KJH
`THE KOREAN JOURNAL OF HEMATOLOGY
`~
`
`V O L U M E 4 6 (cid:564) N U M B E R 2 (cid:564) J u n e 2 0 1 1
`
`R E V I E W A R T I C L E
`
`The pathophysiology of chronic graft-versus-host disease: the
`unveiling of an enigma
`Chang-Ki Min
`Division of Hematology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
`
`p-ISSN 1738-7949 / e-ISSN 2092-9129
`DOI: 10.5045/kjh.2011.46.2.80
`Korean J Hematol 2011;46:80-7.
`
`Received on June 9, 2011
`Accepted on June 10, 2011
`
`*This study was supported by the Korea
`Healthcare Technology R&D Project,
`Ministry of Health, Welfare & Family
`Affairs, Republic of Korea (grant no.
`A092258).
`
`Correspondence to
`Chang-Ki Min, M.D.
`Department of Internal Medicine, Seoul St.
`Mary’s Hospital, The Catholic University
`of Korea, 505 Banpo-dong, Seocho-gu,
`Seoul 137-701, Korea
`Tel: (cid:1024)82-2-2258-6053
`Fax: (cid:1024)82-2-599-3589
`E-mail: ckmin@catholic.ac.kr
`(cid:59926) 2011 Korean Society of Hematology
`
`Chronic graft-versus-host disease (CGVHD) is one of the most significant complications
`of long-term survivors after allogeneic hematopoietic stem cell transplantation
`(allo-HSCT). CGVHD may have protean manifestations and can pose unique diagnostic
`and therapeutic challenges. New recommendations that emphasize the importance of
`qualitative differences, as opposed to time of onset after HSCT, are now being used to
`standardize the diagnosis and clinical assessment of CGVHD, but they require validation.
`During the past 3 decades, experimental studies and clinical observations have elucidated
`the mechanisms of acute GVHD, but its biology is much less well-understood.
`Experimental studies have generated at least 4 theories to explain the pathophysiology
`of CGVHD: (1) thymic damage and the defective negative selection of T cells, (2) regu-
`latory T cell deficiencies, (3) auto-antibody production by aberrant B cells, and (4) the
`formation of profibrotic lesions. Mouse models have provided important insights into
`the pathophysiology of CGVHD, and these have helped improve clinical outcomes follow-
`ing allo-HSCT, but no animal model fully replicates all of the features of CGVHD in humans.
`In this article, recent clinical changes, the pathogenesis of CGHVD, the cellular and cyto-
`kine networks implicated in its pathogenesis, and the animal models used to devise strat-
`egies to prevent and treat CGVHD are reviewed.
`
`Key Words Chronic graft-versus-host disease, Pathophysiology, Acute graft-versus-
`host disease, Fibrosis, Mouse model
`
`INTRODUCTION
`
` Chronic graft-versus-host disease (CGVHD) remains a ma-
`jor cause of late morbidity and mortality after allogeneic
`hematopoietic stem cell transplantation (allo-HSCT) [1]. The
`incidence of CGVHD following allo-HSCT ranges from 25%
`to 80%; the occurrence of CGVHD is associated with immune
`dysfunction and thus, a risk of infection and reduced quality
`of life [2], even though CGVHD is also associated with a
`lower relapse rate, presumably because of graft-versus-leuke-
`mia effects [3]. Over the past 10 years, CGVHD has emerged
`as the most troublesome complication of allo-HSCT. Impro-
`vements in human histocompatibility antigen (HLA) typing
`for unrelated transplantation, the adoption of new acute
`GVHD prophylaxis measures, reductions in conditioning reg-
`imen intensity, the introduction of new antimicrobial agents,
`and advances in supportive care have all helped to mitigate
`early morbidity and mortality in patients after allo-HSCT.
`However, because more and more patients survive the early
`post-transplant period, the number of individuals at risk
`• •o
`This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
`which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
`for CGVHD continues to grow. This trend, in conjunction
`with the escalating use of mobilized peripheral blood cells
`as a preferred stem cell source, has led to a significant increase
`in the number of transplant survivors living with, and in
`some cases dying from, CGVHD [3-8]. Unfortunately, the
`treatment of established CGVHD remains unsatisfactory.
`Corticosteroids are the mainstay of therapy, but are often
`not fully effective, and their long-term use leads to multiple
`complications [1, 9]. Other agents such as calcineurin in-
`hibitors, sirolimus, mycophenolate mofetil, thalidomide,
`pentostatin, mesenchymal stem cells, and extracorporeal
`photopheresis have all produced responses in phase 2 studies,
`but no agent has yet demonstrated superiority to steroids
`alone in a randomized clinical trial [10-19].
`During the past 3 decades, experimental studies and clin-
`ical observations have elucidated the pathophysiology of
`acute GVHD, but the biology of CGVHD has not been deter-
`mined. In particular, defining the pathophysiology of CGVHD
`has been complicated by the absence of animal models that
`accurately recapitulate the disease or its clinical setting; this
`is in contrast to acute GVHD, in which murine models of
`
`

`

`Pathogenesis of chronic GVHD
`
`81
`
`major histocompatibility (MHC) mismatched HSCT provide
`a reasonably comprehensive picture of its pathophysiology
`as a clinical disease [20]. The purpose of this review is to
`briefly describe the pathophysiology of CGVHD, on the basis
`of phenotype and immunologic mechanisms that encompass
`the majority of murine CGVHD models described to date.
`Their relevance to clinical CGVHD is also discussed.
`
`DEFINITION
`
`CGVHD was initially defined as a GVHD syndrome that
`presents more than 100 days post-transplant, either as an
`extension of acute GVHD (progressive onset CGVHD), after
`a disease-free interval (quiescent CGVHD), or without pre-
`ceding acute GVHD (de novo CGVHD) [21]. In patients
`with CGVHD, the skin can exhibit erythema with macules
`and plaques, desquamation, dyspigmentation, lichen planus,
`atrophy, and in severe cases, chronic ulcers. Chronic choles-
`tatic liver disease can develop, as can involvement of the
`gastrointestinal tract, which may result in weight loss and
`malnutrition. CGVHD commonly produces sicca syndrome,
`which is caused by lymphocytic destruction of exocrine
`glands, most frequently affecting the eyes and mouth. The
`pathologic findings of CGVHD in the immune system include
`involution of thymic epithelium, lymphocyte depletion, and
`absence of secondary germinal centers in lymph nodes [22].
`The skin pathology shows epidermal atrophy, dermal fibrosis,
`and sclerosis. Gastrointestinal lesions include inflammation
`and rarely, stenosis and stricture formation, particularly in
`the esophagus. Positive histological findings in the liver are
`often intensified versions of acute GVHD and include chronic
`changes, such as fibrosis, the hyalinization of portal triads,
`and bile duct obliteration. The glands of the skin and digestive
`tract show destruction of centrally draining ducts and secon-
`dary involvement of alveolar components. Pulmonary tissue
`can also be involved, although histological distinctions from
`bacterial and viral infections are sometimes difficult. Never-
`theless, bronchiolitis obliterans, similar to that observed dur-
`ing lung transplant rejection, is now generally considered
`a manifestation of CGVHD.
`
`IMPORTANT CHANGES IN CLINICAL
`CONSIDERATIONS
`
`It is apparent that the clinical and histological changes
`considered characteristic of CGVHD can develop as early
`as 40 or 50 days post-transplant and thus, overlap with those
`of acute GVHD. Hence, the time of onset is increasingly
`becoming an arbitrary criterion, and it has become more
`meaningful to define the disease on the basis of clinical,
`histological, and immunologic findings.
`The National Institutes of Health (NIH) have proposed
`new consensus criteria for the diagnosis and clinical assess-
`ment of CGVHD, which emphasize the manifestations of
`GVHD and not time of onset after allo-HSCT (day 100)
`
`[23]. This proposal involves 2 categories for GVHD (acute
`or chronic), each with 2 subcategories (classic acute and
`late acute or classic chronic and overlap syndrome). In addi-
`tion, a new scoring system is proposed to describe the extent
`and severity of CGVHD at each organ or site at any given
`time and that takes functional impact into account. The
`global composite scores produced and the numbers of organs
`or sites involved have been proposed as a means of assessing
`CGVHD severity, and it is expected that this system will
`replace the old grading system (limited versus extensive
`types). The feasibility of the NIH consensus criteria has been
`examined by us and others, and all studies have demonstrated
`the applicability of the new NIH criteria and described possi-
`ble roles for the new global scoring system in the assessment
`of CGVHD severity [24-26].
`
`PATHOPHYSIOLOGY OF CGVHD
`
`Acute GVHD resembles a toxic, sepsis-like syndrome. Host
`antigen-presenting cells (APCs), especially dendritic cells
`(DCs), present alloantigens to incoming alloreactive cyto-
`toxic T cells, and the subsequent actions of these T cells
`result in tissue damage to the epidermis, hepatic bile ducts,
`and gut epithelium. This process is amplified by cytokine
`release from damaged tissues and the ingress of lipopoly-
`saccharide and other pathogen-associated molecular entities
`through damaged gut mucosa, which in turn up-regulate
`the innate immune system [27]. Not surprisingly, the immune
`mechanisms implicated in the induction and propagation
`of CGVHD differ from those of acute GVHD. However,
`the pathophysiology of CGVHD, unlike that of acute GVHD,
`remains obscure, as do its effective prevention and treatment.
`Fundamental research for the pathophysiology of CGVHD
`is required to develop more effective prophylactic and treat-
`ment regimens. So far, at least 4 theories have been generated
`to explain how CGVHD develops (Fig. 1).
`
`1. Breakage of immune tolerance to self-antigens (central tol-
`erance)
`It has been suggested that immune tolerance to self-anti-
`gens is disrupted in CGVHD, and that these give rise to
`the autoimmune manifestations of the disorder. One attrac-
`tive hypothesis is that thymic epithelial damage caused by
`conditioning regimens and/or acute GVHD leads to dysregu-
`lation of central tolerance mechanisms during the recon-
`stitution of the immune system post-transplantation [28].
`CD4+ T cells generated de novo from donor stem cells appear
`to mediate the evolution of CGVHD from acute GVHD [29].
`In fact, CGVHD occurs, even though it may not be preceded
`by acute GVHD. In healthy individuals, 95-99% of dou-
`ble-positive CD4+ CD8+ immature T cells in the cortex of
`the thymus die through apoptosis, having failed to receive
`survival signals through their T cell receptors, a process
`referred to as “death by neglect.” Those cells that do bind
`with low affinity to MHC class I or class II upregulate CD8
`or CD4 respectively (positive selection) and survive. Since
`
`Korean J Hematol 2011;46:80-7.
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`

`

`82
`
`Chang-Ki Min
`
`Donor
`
`Recipient
`
`Acute GVHD
`
`Bcell
`
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`a
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`Deficiency of regulatory T cells
`
`Thymic
`dysfunction
`
`B-cell
`activation
`
`Fibrosis
`
`Cytokines
`
`Organ faliure
`
`Fig. 1. The pathophysiology of chronic graft-versus-host disease.
`
`self-antigens are also presented in the context of the cortical
`epithelial MHC complex, such T cells will have low self
`affinity. Furthermore, in the thymic medulla, single-positive
`T cells will encounter marrow-derived APCs also bearing
`self-antigens (sequestered from the blood) and if strongly
`autoreactive, will die by apoptosis (negative selection).
`Through these processes, low-affinity, self-reacting naïve
`T cells will enter the periphery, and when they encounter
`the same self-antigen/MHC complex, will receive survival
`but not activation signals. This balance between negative
`and positive selections may be lost in a pro-inflammatory
`environment and high tissue-specific autoantigen load. In
`this inflammatory environment, peripheral tolerance mecha-
`nisms would be critical for regulating GVHD.
`In the setting of CGVHD, central tolerance failure could
`lead to an immune disease state resembling autoimmune
`disease. Although strategies based on the administration of
`keratinocyte growth factor at the time of transplant to pre-
`vent injury or repair thymic epithelium have been successful
`in experimental models [30], they failed in clinical trials
`[31]. Zhang found that host thymus is not required for the
`induction of CGVHD and that quiescent autoreactive T and
`
`B cells in transplants from non-autoimmune donors might
`be activated and expanded to cause CGVHD [32]. In addition,
`Imado found that transfection of the hepatocyte growth fac-
`tor (HGF) gene in vivo prevented the development of CGVHD
`in a murine model [33]. HGF also protected against thymic
`injury caused by acute GVHD and thus, prevented the gen-
`eration of host-reactive T cells and the development of
`CGVHD.
`
`2. CD4+CD25+ regulatory T cells (Tregs) and their relation-
`ship to CGVHD
`In several series, regulatory T cell (Treg) numbers (deter-
`mined by CD4+CD25+FoxP3+ staining) have been reported
`to be diminished in CGVHD [34-36], although data reported
`on Treg numbers and the occurrence of CGVHD are con-
`tradictory. Clark found that CGVHD is associated with ele-
`vated numbers of peripheral blood Tregs and that these num-
`bers returned to normal in patients with resolved CGVHD,
`thus indicating that CGVHD injury is not the result of Treg
`deficiency [37]. The mechanism by which Tregs suppress
`CGVHD remains uncertain, but there is evidence that sup-
`pression is mediated by cytokines, such as transforming
`
`Korean J Hematol 2011;46:80-7.
`
`

`

`Pathogenesis of chronic GVHD
`
`83
`
`growth factor (TGF)-(cid:69) and interleukin (IL)-10, or by contact
`with plasmacytoid DCs through indoleamine 2,3-dioxyge-
`nase [38]. Tregs may also exert an inhibitory influence di-
`rectly in target tissues [39]. For example, mucosal Treg num-
`bers have been documented to be lower in patients with
`GVHD than in normal controls or patients without GVHD
`[34]. Interestingly, extracorporeal photochemotherapy in-
`creases levels of circulating functional Tregs in CGVHD pa-
`tients [40], and recently, a novel photodepleting approach
`was found to both preserve and expand Treg numbers while
`selectively eliminating CD4+ effector T cells from patients
`with CGVHD [41].
`The adoptive transfer of Tregs in animal models of GVHD
`has demonstrated their efficacy, which suggests that Tregs
`can be exploited in the clinical setting [42]. Giorgini con-
`cluded that alloantigen-driven expansion, rather than ho-
`meostatic proliferation, is critical for the effectiveness of
`Tregs in CGVHD, and suggested that cellular therapy with
`alloantigen-induced Tregs in combination with glucocorti-
`coids could prevent CGVHD after immune reconstitution
`[43]. Zhang, using a murine study, suggested that peripheral
`tolerance may be more critical and abrogated by donor Tregs
`[32], and Chen associated the absence of Treg control of
`T helper (Th) 1 and Th17 cells with an autoimmune-mediated
`pathology in CGVHD [44].
`
`3. The roles of B cells and the antibodies they produce
`Historically, research into the prevention and treatment
`of GVHD centered on donor T lymphocytes and strategies
`designed to suppress or deplete these cells. The roles of
`B lymphocytes in the pathogenesis of GVHD were high-
`lighted by a case report of a patient with CGVHD who
`responded to B cell depletion therapy based on rituximab
`[45]. Considerable laboratory evidence has since revealed
`complex interactions between B and T cells that culminate
`in CGVHD. There are numerous examples of autoantibody
`formation in patients with CGVHD, but the role of autoanti-
`body formation in its pathogenesis has not been elucidated
`[46]. One study, in which antibodies to platelet-derived
`growth factor (PDGF) were observed in patients with
`CGVHD but not in those without CGVHD, was of particular
`note [47]. These antibodies were found to have the capacity
`to induce both tyrosine phosphorylation of the PDGF re-
`ceptor and type I collagen gene expression in fibroblasts.
`The role of B cell activity in CGVHD is underscored by
`the observation of high plasma levels of B cell activating
`factor (BAFF), a cytokine that appears to drive B cell auto-
`immunity, in patients with CGVHD [48]. In fact, high plasma
`levels of BAFF at 6 months post-transplantation were found
`to predict the subsequent development of CGVHD in asymp-
`tomatic patients. The development of antibodies to minor
`histocompatibility antigens (mHA) encoded on the Y chro-
`mosome in male patients receiving female grafts has been
`strongly associated with CGVHD incidence [49]. Since this
`was originally observed [45], several clinical trials and case
`series have been conducted on the use of B cell depletion
`using rituximab to treat CGVHD. The evidence obtained
`
`supports the roles of B cells and antibodies in CGVHD and
`prompted trials of rituximab. In phase 2 trials, responses
`were documented in over 50% of subjects [50]. Recently,
`Korean researchers performed a definitive trial in an attempt
`to establish the efficacy of rituximab and concluded that
`B cells represent a promising target for the prevention and
`treatment of CGVHD [51]. Although studies on B cell deple-
`tion in CGVHD have demonstrated the clinical effectiveness
`of this strategy, the mechanisms underlying the exact role
`of B cells on CGVHD are not entirely clear. In a murine
`study on the topic, it was suggested that donor B cell depletion
`protected mice from CGVHD [32], and therefore, it is con-
`ceivable that alloreactive donor CD4+ T cells could be acti-
`vated by host B cells, and that this, in turn, promotes the
`activation and expansion of quiescent autoreactive donor
`B cells in stem cell grafts. Furthermore, these autoreactive
`B cells could have a central role in amplification of auto-
`immune responses and in the epitope spreading of autor-
`eactive T and B cells [52]. Another model of lupus CGVHD
`showed that the cytotoxic T lymphocyte (CTL)- promoting
`properties of CD40 stimulation outweigh CD4+ T cell-driven
`B cell hyperactivity [53].
`
`4. Fibrotic changes
`In the skin, the initial phase of CGVHD is characterized
`by an intense mononuclear inflammatory infiltrate and de-
`structive changes at the dermal-epidermal junction, accom-
`panied by irregular acanthosis, hyperkeratosis, atrophy, pro-
`gressing to dermal fibrosis and sclerosis [54]. Other hallmarks
`of CGVHD include the destruction of tubuloalveolar glands,
`ducts in the skin, salivary and lacrimal glands, respiratory
`epithelium, and bile ducts. A large number of experimental
`models have indicated an association between type 2 polar-
`ized immune responses and the development of fibrosis [55].
`In particular, donor type 2 immune responses were found
`to be required for the induction of cutaneous GVHD in
`mice [56]. Furthermore, Hillebrandt found that complement
`factor 5 (C5) dose-dependently modified liver fibrosis in
`mice and humans [57]. C5b-9 complexes are deposited in
`the skin, liver, lung, and kidney in mice with GVHD [58].
`C3 is deposited at the dermal-epidermal junction in humans
`with CGVHD [59], but deposition of C5b-9 complexes has
`not been described in man. One study found that serum
`levels of TGF-(cid:69) were higher in patients with CGVHD than
`in patients without CGVHD [60]. The interpretation of this
`result is complicated because assays were carried out with
`serum and not plasma, and serum contains large amounts
`of TGF-(cid:69) released by platelets during clotting. Gene ex-
`pression studies have demonstrated that increased TGF-(cid:69)
`signaling in CD4 cells and CD8 cells is associated with a
`reduced risk of CGVHD in man [61]. The association between
`increased TGF-(cid:69) activity and a reduced risk of CGVHD might
`result from a lower risk of acute GVHD, since acute GVHD
`is a well-recognized risk factor of CGVHD. Furthermore,
`skin fibrosis and the upregulation of TGF-(cid:69)1 and collagen
`mRNAs commonly occur in human scleroderma and murine
`sclerodermatous GVHD following transplantation of B10.D2
`
`Korean J Hematol 2011;46:80-7.
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`

`

`84
`
`Chang-Ki Min
`
`lymphoid cells into irradiated BALB/c recipients [62].
`There is now considerable evidence that the preferential
`expansion of Th2 cells after allo-HSCT is associated with
`the development of CGVHD in both murine models and
`humans [63-68]. As is shown by most experimental models
`of fibrosis, CD4+ T cells play an important role in the pro-
`gression of CGVHD, and the type of CD4+ T-cell response
`that develops is crucial. Studies using various cytokine-defi-
`cient mice have shown that fibrogenesis is strongly linked
`with the development of a Th2 CD4+ T-cell response and
`that this involves IL-4, IL-5, and IL-13 [69]. Although an
`equally potent inflammatory response develops when Th1
`CD4+ T cells, which produce interferon (IFN)-(cid:74), dominate
`[70], under these circumstances, the development of tissue
`fibrosis is almost completely attenuated. These studies show
`that chronic inflammation does not always induce the deposi-
`tion of connective-tissue elements and that the magnitude
`of fibrosis is tightly regulated by the phenotype of the devel-
`oping Th-cell response. Furthermore, IL-13 and IL-4 bind
`to the same signaling receptor (IL-4R(cid:68)-IL-13R(cid:68)1) on fibro-
`blasts [71]. Indeed, studies carried out using several fibroblast
`subtypes have demonstrated the potent collagen-inducing
`activities of IL-4 and IL-13 [72-74]. In addition, when the
`productions of IL-4 and IL-13 from fibroblasts are compared,
`the concentration of IL-13 often exceeds that of IL-4 by
`a factor of 10-100. This suggests that IL-13 uses a signaling
`pathway that is different in some way from that used by
`IL-4, which could provide a means of augmenting its fibro-
`genic potential. In contrast to IL-13, the extent to which
`IL-5 and eosinophils participate in fibrotic processes varies
`greatly, and no clear explanation has been proposed that
`adequately explains the widely divergent findings. However,
`Jacobsohn found that monitoring the peripheral eosinophil
`count post-transplantation might provide a means of detect-
`ing the development of CGVHD [75].
`Chemokines are potent leukocyte chemoattractants that
`cooperate with pro-fibrotic cytokines such as IL-13 and
`TGF-(cid:69) during the development of fibrosis by recruiting mac-
`rophages and other effector cells to sites of tissue damage.
`Chemokines and their receptors have been implicated in
`the pathogenesis of scleroderma by recruiting immune cells
`to target tissues and thus, contribute to tissue damage [76].
`Although numerous chemokine signaling pathways are prob-
`ably involved in fibrogenesis, the CC-chemokine family has
`been shown to play an important regulatory role. In partic-
`ular, CCL3 (macrophage inflammatory protein 1(cid:68), MIP-1(cid:68))
`and CCL2 (monocyte chemoattractant protein 1, MCP-1)
`are chemotactic for mononuclear phagocytes and have been
`identified to be essential pro-fibrotic mediators. In a murine
`CGVHD model, high levels of chemokine mRNAs, i.e.,
`MCP-1, CCL5 (RANTES), CCL17, and IFN-(cid:74)-inducible che-
`mokines (CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC),
`which are all monocyte/macrophage- and T cell-related,
`were observed from days 7 to 120 post-transplantation [77].
`In a previous study, we found that pravastatin attenuates
`murine CGVHD by blocking the influx of effector cells into
`target organs and by downregulating the protein expressions
`
`Korean J Hematol 2011;46:80-7.
`
`of MCP-1 and RANTES, thereby reducing collagen synthesis
`[78].
`
`CGVHD ANIMAL MODELS
`
`Several murine allo-HSCT models have been used to study
`the pathogenesis of CGVHD. The first type of model involves
`the transplantation of parental lymphocytes into non-irradi-
`ated MHC-mismatched F1 recipients [79, 80]. In this model
`type, F1 recipients develop high levels of serum anti-double-
`strand DNA (dsDNA) and glomerulonephritis, and autoanti-
`body production is the result of a cognate interaction between
`donor CD4+ T cells and host B cells [79, 81-83]. However,
`it is not clear whether mechanisms revealed by this model
`reflect the pathogenesis of CGVHD in human transplant
`recipients receiving conditioning.
`The second type of model involves the transplantation
`of donor lymphocytes into MHC-matched but mHA-mis-
`matched irradiated recipients. In this model, donor LP/J
`(H-2b) bone marrow and spleen cells were transplanted into
`lethally irradiated C57BL/6 (H-2b) recipients, which later
`developed acute and chronic forms of GVHD [84]. Clonal
`analysis of T cells from the C57BL/6 recipients indicated
`that acute GVHD development was due primarily to recipi-
`ent-specific donor CTL, whereas CGVHD development was
`caused by autoreactive CD4+ T lymphocytes [84].
`In another mHA-disparate model, B10D2 (H-2d) donor
`spleen cells were transplanted into lethally irradiated BALB/c
`recipients, which then developed sclerodermatous organ
`damage [32, 85]. Skin changes in this model include a mono-
`nuclear infiltrate deep in dermis, loss of dermal fat, increased
`collagen deposition, and “dropout” of dermal appendages,
`such as hair follicles; unlike that found in acute GVHD,
`the apoptosis of basal epithelial cells at the dermal-epidermal
`junction does not occur. Clinical manifestations begin as
`early as day 11 post-transplantation, and cutaneous fibrosis
`is apparent as early as day 21. Deposits of IgG, IgA, and
`IgM appear at the dermal epidermal junction in recipients
`[85]. Additional features of CGVHD in this model include
`inflammation and fibrosis in salivary and lacrimal glands,
`sclerosing cholangitis, progressive renal and gastrointestinal
`fibrosis, and the development of anti-Scl-70 antibody [86].
`Naïve donor CD4 cells initiate the disease in this strain
`combination [87], and the dermal infiltrate is comprised
`of T cells, monocytes, and macrophages [88]. T cells and
`macrophages in skin express TGF-(cid:69)1 but not TGF-(cid:69)2 or
`TGF-(cid:69)3 mRNA [89]. In a microarray analysis study, the
`expression of type 1 (IFN-(cid:74)) and type 2 (IL-6, IL-10, and
`IL-13) cytokines, chemokines, and a variety of growth factors
`and cell adhesion molecules were upregulated in recipients
`with CGVHD compared to recipients without it [77].
`Zhang developed a new type of CGVHD model based
`on the transplantation of DBA/2 (H-2d) spleen cells into
`MHC-matched but mHA-mismatched, sub-lethally irradi-
`ated BALB/c (H-2d) recipients; in this model, both donor
`CD25-CD4+ T cells and B cells were required for CGVHD
`
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`Pathogenesis of chronic GVHD
`
`85
`
`development [32]. However, the relevance of this model
`for human CGVHD is questionable because even though
`dsDNA-specific autoantibodies, immune complex glomer-
`ulonephritis, and proteinuria are characteristic of systemic
`lupus, they rarely occur in patients with CGVHD [90].
`
`CONCLUSION
`
`Alloreactivity forms the basis of the pathogenesis of
`CGVHD, but the phenotypes and origins of the alloreactive
`cells involved remain somewhat ambiguous. Attempts to
`study CGVHD experimentally have been somewhat ham-
`pered by the absence of a reliable animal model that exactly
`represents variable manifestations in humans. Nevertheless,
`thymic dysfunction, Treg deficiency, autoantibody formation
`with B cell activation, and dysregulatory fibrotic processes
`have been shown to be associated with the occurrence of
`CGVHD. Fundamental research on the pathophysiology of
`CGVHD is required for the development of more effective
`prophylactic and treatment regimens. Finally, improved
`methods of diagnosis and staging based on an understanding
`of the pathogenesis of CGVHD should help to exploit novel
`therapeutic approaches in the future.
`
`REFERENCES
`
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