, regulatory T-cell restoration, and
steroids, effective treatment options are ate antibody-secreting cells that cause the CSF-1 inhibition. This new understanding
limited. Thus, new strategies to both pre- deposition of antibodies to polymorphic of cGVHD finally gives hope that effective
vent and treat disease are urgently re- recipient antigens (ie, alloantibody) or therapies are imminent for this devastat-
quired. Over the last 5 years, our nonpolymorphic antigens common to ing transplant complication. (Blood. 2017;
understanding of cGVHD pathogene- both recipient and donor (ie, autoanti- 129(1):13-21)
sis and basic biology, born out of a body). It is now clear that alloantibody

Introduction
Chronic graft-versus-host disease (cGVHD) remains the major cause of patients receive some form of conditioning, nonconditioned murine
morbidity and nonrelapse mortality after allogeneic hematopoietic stem cGVHD models will not be discussed in this review; instead, we refer
cell transplantation (SCT).1-3 Progress in improving cGVHD preven- the reader to Chu et al.9
tion 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 cGVHD manifestations and initiating factors in
preclinical models. Such progress has been supported by analysis of the clinic
human materials acquired from cGVHD patients.
This review draws from animal model and clinical studies to cGVHD typically manifests with multiorgan pathology and historically
provide an overview; we combined interpretation of our current under- has been defined temporally as GVHD that occurred later than 100 days
standing of the cellular and molecular mediators of cGVHD. In turn, we post-SCT. The commonly seen diagnostic features, as outlined by the
highlight promising new therapeutic approaches. Additionally, we will National Institutes of Health (NIH) consensus criteria,14 include skin
provide our perspective on the gaps in cGVHD basic biology that pathology varying from lichen planus–like lesions to full sclerosis,
deserve more attention as the prevalence of clinical cGVHD grows. bronchiolitis obliterans (BO), and oral lichen planus–like lesions (ie,
Finally, we will review translation of current and possible future skin, lung, and mouth involvement). Esophageal webs and strictures
cGVHD therapies that have evolved from cGVHD basic biological and muscle or joint fasciitis are also diagnostic. Importantly, these
insights. diagnostic features can be seen before day 100 and may occur
Because no individual review can cover all aspects of cGVHD simultaneously with features commonly seen in acute GVHD
pathogenesis and preclinical studies leading to clinical applications, the (aGVHD) (eg, macular-papular rashes, weight loss, diarrhea, and
reader is referred to several excellent reviews on this subject.8-13 Mouse hepatitis). Thus, cGVHD occurs as a continuum in time with clinical
models have served as a mainstay for recent advances in cGVHD features that are distinct from, but not mutually exclusive with, those
therapies, and hence, will be a focus of this review. As virtually all seen in aGVHD.

Submitted 3 June 2016; accepted 6 July 2016. Prepublished online as Blood © 2017 by The American Society of Hematology
First Edition paper, 7 November 2016; DOI 10.1182/blood-2016-06-686618.

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

BLOOD, 5 JANUARY 2017 x VOLUME 129, NUMBER 1 13

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14 MacDONALD et al BLOOD, 5 JANUARY 2017 x VOLUME 129, NUMBER 1

Over the last decade granulocyte colony-stimulating factor (G-CSF)- negative selection and loss of regulatory T-cell (Treg) production (see
mobilized peripheral blood stem cell (G-PBSC) grafts have been “Immune regulators of cGVHD”).23,36-38 Conversely, strategies that
rapidly adopted as an increasingly used stem cell source for SCT. prevent or treat cGVHD may be efficacious if they inhibit aGVHD,
From its inception, it was clear that G-CSF exerts immunomodu- whereas in settings in which aGVHD is no longer present, successful
latory effects on the graft,15-17 resulting in altered transplant outcomes cGVHD therapy approaches must focus on reversing fibrosis, if
in patients receiving G-PBSC grafts as compared with unmanipulated debilitating, and any ongoing immune mechanisms that continue to
bone marrow (BM) grafts, with the primary advantage of G-PBSC grafts propagate the cGVHD injury response.
being accelerated engraftment. A randomized trial of BM vs G-PBSC Further complicating the analysis of cGVHD pathogenesis using
revealed similar overall survival with secondary end points showing preclinical models are the specifics of cGVHD generation. As in
that G-PBSC grafts provided decreased graft failure but increased patients, variables that can contribute to differences in cGVHD
cGVHD incidence.18,19 Consistent with G-CSF immune-regulatory pathogenesis and its manifestations between laboratories in-
effects on PBSCs, aGVHD incidence was similar despite the higher clude radiation dose/source/dose rate, use of chemotherapy,
T-cell dose that accompanied G-PBSC grafts. Risk factors for subset and numbers of infused donor T cells, and hematopoietic
cGVHD development include preceding aGVHD, use of PBSCs,18 stem cell (HSC) source and manipulations, if any. Other key
use of mismatched or unrelated donors (as opposed to matched variables may include mouse vendors 39 and distinct microbiome
siblings), transplant of female donors to male recipients, absence of colonization as well as antibiotic usage in each mouse colony
antithymocyte globulin in conditioning, and older recipients.20 that has been shown to affect immune responses,40,41 including
Given the expanding allogeneic SCT and G-PBSC graft use as well aGVHD in mouse 42,43 and humans. 44 Recipient age may be a
as the treatment of older recipients who historically were not candi- factor as older mice have augmented allostimulatory function. 45
dates for allogeneic SCT, it is not surprising that the prevalence of Although in most cGVHD models, donor and host strains are
cGVHD has reached new heights. 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
Overview of mouse models and generation in minor histocompatibility antigen (miH)-only dispa-
cGVHD pathogenesis rate models, though such strain combinations are frequently used for
analysis of cGVHD pathogenesis. Rather, we favor the explanation
With clinical cGVHD heterogeneity and frequent preceding aGVHD that the intensity of the GVHD response and responding T-cell type
manifestations, it is somewhat surprising that GVHD models in mice (CD4 vs CD8 subset and differentiation stage, cytokine profile,
have been described in the literature with such a clear demarcation as chemokine/integrin expression levels) are the major determining
representing aGVHD or cGVHD. Similar to patients, it is now clear that factors for aGVHD vs cGVHD independent of the type (major
transplanted mice receiving pre-SCT conditioning regimens, typically histocompatibility complex [MHC] and/or miH) of antigenic dispar-
radiation-containing, can progress through a continuum of aGVHD to ities between donor and host. This hypothesis is supported by the fact
cGVHD which can evolve over time.21 In fact, autoreactive T cells that miH only as well as models in which MHC antigen disparities are
can coexist with or emerge from alloreactive T cells.22-24 Indeed, present each have been reported to induce aGVHD and cGVHD,
many aGVHD model systems have been adapted to infuse lower dependent upon transplant conditions. Therefore, our collective
donor T-cell numbers25-27 or use G-CSF treatment of donors,28 recommendation is for the field to focus on discussing the
permitting mice to escape uniform aGVHD lethality and donor immunological and pathophysiological mechanisms that result in
T cells to chronically receive T-cell receptor (TCR) signals from cGVHD, not the system used. As such, we have chosen not to
host or donor alloantigen/peptide-expressing cells. Features of summarize particular strain combinations and SCT conditions that have
cGVHD can be seen in most “aGVHD” models if T-cell doses are been reported to cause cGVHD that is typically a part of such reviews.
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 Relationship between aGVHD and
cGVHD is the typical tissue inflammatory T-cell infiltrate and cGVHD pathogenesis
destructive features of aGVHD and the relatively acellular, fibropro-
liferative findings in cGVHD. In particular, scleroderma,15,16,22,23 The initiation of and resultant target organ injury observed in both
BO,25 and fibrosis in liver, gastrointestinal tract, salivary glands, and aGVHD and cGVHD is a consequence of the coordinated interplay
tongue can be seen in cGVHD mouse models.26,27,29 Intriguingly, between multiple cellular and molecular immune mediators that is
many, but not all, cGVHD appear to have either scleroderma (reviewed dependent on the presence and function of donor graft T cells.49
in Reddy et al30) or multiorgan system involvement without sclero- Following SCT, tissue injury and inflammation characterized by
derma as their predominant manifestations, further highlighting the fact proinflammatory cytokine release (eg, tumor necrosis factor [TNF],
that no single model can replicate the wide spectrum of clinical interleukin-6 [IL-6], and IL-1) is initiated by the conditioning regimen
manifestations which themselves are not all seen in an individu- that would be common for both aGVHD and cGVHD, especially
al patient. There are no unique strain combinations that only cause in the clinic, as both diseases can emanate in patients who receive
cGVHD and are incapable of experiencing aGVHD if conditions are the transplantation procedure. These cytokines, together with luminal
modified to favor aGVHD. Because aGVHD can attack the thymus, damage-associated molecular patterns and pathogen-associated molec-
BM, and secondary lymphoid organs (SLOs), preceding aGVHD, ular patterns released from damaged gut tissue and the microbial luminal
even at a subclinical level in mice and patients, may have profound contents, result in the activation of antigen-presenting cells (APCs).
immunological manifestations resulting in T-cell or especially B-cell Activated APCs then prime naive donor T cells and preferentially drive
depletion31-33 or loss of thymic function34,35 that results in failed T-helper 1 (Th1)/T-cytotoxic 1 (Tc1) and Th17/Tc17 differentiation and
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BLOOD, 5 JANUARY 2017 x VOLUME 129, NUMBER 1 BASIC BIOLOGY OF cGVHD 15

expand T-effector cells, which can mediate target tissue GVHD, recently, aGVHD was largely considered Th1-dominated, whereas
including the thymus and SLO, as well as the skin, liver, gastrointes- cGVHD was considered to represent a Th2-mediated disease.12,61
tinal tract, and lung, likely predisposing to cGVHD later after SCT. This notion had its support in studies showing differential cytokine
Whereas aGVHD is generally defined as a Th1/Th17 paradigm, expression in aGVHD and cGVHD mice,62 Th2 cell accumulation in
which results in extensive tissue destruction characterized by apoptosis, cGVHD mice,63 the relationship between G-PBSC, Th2/plasmacytoid
cGVHD and aGVHD in fact may share initiating mechanisms. For dendritic cell (DC) skewing, and the higher incidence of cGVHD in
example, Th17/Tc17 cells have been shown, in some but not all patients.15,16,18 However, in both mice64 and humans,65 there is not a
systems, to cause either aGVHD50-52 or sclerodermatous cGVHD.28,53 clear paradigm demonstrating that Th1 cells are required for aGVHD,
Although donor natural killer (NK) cells, Tregs, regulatory B cells whereas Th2 cells cause cGVHD.
(Bregs), and macrophages play important roles in dampening both Recently, the Th/Tc17 pathway has been shown to promote
aGVHD and cGVHD (see “Immune regulators of cGVHD”), the role pathogenic autoimmune-mediated organ damage in multiple sclerosis,
of B cells in controlling aGVHD pathogenesis in murine models is rheumatoid arthritis, inflammatory bowel disease, and psoriasis.66 In
more controversial.54-56 In cGVHD, there is a preponderance of systemic sclerosis, a condition closely resembling sclerodermatous
evidence for an interplay between donor T cells and donor B cells for cGVHD, fibrosis, is mediated by Th17 cells infiltrating the skin
disease pathogenesis (see “Immune regulators of cGVHD”). In this and serum IL-17 levels positively correlate with disease severity.67,68
section, we define the contribution of each of these mediators to Preclinical and clinical data support a role for IL-17 as a predictor69 and
cGVHD pathology as instructed by preclinical studies with central mediator of pathology, especially the skin.28,53,70,71 In a
confirmation in the clinical setting where applicable. 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
Thymic and peripheral T-cell selection defects thickening, loss of subcutaneous fat and hair follicles, and increased
resulting in cGVHD cellular infiltrate) and cutaneous fibrosis, manifesting as scleroderma,
providing a logical explanation for the propensity of G-PBSCs to
The donor graft T-cell compartment is composed of antigen-inexperienced invoke sclerodermatous cGVHD and highlighting Tc17 as an important
naive and antigen-experienced T-effector and memory subsets. In both cGVHD effector population. In clinical cGVHD studies, increased
preclinical and clinical studies, naive T-cell–depleted grafts have a IL-17 messenger RNA transcripts and significant Tc17 infiltration were
significantly reduced cGVHD incidence, while allowing transferred demonstrated in skin,72 whereas in the oral mucosa, Th17 infiltration
memory T cells to contribute to immune reconstitution and protective dominated. Cytokines (IL-6, IL-21) known to support Th17 generation
immunity.57,58 As briefly mentioned above, failed intrathymic deletion in GVHD are elevated in GVHD,73-76 and STAT3, which drives Th17
of “autoreactive” donor T cells can also contribute to cGVHD as development and Th17-dependent autoimmunity,77 is essential for
evidenced by cGVHD induced by reconstitution of murine recipients CD41 T-cell–mediated sclerodermatous cGVHD.78 Lichenoid cGVHD
with T-cell–depleted BM from allogeneic MHC class II–deficient in patients has coexisting Th1 and Th17 cells with increased CD81
donors that precludes thymic DC-mediated negative selection of T cells producing IL-17 and IFNg,72,79 and IL-17 is systemically
maturing T cells.38 Intriguingly, thymectomy can prevent cGVHD elevated late after SCT as cGVHD develops.76 In multiple disease
pathology, suggesting that thymic dysfunction in cGVHD recipients models including GVHD, both Th17 and Tc17 cells coexpress multiple
favors selection of autoreactive and alloreactive T cells. Moreover, proinflammatory cytokines (eg, IL-22, IFNg, granulocyte-macrophage
cGVHD and/or its therapy themselves are highly detrimental to colony-stimulating factor [GM-CSF]) and exhibit significant functional
thymic function.59 The possibility of shared mechanisms in the plasticity.50,80-83 Just how these IL-17–producing T cells generate
thymus and periphery is suggested by the finding of defective APC fibrosis remains to be elucidated but some clear pathways have been
function in aGVHD mice.60 Collectively, these mechanisms can highlighted and are outlined in the following list.
facilitate the emergence of self-reactive thymic emigrants and Burgeoning areas of investigation include analysis of:
cGVHD induction caused by the de novo generation of both
1. TCR repertoires in the blood and organs of cGVHD mice and
autoreactive and alloreactive donor CD41 T cells as indicated by
patients to determine whether there are dominant TCR clones
their capacity to induce cGVHD pathology upon their adoptive
that cause cGVHD;
transfer in both syngeneic and allogeneic secondary recipients.24
2. Chemokine-facilitated migratory properties of T-effector cells
Conversely, keratinocyte growth factor administration, by reduc-
in cGVHD84,85; and
ing aGVHD-induced thymic injury, can improve thymopoiesis
3. The metabolic state of cGVHD T-effector cells that may
and restore thymic DC, resulting in amelioration of cGVHD.24
suggest interventional approaches to prevent or treat cGVHD,
In summary, both mature T cells contained within the graft and
as has been shown in preclinical aGVHD models.86-90
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.
B cells and antibodies in cGVHD
pathogenesis
T-cell effector mechanisms driving Emerging evidence supports an important role for donor B cells in both
cGVHD pathology the initiation and perpetuation of cGVHD. In both mice and humans,
B-cell homeostasis and tolerance mechanisms are disrupted after
Conventional T cells can be broadly divided into Th1/Tc1 (interferon g SCT, resulting in reduced memory B-cell formation and enrichment of
[IFNg]), Th17/Tc17 (IL-17), and Th2 (IL-4/IL-10) subsets. Until activated transitional B cells in the reconstituting donor B-cell pool.91-93
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16 MacDONALD et al BLOOD, 5 JANUARY 2017 x VOLUME 129, NUMBER 1

A correlation between reduced IL-10–producing Bregs (B10 cells94) and clinical cGVHD, macrophages have been shown to accumulate in
and cGVHD severity is increasingly reported.95-97 B-cell–activating fibrotic lesions.28,72,112 However, the factors promoting macrophage
factor (BAFF), a cytokine critical for B-cell survival and maturation, is tissue sequestration, and their mechanistic contribution to pathology
found in excess levels in patients with active cGVHD, resulting in have only recently been examined. In preclinical cGVHD models
increased BAFF-to-B-cell ratios.98,99 In the setting of elevated BAFF characterized by scleroderma or BO with multiorgan system fibrosis
levels, B cells reactive against polymorphic recipient (allo) or but without scleroderma, the sequestration of macrophages within skin
nonpolymorphic antigens shared by donor and host (auto)antigens, and lung, and the subsequent development of cGVHD pathology,
normally targeted for apoptotic death through negative selection, are was shown to be both IL-17 and colony-stimulating factor 1 (CSF-1)
protected and persist. Indeed, the association of BAFF and autoanti- dependent.28,112 Tissue-infiltrating macrophages were of donor
body production in cGVHD patients has been reported.99 Recent origin, alternatively activated (skewed toward anti-inflammatory
preclinical studies in a multiorgan nonsclerodermatous cGVHD model responses) as indicated by their expression of CD206 rather than
have demonstrated the requirement for increased T-follicular helper inducible NO synthase, and promoted pathology through their
cells (Tfh), germinal center (GC) B cells, and antibody which accu- production of transforming growth factor b (TGFb), a key cytokine
mulates in target tissues, resulting in the development of some, although for myofibroblast activation and collagen production. Importantly,
not all, manifestations of cGVHD.26,29,100,101 Tfh cells produce IL-21, a the attenuation of CSF-1 receptor (CSF-1R) signaling using an
cytokine known to be critical for GC formation and the cutaneous and anti-CSF-1R–blocking antibody depleted circulating and tissue-
pulmonary manifestations of cGVHD.28,29 Alloantibodies (predomi- associated Ly6Clo monocytes, ablated tissue-infiltrating macro-
nantly to HY antigen) have been well described in cGVHD and phages, and markedly attenuated both cutaneous and preexisting
correlate with disease activity.47,48,102,103 Autoantibodies are widely pulmonary cGVHD.112 The mechanism by which IL-17 contrib-
detected in patients with cGVHD. Although initial reports suggested utes to pathogenic macrophage migration and differentiation in
that antibodies to the platelet-derived growth factor receptor may be cGVHD target organs remains undefined. However, IL-17 has
pathogenic,104 this finding has been debated.105 Mechanistically, the been reported to function as a monocyte chemokine, to promote
aberrant GC B-cell reaction seen in cGVHD results in antibody monocyte adhesion and elicit a proinflammatory transcriptome in
formation.29 Elegant serum transfer experiments have now shown that macrophages, suggesting direct signaling of this lineage may
antibody can be directly pathogenic and initiate disease.106 Increasing be involved.113 Other proinflammatory cytokines coproduced
BAFF concentrations have been associated with pre-GC B cells and by Tc17/Th17 such as GM-CSF50 may contribute synergistically
post-GC plasma-like cells in patients,107 which may be the result of to macrophage differentiation/polarization at localized sites.
either GC or extrafollicular B-cell responses, mechanisms yet to be Macrophages express very high levels of Fc-g receptors and are
determined in patients. Although peripheral blood Tfh cell frequency highly efficient at opsonization of antibody-coated targets which in turn
has been reported to be reduced in patients with cGVHD,108,109 Tfh can generate very high levels of TGFb.114,115 Consistent with a link
cells were skewed toward a highly activated profile with a predom- between antibody secretion and fibrosis, mice incapable of producing
inance of Th2 and Th17 (IL-17, IL-21 producing) subsets, increased B cells or that produce B cells incapable of immunoglobulin
functional ability to promote B-cell immunoglobulin secretion and isotype switching,26 or that receive agents that either preclude GC
maturation, and an activation signature highly correlated with formation29,73,116 or deplete B cells29,117-119 are unable to induce
increased B-cell activation and plasmablast maturation.108 Because fibrosis or cGVHD. Thus, although unproven at this point, the
in rodents GC B cells were quantified in the spleen, a plausible interaction of allo-(and/or auto) antibody with tissue macrophages
explanation for the reduced peripheral blood Tfh frequency in would appear an attractive unifying mechanism driving the aberrant
cGVHD is that the Tfh cells are localized in GCs within SLOs. macrophage differentiation and function that culminates in tissue
However, cGVHD therapy or GVHD-induced injury to lymphoid fibrosis during cGVHD.
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 autoan- Immune regulators of cGVHD
tibody formation, it remains to be established whether the
pathogeneic antibodies in question are directed solely to allogeneic Immune populations contained within the graft or that emerge from graft
polymorphic antigens or also to nonpolymorphic “autologous” progeny can exhibit immune-modulatory capacity.120 Tregs, defined by
antigens shared by donor and recipient. Moreover, it is unclear their coexpression of CD4, CD25, and the master transcription factor
whether antibody-dependent mechanisms are operative in all FoxP3, are critical for the control of innate and adaptive immune responses
recipients with cGVHD, or only a subset; also unclear is the and can mediate tissue regeneration via amphiregulin release.121 GC
mechanism by which antibody initiates fibrosis and the cellular migratory Tregs, known as T-follicular regulatory cells, suppress GC
mediators involved remain to be elucidated. 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
Role of macrophages in cGVHD pathogenesis aGVHD,124-128 and cGVHD is associated with decreased numbers of
circulating Tregs.21,129-131 Factors contributing to diminished Treg
Fibrotic injury is characterized by excessive accumulation of extracel- numbers in cGVHD recipients remain to be fully elucidated although
lular matrix (predominantly collagen) and fibroblasts, which replace there are multiple candidates including diminished thymic production,
parenchymal cells and impair normal tissue function. Macrophages reduced proliferative capacity of naive Tregs,132 and a failure in memory
play a crucial role in the tissue-repair response, are found in close Treg survival due to their increased susceptibility to apoptosis.131,133 DCs
proximity with collagen-producing fibroblasts and as demonstrated in play an important role in the maintenance of Tregs in steady state and
multiple disease models, contribute to fibrosis.110,111 In both preclinical following SCT,88,134,135 including cGVHD.88,134-136 However, in recent
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BLOOD, 5 JANUARY 2017 x VOLUME 129, NUMBER 1 BASIC BIOLOGY OF cGVHD 17

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 (MF), which are polarized toward an M2 phenotype under the influence of multiple
proinflammatory cytokines (GM-CSF, IL-22, IL-13, and IFNg) produced by Th17/Tc17. Plasma cell–derived allo/autoantibodies (Ab) can bind to Fc receptors on
macrophages, contributing to their polarization and promotion of TGFb secretion, which promotes fibroblast activation and collagen production. Fc, receptor for
immunoglobulins; Tallo, alloreactive T cell; TEFF, effector T cell.

preclinical studies, donor DC MHC class II antigen presentation was

shown to be impaired during aGVHD, and this resulted in a failure of Treg New therapeutic strategies based on recent
homeostasis that promoted cGVHD pathology.60,136 insights to pathophysiology
Although less well studied, altered Breg and NK development after
SCT is thought to contribute to cGVHD. Breg function to suppress Treatment of cGVHD is currently based on steroid administration
immune responses through multiple IL-10 and cell-cell contact- and although many other approaches, including additional immune
dependent mechanisms, including suppression of CD4 T-cell prolif- suppressants, UVB phototherapy, and extracorporeal photopho-
eration and IFNg production, and monocyte TNF production.137,138 resis are commonly used, none have proven clearly effective.144,145
In patients with cGVHD, recent studies show that Breg numbers, Thus, well-designed prospective studies based on NIH response
including immunoglobulin M memory and transitional subsets, are criteria and our new understanding of cGVHD pathophysiology are
reduced and exhibit a diminished capacity to produce IL-10.95,97 needed. We now know that cGVHD develops via a complex
Enhanced NK reconstitution has also been shown to correlate with cellular and molecular network involving thymic damage and
reduced incidence of cGVHD in the clinical setting,139 although not all aberrant antigen presentation leading to aberrant T- and B-cell
studies show an inverse correlation between alloreactive NK cells and reaction characterized by Th17/Tc17 differentiation, macrophage
cGVHD.140 Mechanistically, in preclinical studies, NK cells contribute sequestration in tissue, alloantibody formation, and TGFb-dependent
to the regulation of CD4 and CD8 T-cell expansion through Fas- fibrosis (Figure 1). Collectively, these studies highlight a number of
mediated killing and competition for IL-15, respectively.141,142 therapeutic options. From a preventative aspect, the direct removal of
Additionally, NK cells also produce cytokines that promote tissue naive ab T cells from the graft (eg, using in vitro magnetic-based
regeneration, although whether this represents a functioning cGVHD antibody approaches of T-cell removal or CD341 stem cell selection)
mechanism remains to be investigated.143 Together, these studies 58,146
or depletion of differentiating T cells early after transplant (eg,
highlight the potential clinical utility of therapeutic strategies, which by administering posttransplant cyclophosphamide to preferentially
promote the expansion of Bregs and NK cells after transplant. deplete alloreactive T cells while sparing Tregs)147 appears highly
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18 MacDONALD et al BLOOD, 5 JANUARY 2017 x VOLUME 129, NUMBER 1

effective at eliminating cGVHD. Approaches to inhibit the more

terminal stages of aberrant (Th17/Tfh) T-cell development in Acknowledgments
cGVHD include small-molecule RORgt148 or STAT3 inhibitors
and antibody-based therapeutics targeting IL-17 or IL-21 and their The authors thank members of their laboratories, their collaborators,
receptors.28,29 and the scientific community for providing the foundation for this
Strategies to enhance Treg numbers after SCT including Treg review. The authors apologize to those investigators whose work
adoptive therapy to reconstitute the Treg pool have been adopted from they were unable to cite here. Lastly, the authors thank the patients
rodent studies and are showing potential in the clinic.127,128,146,149-152 who have participated in clinical studies that have fostered the
Recent preclinical studies show that Treg adoptive transfer can advancement of the new therapies for this devastating disease.
both prevent and treat cGVHD in mice with multiorgan system This work was supported by grants from the Australian National
disease.136,153 Given the failure of Tregs during cGVHD and the Health and Medical Research Council (NH&MRC) APP1031728
challenges of generating sufficient Tregs for adoptive transfer to (K.P.A.M.), National Institutes of Health, National Cancer Institute
treat cGVHD patients, restorative approaches to date have focused grants P01 CA142106-06A1 and P01 CA047741-20, National
on low-dose IL-2 administration to expand Tregs in vivo with Institutes of Health, National Institute of Allergy and Infectious
;50% of patients showing Treg expansion and some clinical Diseases grants P01 AI056299 and R01 AI11879, and Leukemia &
response as long as therapy is continued.154,155 Recently, the Lymphoma Society Translational Research grant 6458-15 and 6462-
adoptive transfer of Tregs with or without IL-2 and/or rapamycin 15 (B.R.B.). G.R.H. is a NH&MRC Senior Principal Research
has begun to be tested in clinical trials in an effort to increase the Fellow and Queensland Health Senior Clinical Research Fellow.
proportion and depth of patient response. K.P.A.M. is a Cancer Council Queensland Senior Research Fellow.
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 Authorship
strategy, likely due to the more effective B-cell depletion than that
of antibody-secreting plasmablasts and plasma cells formed Contribution: K.P.A.M., G.R.H., and B.R.B. wrote the paper.
after cGVHD is established.156,157 Pursuing pharmacological Conflict-of-interest disclosure: The authors declare no competing
agents that inhibit B- (with or without T-) cell activation, financial interests.
differentiation, and GC integrity by kinase inhibition (eg, Syk ORCID profiles: K.P.A.M., 0000-0003-3451-4221; G.R.H.,
kinase, fostamatinib118; Bruton kinase; ibrutinib117; Rho-associated 0000-0003-2994-0429.
kinase, KD025,73 and Janus kinase-1, ruxolitinib158) has a strong Correspondence: Kelli P. A. MacDonald, Antigen Presentation
biological foundation, as confirmed in part by promising early clinical and Immunoregulation Laboratory, QIMR Berghofer Medical
results already achieved with ruxolitinib159 and ibrutinib. At the most Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia;
final stage of aberrant B-cell response, depletion of alloantibody- e-mail: [email protected]; Geoffrey R. Hill,
producing plasma cells by proteosome inhibition (eg, bortezomib) is Bone Marrow Transplantation Laboratory, QIMR Berghofer
supported by evidence of efficacy in animal systems and early clinical Medical Research Institute, 300 Herston Rd, Herston, QLD 4006,
studies.160 Finally, targeting macrophages by preventing differenti- Australia; e-mail: [email protected]; and Bruce R.
ation and survival in tissue through the inhibition of CSF-1R has Blazar, Department of Pediatrics, Division of Blood and Marrow
proven highly effective in animal systems,112 as has the inhibition of Transplantation, University of Minnesota, MMC 109, 420 SE
TGFb.112,161 Delaware St, Minneapolis, MN 55455; e-mail: [email protected].

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 From www.bloodjournal.org by guest on April 8, 2019. For personal use only.

2017 129: 13-21

doi:10.1182/blood-2016-06-686618 originally published
online November 7, 2016

Chronic graft-versus-host disease: biological insights from preclinical

and clinical studies
Kelli P. A. MacDonald, Geoffrey R. Hill and Bruce R. Blazar

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