Acute Graft Versus Host Disease:
`Pathophysiology, Risk Factors, and
`Prevention Strategies
`
`James L. M. Ferrara, MD, and Gregory Yanik, MD
`
`Dr. Ferrara is Professor of Pediatrics
`and Medicine and Dr. Yanik is Clinical
`Associate Professor of Pediatrics at the
`University of Michigan Medical School in
`Ann Arbor, Mich.
`
`Address correspondence to:
`James L.M. Ferrara, MD, University of
`Michigan Medical School, 1500 E. Medical
`Center Drive, 6308 CCGC, Ann Arbor, Ml
`48109-0942; E-mail: ferrara@umich.edu.
`
`Abstract: Acute graft versus host disease (GVHD) remains the great(cid:173)
`est complication of allogeneic bone marrow transplantation and a
`major cause of morbidity and mortality. This article summarizes the
`risk factors and prevention strategies for acute GVHD by considering
`them within the context of disease pathophysiology. Acute GVHD
`can be considered a 3-step process: 1) damage from chemotherapy/
`radiotherapy; 2) host antigen-presenting cell activation and amplifi(cid:173)
`cation of donor T cells; and 3) target cell apoptosis via cellular and
`inflammatory mediators. This conceptual framework helps to explain
`the effectiveness of current prevention strategies _and points to areas
`where new drugs and approaches may be of clinical benefit.
`
`Pathophysiology
`
`In order to appreciate the strategies to prevent acute graft versus
`host disease (GVHD), it helps to understand the pathophysiology
`of the disease, which can be considered as a 3-step process
`(Figure 1). These 3 steps are tissue damage to the recipient by the
`radiation/chemotherapy pretransplant conditioning regimen, donor
`T-cell activation and clonal expansion, and cellular and inflamma(cid:173)
`tory factors. In the first step, the conditioning regimen (irradiation
`and/or chemotherapy) leads to damage and activation of host anti(cid:173)
`gen presenting cells (APCs) by inflammatory cytokines. In step 2,
`host APCs present alloantigens to the resting T cells and activate
`them. _Donor T-cell activation is characterized by cellular prolif(cid:173)
`eration and the secretion of cytokines, including interleukin (IL)-2
`and interferon-y (INF-y). In step 3, mononuclear phagocytes·and
`neutrophils cause inflammation and are triggered by mediators such
`as lipopolysaccharides (LPS) that leak through the intestinal mucosa
`damaged during step 1. The inflammation recruits effector cells into
`target organs, amplifying local tissue injury with further secretion of
`a inflammatory cytokines response that, together with cytotoxic T
`lymphocytes (CTLs), leads to target tissue destruction. 1•2
`
`Step 1: Effects of Hematopoietic Cell Transplantation
`Conditioning
`
`The first step of acute GVHD starts before donor cells are infused.
`Prior to hematopoietic cell transplantation (HCT), a patient's tissues
`
`Clinical Advances in Hematology & Oncology Volume 3, Issue 5 May 2005
`
`415
`
`Pharmacyclics Exhibit 2051
`Sandoz v. Pharmacyclics
`IPR2019-00865
`
`Keywords
`Inflammatory cytokines, immunotherapy; tumor
`immunology, T-cdl mediated cyroroxiciry, hone
`marrow transplantation
`
`

`

`FERRARA AND YANIK
`
`------·-·----··-·•·--·--·········---·-·--··-·-·-······--·------
`
`GVHD
`Pathophysiology
`
`(I) Condldanln1
`
`,,__,,
`
`~ ...
`
`T-..U
`•dlv•dOll
`
`~armd
`lnflammatD'7
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`
`Figure 1. Graft-versus-host disease (GVHD) pathophysiology.
`
`LPS • lipopolysaccharide; TN F • tumor necrosis factor.
`
`have been damaged by a number of factors, including the
`underlying disease and its treatment, infection, and trans(cid:173)
`plant conditioning. High-intensity chemoradiotherapy,
`characteristic of many HCT conditioning regimens,
`activates host APCs that are critical to the stimulation
`of donor T cells infused in the stem cell inoculum. Total
`body irradiation (TBI) is particularly important in this
`process because it activates host tissues to secrete inflam(cid:173)
`matory cytokines, such as tumor necrosis factor (TNF)-a
`and IL-1, and it induces endothelial apoptosis that leads
`to epithelial cell damage in the gastrointestinal (GI)
`4 GVHD damage to the GI tract amplifies GVHD
`tract3•
`by allowing the translocation of microbial products such
`as LPS into systemic circulation. This scenario helps to
`explain the . increased risk of GVHD associated with
`intensive conditioning regimens,>-7
`
`Step 2: Donor T-CellActivation and
`Cytokine Secretion
`
`Murine studies have demonstrated that host APCs alone
`are both necessary and sufficient to stimulate donor
`T cells to proliferate as early as day 3 after HCT, preced(cid:173)
`ing the engraftment of donor stem cells.8•10 Inflammatory
`cytokines and microbial products such as LPS may all be
`considered "danger signals" 11 that help to activate T cells
`and may make the difference between an immune response
`and tolerance. 12 When T cells are exposed to antigens in
`the presence of adjuvants such as LPS, the migration and
`survival of T cells are dramatically enhanced in vivo. 13
`The effect of advanced age in enhancing allostimula(cid:173)
`tory activity of host APCs may also help explain the
`increased incidence of acute GVHD in older recipients. 14
`The elimination of host APCs by activated natural killer
`
`(NK) cells can prevent GVHD in experimental models. 15
`This suppressive effect of NK cells on GVHD has been
`confirmed in humans: human leukocyte antigen (HLA)
`class I differences driving donor NK-mediated alloreac(cid:173)
`tions in the graft-versus-host direction mediate potent
`(GVL) effects and
`graft-versus-leukemia/lymphoma
`produce higher engraftment rates without causing severe,
`acute GVHD. 15•16 Cytokines secreted by activated T cells
`are generally classified as Thi (secreting IL-2 and INF-y)
`or Th2 (secreting IL-4, IL-5, IL-10, and IL-13). 17
`Monoclonal antibodies (mAbs) against IL-2 or its
`receptor can prevent GVHD when administered shortly
`20 but this strategy was only
`after the infusion ofT cells, 18•
`22
`moderately successful in reducing established GVHD.21
`•
`Cyclosporine (CSP) and tacrolimus dramatically reduce
`IL-2 production and effectively prevent GVHD. IL-15
`is another critical cytokine in initiating allogeneic T-cell
`division in vivo,23 and elevated serum levels of IL-15
`are associated with acute GVHD in humans.24 INF-y
`increases the expression of numerous molecules invol~ed
`in GVHD, including adhesion molecules, chemokines,
`major hisrocompatabililty complex antigens, and Fas,
`resulting in enhanced antigen presentation and the
`recruitment of effector cells into target organs. 25
`•27 INF-y
`also alters target cells in the GI tract and skin so that
`they are more vulnerable to damage during GVHD; the ·
`administration of anti-INF-y mAbs prevents GI GVHD28
`and high levels of both INF-y and TNF-a correlate with
`the most intense cellular damage in skin.29 Paradoxi(cid:173)
`cally, at early time points after HCT, INF-y can reduce
`GVHD by enhancing Fas-mediated apoptosis of activated
`donor T cells. 8•9•30
`Subpopulations of regulatory donor T cells can pre(cid:173)
`vent experimental GVHD. Repeated in vitro stimulation
`of donor CD4(+) T cells with alloantigens results in the
`emergence of a population of regulatory T cell clones
`that secretes high amounts of IL-10 and tissue growth
`factor-ft 31 The immunosuppressive properties of these
`cytokines are explained by their ability to inhibit APC
`function and co suppress proliferation of responding T
`cells directly.32-34 Natural suppressor cells and NKI.1(+) T
`cells can also prevent GVHD in experimental models.35•37
`
`Step 3: Cellular and Inflammatory Effectors
`
`Significant experimental and clinical data suggest that
`soluble inflammatory mediators act in conjunction with
`direct cell-mediated cytolysis by CTLs and NK cells to
`cause the full spectrum of deleterious effects seen during
`acute GVHD. As such, the effector phase of GVHD
`involves aspects of both the innate and adaptive immune
`response and the synergistic interactions of components
`generated during steps 1 and 2.
`
`416
`
`Clinical Advances in Hematology & Oncology Volume 3, Issue 5 May 2005
`
`

`

`GVHD PATHOPHYSIOLOGY, RISK, AND PREVENTION
`
`The Fas/Fas ligand (FasL) and the perforin/granzyme
`(or granule exocytosis) pathways are the principal effec(cid:173)
`tor mechanisms used by CTLs and NK cells to lyse their
`target cells.38·39 A number ofT-cell surface proteins also
`possess the capability to trimerize TNF receptor-like
`death receptors that also induce apoptosis in their tar(cid:173)
`gets.4042 CD4(+) CTLs preferentially use the Fas/FasL
`pathway during acute GVHD, while CDS+ CTLs pri(cid:173)
`marily use the perforin/granzyme pathway, consistent
`with other conditions involving cell-mediated cytolysis.
`FasL defective donor T cells cause markedly reduced
`experimental GVHD in liver, skin, and lymphoid
`organs. The Fas/FasL pathway is particularly important
`in hepatic GVHD, consistent with the marked sensitivity
`of hepatocytes to Fas-mediated cytotoxicity in models of
`murine hepatitis.43
`A central role for inflammatory cytokines in acute
`GVHD was confirmed by a recent murine study using
`bone marrow chimeras where GVHD-target organ
`injury was induced, even in the absence of epithelial
`alloantigens, and mortality and target organ injury
`were prevented by the neutralization of TNF-a and
`IL-1.2 TNF-a plays a central role in intestinal GVHD
`in murine and human studies.32·44·45 Two recent studies
`demonstrated that neutralization ofTNF-a alone or in
`combination with IL-1 resulted in a significant reduc(cid:173)
`tion ofGVHD.2·33 Although neutralization ofIL-1 with
`an IL-1 receptor antagonist was able to prevent GVHD
`in mice, its use in a randomized clinical trial did not
`prevent GVHD.34•42
`Macrophages s~crete cytokines after ligation of
`Toll-like receptors by LPS and other microbial products
`that have leaked though a damaged intestinal mucosa.
`Since the GI tract is known to be particularly sensitive
`to the injurious effects of cytokines,44·46 damage to the
`GI tract incurred during the effector phase can lead to a
`positive feedback loop wherein increased translocation of
`LPS results in further cytokine production and progres(cid:173)
`sive intestinal injury. Thus, the GI tract may be critical
`to propagating the "cytokine storm" characteristic of
`acute GVHD.47 Elevated serum levels of LPS have been
`shown to correlate directly with the degree of intestinal
`histopathology occurring after allogeneic HCT,46.48·49 and.
`gram-negative gut decontamination during HCT has
`been shown to reduce GVHD.50·53
`
`Risk Factors and Prevention
`
`GVHD pathophysiology can thus be considered an exag(cid:173)
`gerated and dysregulated response of a normal immune
`system {that of the donor) to tissue damage that is
`intrinsic to transplantation. Risk factors for acute GVHD
`can be considered according to this 3-phase model,
`
`as can the prophylactic strategies designed to reduce
`its morbidity.
`
`Reduced Intensity Conditioning Regimens
`
`One common thread among GVHD target organs is their
`exposure to the environment. Skin and gut have very obvi(cid:173)
`ous barrier functions and a well developed reticuloendo(cid:173)
`thelial system. Similarly, the liver is the first line of defense
`downstream of the gut. The lung's less intense exposure
`to organisms, particularly Gram-negative rods, reduces
`the frequency of its involvement. All of these organs
`are subject to injury from conditioning and breaches of
`a protective barrier that allows organisms or endotoxins
`into the circulation. The 3-phase model predicts that less
`intense conditioning regimens will be associated with less
`severe GVHD. Available data also suggest that the sever(cid:173)
`ity of GVHD after reduced intensity regimens is, indeed,
`.less than that seen after conventional-dose conditioning
`despite the fact that these patients were at risk for a much
`more severe form ofGVHO,54-57
`
`Mod11lation of Donor T Cells
`
`Histocompatibility differences between donor and recipi(cid:173)
`ent are major determinants of donor T-cell activation
`and, thus, increased HLA disparity is one of the most
`important risk factors for acute GVHD. Female donors,
`partic1:1larly those with multiple pregnancies, cause greater
`GVHD in male recipients because proteins encoded on
`the Y chromosome can serve as minor histocompatibility
`antigens in male recipients.
`The number ofT cells in the donor marrow is directly
`associated with the severity of acute GVHD, and T-cell
`depletion is one of the most effective forms of prophy(cid:173)
`laxis; a T-cell dose less than 105 /kg was associated with
`complete control of GVHD if an HLA-identical sibling
`served as the donor.58 The combination of very high seem
`cell numbers and CD3 .T-cell numbers less than 3 x 104/kg
`allowed haploidentical transplantation without GVHO.59
`Unfortunately, the nonspecific removal or clearance of
`T cells results in increased fatal opportunistic infections,
`resulting in equivalent overall survivai.60-62
`Administration ofintermittent low-dosemethotrexate
`immediately after bone marrow transplantation induces
`proliferation of T cells that have started to divide after
`exposure to allogeneic antigens.34 CSP inhibits signaling
`through the T-cell receptor and is about as effective as
`methotrexate alone. The combination of methotrexate ·
`and CSP significantly reduces GVHD and is widely
`used.63·64 More recently, the immunosuppressive agent
`tacrolimus, which is similar to colony-stimulating factor,
`has shown similar control of GVHD. Both drugs inhibit
`
`Clinical Advances in Hematology & Oncology Volume 3, Issue 5 May 2005
`
`417
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`

`

`FERRARA AND YANIK
`
`Cyclosporine
`la!1Jel levels:
`150-350 ng/ml .
`
`Tacrollmus
`Ta'1)etie'lels:
`10-15nglml
`
`Figure 2. Two-drug regimens for GVHD prophylaxis.
`
`T-lymphocyte activation by binding to immunophilins;
`CSP binds cyclophilin and tacrolimus binds FKBP-12.
`The net result is the inhibition of T lymphocyte activa(cid:173)
`tion.65 Subsequent comparisons of tacrolimus versus CSP
`in combination with methotrexate showed no advantage
`for either combination.66
`67
`•
`More recently, mycophenolate mofetil (MMF), an
`inhibitor of the de novo pathway of guanosine nucleotide
`synthesis, has been studied. MMF does not inhibit the
`activation ofT cells as such, bur blocks the coupling of
`activation to DNA synthesis·and proliferation.68 Recent
`limited trials of the combination of MMF with CSP
`or tacrolimus are promising.57•69•71 The most common
`approaches to chemical control of donor T cells as pro(cid:173)
`phylaxis for GVHD are schematized in Figure 2.
`
`Blockade of b,jlammatory Stimuli and Effectors
`
`Elimination of intestinal colonization with bacteria
`reduces GVHD by minimizing the triggering signal for
`monocytes and macrophages, as well as minimizing the
`actuation of APCs. Elimination of exposure to micro(cid:173)
`organisms prevents GVHD in germ-free mice, where
`GVHD was not observed until the mice were colonized
`with Gram-negative organisms,72 Additionally, gut decon(cid:173)
`tamination and use of a laminar air flow environment was
`associated with less GVHD and better survival in patients
`with severe aplastic anemia.50
`An important role forTNF-a in clinical acute GVHD
`was suggested by studies demonstrating elevated levels of
`TNF-a in the serum of patients with acute GVHD and
`other endothelial complications, such as veno-occlusive
`disease,73-7S Recently, therapy of GVHD with humanized
`anti-TNF-a (infliximab [Remicade, Centocor])76•77 or a
`dimericTNF receptor fusion protein (etanercept [Enbrel,
`Wyeth/Amgen]) have shown some promise.78 More
`
`studies are required to understand the pharmacokinetics
`and proper use of these agents after allogeneic transplan(cid:173)
`tation, since TNF inhibition may increase the risk of
`opportunistic infections.
`Two phase I/II trials showed promising data suggesting
`that specific inhibition ofIL-1 (with soluble IL-1 receptor
`or IL-I receptor antagonist), could result in remissions
`80
`in 50-60% of patients with steroid-resistant GVHD.79
`•
`However, a randomized trial of the addition ofIL-1 recep(cid:173)
`tor antagonist or placebo to CSP and methorrexate did
`not show any protective effect of the drug, despite attain(cid:173)
`ing very high plasma levels.34 IL-11 was able to protect
`82
`the GI tract and prevent GVHD in animal models,81
`•
`but it did not prevent clinical GVHD.83 Therefore, not all
`preclinical data successfully translate to new therapies.
`
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`------------------·-
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`Clinical Advances in Hematology & Oncology Volume 3, Issue 5 May 2005
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`

`

`MIDATHADA ET AL
`
`systemic workup should always be done whenever there is
`a choroidal tumor to help further elucidate the diagnosis.
`Choroidal melanoma is usually localized to the eye at
`diagnosis. 5·6 Once metastatic, the median survival ranges
`from 2 to 9 months.7•9 In a series of 679 patients, 10 the most
`common metastatic sites were the liver (91%), followed
`by the lungs (28%}, bone (18%), subcutaneous tissue
`(12%), and brain (5%), regardless of the size of the pri(cid:173)
`mary tumor. In this same study, the 5- and 10-year cumu(cid:173)
`lative metastatic rates were 24% and 32%, respectively,
`and the rates of metastasis increased with the size of the
`primary tumor.
`In the case presented, the pattern of metastasis was
`consistent with either a metastatic choroidal melanoma
`or a metastatic carcinoma. Nevertheless, metastases at
`presentation are unusual for choroidal melanoma, which
`tends to spread after the diagnosis is made. In a retro(cid:173)
`spective review of 99 patients with metastatic choroidal
`melanoma, the time from primary to m~tastasis diagnosis
`ranged widely, from 3 months to 9 years 8 months. 11
`This case report shows the significance of making
`a pathological diagnosis in oncology. Although they are
`both lethal diseases, the treatment, response to therapy,
`and prognosis are different in these 2 neoplasms. These
`are important variables to be discussed with patients in
`
`order to make informed decisions and before administer(cid:173)
`ing potentially harmful cytotoxic therapies.
`
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