Graft-versus-host disease Graft Versus Host Disease - MywallpapersMobi

Graft-versus-host disease Graft Versus Host Disease

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  • Ther Adv Hematol
  • v.4(6); 2013 Dec
  • PMC3854558
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Ther Adv Hematol. 2013 Dec; 4(6): 366–378.
doi:  [ 10.1177/2040620713489842 ]
PMCID: PMC3854558
PMID: 24319572

Treatment and management of graft-versus-host disease: improving response and survival

Catherine Garnett , Jane F. Apperley , and Jiří Pavlů corresponding author

Catherine Garnett

Imperial College London at Hammersmith Hospital, London, UK

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Jane F. Apperley

Imperial College London at Hammersmith Hospital, London, UK

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Jiří Pavlů

Department of Haematology, Imperial College Healthcare NHS Trust, Room 2.20 Catherine Lewis Centre, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK

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Catherine Garnett, Imperial College London at Hammersmith Hospital, London, UK;
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corresponding authorCorresponding author.
Copyright © The Author(s), 2013
This article has been cited by other articles in PMC.

Abstract

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despite considerable advances in our understanding of the pathophysiology, diagnosis and predisposing factors for both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions. Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in such patients. It is hoped that in the future systematic research strategies and the identification of novel therapeutic targets may improve outcome further. The following review aims to outline some of the existing options for the treatment and management of acute and chronic GVHD.

Keywords: graft-versus-host disease, GVHD, therapy

Introduction

Despite decades of research and improvements in post-transplant immunosuppressive therapies, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in allogenic haematopoietic stem-cell transplant (HSCT) recipients. Classically defined by Billingham in 1966 as a syndrome in which immunocompetent donor cells recognize and attack host tissues in an immunocompromised recipient, GVHD demonstrates a heterogeneous clinical presentation primarily involving the skin, mucosa, gastrointestinal tract, liver and lungs [ Billingham, 1966 ]. Historically, features occurring within 100 days of HSCT were classified as acute GVHD (aGVHD) and those occurring beyond 100 days as chronic GVHD (cGVHD). However, it is now recognized that clinical features of cGVHD can occur within 100 days of transplant and that features of aGVHD and cGVHD may coexist, leading to new definitions in which diagnosis focuses on the constellation of symptoms rather than their time of onset [ Filipovich et al. 2005 ].

Depending on a number of patient- and transplant-related variables, the incidence of aGVHD ranges from 10% to 80% with symptoms usually developing 2–3 weeks post transplant. Risk factors for aGVHD include degree of human leukocyte antigen (HLA) mismatch, older age, previous donor alloimmunization and the nature of GVHD prophylaxis. It is estimated that cGVHD affects 30–70% of allogenic HSCT recipients surviving beyond 100 days, with a median onset of 4–6 months following HSCT. Although associated with reduced relapse rate in patients transplanted for leukaemia, cGVHD remains the leading cause of late death in HSCT survivors. With increasing use of HSCT in older recipients, mismatched and unrelated donors and mobilized peripheral blood stem-cell grafts, the clinical and economic impact of GVHD looks set to further increase in future years [ Lee et al. 2002 ; Flowers et al. 2011 ].

Management of GVHD is challenging. Immuno-suppression with corticosteroids forms the basis of first-line therapy in both acute and chronic GVHD, producing sustained responses in less than 50% of patients with aGVHD and 40–50% of patients with cGVHD depending on initial disease severity. Despite ongoing research, there are few randomized controlled trials focusing on management of steroid-refractory GVHD. Evaluation of therapeutic options is complicated by the heterogeneous nature of the patient group (variable organ involvement, age, conditioning regimens, GVHD prophylaxis and type of HSCT), lack of a clear definition of corticosteroid-refractory disease and inconsistent treatment end points. As a consequence, there remains no clear consensus as to the best second- and third-line options in GVHD management and local treatment regimens often depend largely on financial considerations, availability of therapies, and the preferences and experience of treating physicians.

Pathophysiology

As yet, the pathophysiology underlying aGVHD and cGVHD remains incompletely understood. One commonly quoted model suggests three distinct stages in the development of aGVHD: a conditioning regimen which damages host tissues, including intestinal mucosa and liver; activation of donor T cells against host antigens and subsequent clonal T-cell expansion; and release of inflammatory cytokines such as interleukin 1 (IL-1) and tumour necrosis factor α (TNFα), leading to further host tissue damage [ Ferrara et al. 1999 ]. Several mechanisms have been implicated in cGVHD pathogenesis, including persistence of donor-derived alloreactive T cells, autoreactive T cells, B cells producing antibodies against the host, and mechanisms of chronic inflammation leading to end organ fibrosis. The existence of such complex parallel networks remains subject to much ongoing research, not least because they form the basis for many new and existing therapeutic targets (reviewed by Ferrara and colleagues) [ Ferrara et al. 2009 ].

Management of acute graft-versus-host disease

Overview

Acute GVHD classically affects the skin, liver and gastrointestinal tract. Using criteria first published by Glucksberg and colleagues in 1974, it is graded based on degree of organ involvement (surface area of skin rash, serum bilirubin and volume of diarrhoea) and assessment of clinical status [ Glucksberg et al. 1974 ]. While comparison of published data is limited to some extent by variation in diagnosis and grading between physicians, it is recognized that the overall grade of aGVHD has a major impact on survival post HSCT, with transplant-related mortality (TRM) ranging from 28% in grade 0 aGVHD to 92% in grade IV aGVHD in one large-scale study [ Gratwohl et al. 1995 ].

Although beyond the scope of this review, much emphasis in current transplant management is based on preventing development of aGVHD. Current prophylactic regimens aim to either suppress donor T-cell function with immunomodulatory agents [e.g. ciclosporin, methotrexate, tacrolimus, mycophenolate mofetil (MMF)] or deplete donor T cells before or after stem-cell infusion using monoclonal (e.g. alemtuzumab, anti-CD52) or polyclonal antibodies [antithymocyte globulin (ATG)].

First-line management of acute graft-versus-host disease

Grade I aGVHD may respond to topical steroid therapy alone. Calcineurin inhibitor levels should be optimized to ensure therapeutic dosing. In cases which do not resolve with topical management systemic treatment may be required.

Systemic corticosteroids remain the mainstay of first-line treatment in grade II–IV aGVHD. A number of studies have looked at response of patients with aGVHD to steroid therapy, although variation in dose, regimen and length of therapy means that there remains no clear consensus as to optimal use. In 1990, Martin and colleagues retrospectively analyzed the results of treatment in 740 patients with grade II–IV aGVHD. Of these, primary treatment was with corticosteroids in 531 patients. Overall complete or partial responses were reported in 44%, with improvement rates in skin disease, evaluable liver disease and evaluable gut disease of 43%, 35% and 50% respectively [ Martin et al. 1990 ]. Broadly comparable results were obtained by Weisdorf and colleagues and MacMillan and colleagues in retrospective studies of 197 patients and 443 patients [ Weisdorf et al. 1990 ; MacMillan et al. 2002b ]. Significantly, response to primary therapy has been shown to correlate well with post-transplant survival [ Saliba et al. 2012 ].

In most centres, the starting dose of prednisolone or methylprednisolone is 1–2 mg/kg/day depending on GVHD severity. Figure 1 outlines the current initial treatment strategy at our centre. No significant difference in outcome was identified in patients with grade I/II aGVHD treated with 1 or 2 mg/kg/day of corticosteroid in one retrospective study. The small number of patients with grade III/IV aGVHD at diagnosis limited conclusions in this group [ Mielcarek et al. 2009 ]. Equally, a prospective randomized trial comparing 2 mg/kg/day of methylprednisolone with 10 mg/kg/day over a 5-day period with subsequent tapering doses found no significant difference in response of aGVHD, evolution to more severe disease, 3-year TRM or 3-year survival. Logically, patients who had responded to 2 mg/kg/day of steroid therapy by day 5 showed a lower TRM than nonresponders [ Van Lint et al. 1998 , 2006 ].

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Figure 1.

First six days of systemic therapy for acute graft-versus-host disease grade I–IV as used at the Hammersmith Hospital, London. Please note this represents our local protocol and is not a generalized guideline.

ATG, antithymocyte globulin; bd, twice daily; GVHD, graft-versus-host disease; i.v., intravenous; MMF, mycophenolate mofetil; MP, methylprednisolone; MSC, mesenchymal stem cell; od, once daily.

Steroids have many well documented side effects, including immunosuppression, hyperglycaemia and osteopenia, meaning that a balance must be drawn between benefit and risk of prolonged courses. There remains no consensus as to the best way of tapering steroids in responding patients. One prospective trial randomized 30 patients with aGVHD who had responded to initial steroid treatment to short (86-day) versus long (147-day) taper of steroid dose. Patients in the short taper group achieved resolution of aGVHD after a median of 42 days compared with 30 days in the longer taper group. No difference was reported in incidence of steroid-related side effects, cGVHD or 6-month survival [ Hings et al. 1993 ]. Practically, when steroid taper leads to worsening of symptoms, simply increasing the steroid dose and reducing again gradually may prove an effective solution. As fungal and viral infections are frequent complications of prolonged treatment, anti-infective prophylaxis is recommended.

In an effort to improve disease response, additional first-line therapies have been studied. In a four-arm phase II trial, 180 patients with aGVHD were randomized to receive 2 mg/kg/day of methylprednisolone plus either etanercept, MMF, denileukin or pentostatin as initial therapy. Complete response (CR) rates at day 28 were 26%, 60%, 53% and 38% respectively with 9-month overall survival of 47%, 64%, 49% and 47% [ Alousi et al. 2009 ]. Based on these findings, a phase III trial comparing steroid therapy plus MMF with steroid therapy alone was initiated (BMT CTN Study 0802). Preliminary results suggest no benefit of the addition of MMF to standard first-line therapy [ Bolanos-Meade et al. 2013 ].

Second-line management of acute graft-versus-host disease

Although the definition of steroid-refractory aGVHD remains subject to ongoing debate, it is generally acknowledged that if aGVHD worsens in any organ over 3 days of treatment or there is no response to steroid therapy in 5–14 days, secondary therapy should be considered [ Dignan et al. 2012a ]. Numerous therapeutic agents have been studied in this context ( Table 1 ). However, as yet, none have demonstrated convincing long-term benefit. Therefore the outcome of refractory aGVHD is poor with a high rate of morbidity and mortality figures approaching 80% [ Van Lint et al. 2006 ; MacMillan et al. 2002a ].

Table 1.

Therapy commonly used for steroid-refractory acute graft-versus-host disease and usual dosing regimens.

TherapyUsual dosingComments
Antithymocyte globulin10–15 mg /kg daily for 3–10 days intravenouslySteroid sparing. Durable effects infrequent. Considerable acute toxicity during administration, infections
Alemtuzumab10 mg daily for 5 days intravenouslyBetter tolerated than antithymocyte globulin. Significant infections (including CMV reactivation). Rarely durable responses
Dacluzimab5 mg/kg once a week intravenouslyLimited availability. Infections
Infliximab10 mg/kg once a week intravenouslyPreferable in gut disease. Considerable risk of infections
Extracorporeal photophoresisOptimal treatment schedule and duration not yet establishedSpares steroids. Excellent safety profile. Requires venous access and minimal platelet count of 30 × 109/liter
Mycophenolate mofetil1g twice per day orally or intravenouslySpares steroids. Gut toxicity may mimic gut GVHD. Can cause nausea and diarrhoea but usually well tolerated
Sirolimus1–4 mg/day orally, adjusted to trough serum levels of 4–12 ng/mlRequires close monitoring. Increased risk of thrombotic microangiopathy when used with calcineurin inhibitors or with higher levels. Can cause hyperlipidaemia, myelosuppression, seizures and renal dysfunction
Pentostatin1.5 mg/m2/day intravenously for 3 daysCan cause infection and cytopenias
Mesenchymal stem cells1–6 million cells/kg intravenously, dose can be escalated in respondersSpares steroids. Preferable in gut disease. Generally low side-effect profile
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CMV, cytomegalovirus; GVHD, graft-versus-host disease.

Antithymocyte globulin

A number of retrospective studies have suggested the benefit of ATG in steroid-refractory aGVHD, particularly when used early in the disease and in the context of skin involvement [ MacMillan et al. 2002a ]. However, evidence that ATG improves survival in this context is lacking. In one prospective study, patients (n = 61) not responding to 5 days of 2 mg/kg/day methylprednisolone were randomized to receive 10 days of 5 mg/kg/day methylprednisolone, either alone or in combination with rabbit ATG. No significant difference was reported between the groups in terms of survival, TRM or response rate [ Van Lint et al. 2006 ].

Alemtuzumab (Campath)

Similarly, small studies using the humanized monoclonal anti-CD52 antibody alemtuzumab in steroid-refractory disease have failed to show convincing long-term benefit. In one prospective study, 18 patients with steroid-refractory aGVHD received subcutaneous alemtuzumab for 5 days. At day 28, 15 patients had responded to treatment. Ten of these responders were still alive at 11 months. Fourteen patients developed infections, including cytomegalovirus reactivation in 11 patients [ Gomez-Almaguer et al. 2008 ]. In a subsequent phase II trial of 10 adult patients with grade III/IV aGVHD, five responded to treatment but all 10 died within a median period of 40 days [ Martinez et al. 2009 ].

Interleukin-2 receptor antagonists

Several monoclonal IL-2 receptor antibodies, thought to act by targeting activated T cells, have been trialled in the treatment of steroid-refractory aGVHD. Although of limited availability in Europe, a number of studies have suggested a potential role for daclizumab, with a favourable toxicity profile [ Przepiorka et al. 2000 ]. However, a multicentre randomized control trial comparing use of methlyprednisolone 2 mg/kg/day with or without daclizumab for the initial treatment of aGVHD demonstrated a significantly worse 100-day survival in the daclizumab group (77% versus 94%, p = 0.02) at interim analysis which was sufficient to halt the trial. This was secondary to both relapse and GVHD-related mortality [ Lee et al. 2004 ]. Several smaller, largely retrospective studies have demonstrated clinical response in patients with steroid-refractory aGVHD treated with other IL-2 receptor antagonists: inolimomab [ Pinana et al. 2006 ], denileukin [ Ho et al. 2004 ], basiliximab [ Wang et al. 2011 ]. However, a recent retrospective study of 92 patients with corticosteroid-refractory aGVHD treated with inolimomab reported an overall response rate of 42% on day +30, but an overall survival of just 33% at 2 years in the day 30 responders, suggesting that the initial benefit of treatment may not correlate well with long-term survival [ Garcia-Cadenas et al. 2013 ]. Of interest is a potential role for IL-2 in the management of cGVHD (see below).

Antitumour necrosis factor antibodies

The inflammatory cytokine TNFα has been implicated in the pathophysiology of GVHD, hypothesized to activate antigen-presenting cells (APCs), recruit effector cells and induce cellular apoptosis. Trials involving the anti-TNFα monoclonal antibody infliximab have produced mixed results in patients with steroid-refractory aGVHD. Retrospective studies have suggested some benefit of infliximab, particularly in patients with primarily gut involvement, albeit associated with an increased risk of infection [ Couriel et al. 2004 ]. More recent reports are less positive. When Couriel and colleagues randomized 63 patients with refractory aGVHD to receive either steroid therapy alone or steroid plus infliximab, GVHD-related mortality, non-relapse mortality and overall survival were not significantly different between the groups [ Couriel et al. 2009 ]. Etanercept, a recombinant human soluble TNF-α receptor fusion protein which competes for TNFα binding and renders it inactive, has also shown some promise. In 13 patients with steroid-refractory aGVHD, six responded to etanercept therapy, with the best response seen in those with gastrointestinal disease [ Busca et al. 2007 ].

Combination therapies may also be efficacious. Of 22 children with steroid-resistant aGVHD treated with a combination of daclizumab and infliximab, 19 responded and 15 were still alive at a median of 31 months. Only two of the deaths were attributed to infection [ Rao et al. 2009 ].

Extracorporeal photophoresis

Experience with extracorporeal photophoresis (ECP) in aGVHD is less than with chronic forms of the disease. The treatment consists of a combination of leucapheresis and photodynamic therapy, in which patient blood is exposed to 8-methoxypsoralen followed by ultraviolet A irradiation, before being reinfused. This is thought to induce leukocyte apoptosis, phagocytosis of apoptotic cells by APCs and a switch in APC activity in favour of immunomodulation. ECP has a good safety profile, with no significant increase in infection, secondary malignancy or disease relapse reported [ Couriel et al. 2006 ]. Retrospective studies have suggested ECP therapy is of benefit in aGVHD [ Perfetti et al. 2008 ]. A prospective phase II study included 59 patients with steroid-dependent or steroid-refractory GVHD treated with weekly ECP until maximum disease response. CR was achieved in 82% of patients with cutaneous, 61% with liver and 61% with gut involvement. TRM at 4 years was 14% in patients who achieved CR and 73% in those who did not [ Greinix et al. 2006 ].

Mycophenolate mofetil

MMF, which inhibits purine synthesis in lymphocytes and has the advantage of oral or intravenous administration, has been studied in a number of small retrospective and prospective trials, with a possible role as a steroid-sparing agent in refractory disease. In 2009, Furlong and colleagues demonstrated clinical response in 9 of 19 patients with steroid-resistant aGVHD, although they found only a 16% 1-year survival [ Furlong et al. 2009 ].

Sirolimus

The mammalian target of rapamycin inhibitor sirolimus has also been used in the treatment of steroid-refractory aGVHD, although concerns have been raised over its side effects, which include hyperlipidaemia, myelosuppression, seizures and thrombotic microangiopathy (TAM). In one pilot study of 21 patients with steroid-refractory grade III/IV aGVHD treated with sirolimus, the reported response rate was 57% (CR 24%) but the drug was discontinued in 10 patients due to toxicity or disease progression [ Benito et al. 2001 ]. Broadly similar results were observed in retrospective studies [ Hoda et al. 2010 ].

Pentostatin

In a phase I dose escalation study involving 23 patients with steroid-refractory aGVHD treated with the nucleotide analogue pentostatin, Bolanos-Meade and colleagues demonstrated CR in 14 patients but a median survival of only 85 days. Notably, several of these patients had already received additional aGVHD therapies [ Bolanos-Meade et al. 2005 ]. A small retrospective series of 12 patients reported an overall response to pentostatin of 50% [ Pidala et al. 2010 ].

Mesenchymal stem cells

Since the first treatment of steroid-resistant aGVHD in a 9-year-old boy with haploidentical third-party derived mesenchymal stem cells (MSCs) [ Le Blanc et al. 2004 ], a number of phase I–II studies have suggested that MSC infusion is safe and may be effective in aGVHD treatment. One nonrandomized multicentre phase II study of 55 patients with refractory aGVHD treated with MSCs from either HLA-identical stem-cell donors, haploidentical family donors or unrelated HLA-mismatched donors demonstrated CR in 30 patients and improvement of GVHD in nine patients [ Le Blanc et al. 2008 ]. Research in this area is ongoing, and growing evidence that MSCs may play a key role in modulating inflammation [ Dazzi et al. 2012 ] perhaps suggests a more central role in the future management of GVHD.

Management of chronic graft-versus-host disease

Overview

Chronic GVHD commonly affects the skin, eyes, mouth, liver, gastrointestinal tract, lungs and genitalia and is classified as mild, moderate or severe according to National Institutes of Health consensus criteria, reflecting the number of organs involved, severity of GVHD and whether or not there is pulmonary involvement [ Filipovich et al. 2005 ]. Several risk factors for cGVHD have been identified, including degree of HLA mismatch, age of recipient and prior aGVHD. Considerations regarding the impact of GVHD on survival following HSCT must be balanced with the fact that GVHD is associated with lower rates of relapse in leukaemia (the graft versus leukaemia effect). Data are conflicting as to how well this correlates with GVHD severity [ Horowitz et al. 1990 ; Lee et al. 2002 ; Gratwohl et al. 2002 ].

Given the paucity of robust data, particularly regarding management of steroid-refractory disease, it is recommended that patients are enrolled in clinical trials whenever possible.

First-line management of chronic graft-versus-host disease

While patients with mild cGVHD may respond well to topical therapies, systemic treatment is usually indicated in moderate to severe cGVHD [ Filipovich et al. 2005 ]. Corticosteroids remain the mainstay of first-line treatment, either alone or in combination with other agents. The standard starting dose is 1 mg/kg/day and there are very few data supporting use of higher or lower doses in clinical practice. Duration of immunosuppressive therapy is determined largely by clinical response, but is often prolonged, with median duration estimated at 2–3 years [ Stewart et al. 2004 ]. Rate of steroid taper varies considerably with no randomized trials comparing protocols.

Early studies suggested benefit of the calcineurin inhibitor ciclosporin in first-line treatment of cGVHD and more recently Koc and colleagues randomized 287 patients to receive either cyclosporine plus 1 mg/kg prednisolone or prednisolone alone as primary treatment for cGVHD. No significant difference in transplant-related mortality (17% versus 13%), progression to secondary therapy (11% versus 17%) or duration of immunosuppression was noted between the two arms of the trial. The incidence of avascular necrosis was higher in the prednisolone-only arm (22% versus 13%), however, suggesting that while combination therapy may not result in a survival advantage, it could help ameliorate steroid-related side effects [ Koc et al. 2002 ]. In 2009, Martin and colleagues initiated a double-blind randomized multicentre trial investigating the effect of adding MMF to first-line management of cGVHD on disease outcome. The study was closed early, however, following interim analysis revealing no benefit from adding MMF and a marginally higher death rate in the MMF arm [ Martin et al. 2009 ].

Second-line management of chronic graft-versus-host disease

One of the many difficulties of cGVHD management and research is reproducibly defining response to treatment. Martin and colleagues suggest that failure of primary therapy is indicated by progression of cGVHD despite prednisolone at doses of 1 mg/kg/day for 2 weeks, a lack of improvement after 4–8 weeks of sustained treatment or an inability to taper steroids [ Martin et al. 2006 ]. Many of these end points are subjective and some manifestations of cGVHD are irreversible despite appropriate therapy. As yet, there remains no standard treatment for steroid-refractory cGVHD. Commonly used treatments are discussed below and summarized in Table 2 .

Table 2.

Therapy commonly used for steroid-refractory chronic graft-versus-host disease and usual dosing regimens.

TherapyUsual dosingComments
Extracorporeal photophoresisFortnightly paired treatments for an assessment period of 3 monthsSpares steroids. Excellent safety profile. Particularly efficacious in cutaneous chronic GVHD. Requires venous access and minimal platelet count of 30 × 109/liter
Mycophenolate mofetil1 g twice per day orally or intravenouslySpares steroids. Gut toxicity may mimic gut GVHD. Can cause nausea and diarrhoea but usually well tolerated
Methotrexate5 mg/m2 or 7.5 mg/m2 per week orallySpares steroids. Most benefit in skin and mouth GVHD. Can cause cytopenias
Rituximab375 mg/m2 weekly intravenously. Assess at 4 weeksBenefit in skin and musculoskeletal GVHD. Risk of infection
Sirolimus1–4 mg/day orally, adjusted to trough serum levels of 4–12 ng/mlRequires close monitoring. Increased risk of thrombotic microangiopathy when used with calcineurin inhibitors. Can cause hyperlipidaemia, myelosuppression, seizures and renal dysfunction
Pentostatin4 mg/m2 every 2 weeks intravenouslyCan cause infection and cytopenias
Thalidomide100–800 mg/day orally in divided dosesDoses >200 mg are poorly tolerated. Side effects include neurotoxicity, constipation, sedation and thrombosis
Imatinib100–200 mg once daily orally increased to 400 mg daily if toleratedBest response in refractory sclerotic chronic GVHD. Some benefit in mild–moderate lung GVHD. May cause fluid retention, shortness of breath and myelosuppression
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GVHD, graft-versus-host disease.

Extracorporeal photophoresis

ECP has been extensively evaluated in cGVHD management, with a number of studies demonstrating benefit in steroid-refractory disease, especially involving the skin, mouth or liver [ Couriel et al. 2006 ; Scarisbrick et al. 2008 ]. In 2008, Flowers and colleagues performed a prospective multicentre trial of 95 steroid-refractory or steroid-dependent patients with cutaneous cGVHD comparing ECP plus standard treatment to standard treatment alone [ Flowers et al. 2008 ]. The primary end point was defined as a change in total skin score (TSS) measured by a blinded physician at 12 weeks. As with many trials in cGVHD management, conclusions were limited by the large variation in immunosuppressive regimens used. Although statistically significant results were not obtained for the primary end point, the proportion of patients reaching at least a 50% reduction in steroid dose and 25% decrease from baseline in TSS was greater in the ECP arm, suggesting that ECP may have a role as a steroid-sparing agent. The response to ECP of gut and lung cGVHD has been reported but is less consistent. Although associated with relatively few significant side effects, ECP does require effective venous access, which can be challenging.

Mycophenolate mofetil

Although not infrequently used in the management of steroid-refractory cGVHD, published data surrounding the efficacy of MMF in this context is limited. Lopez and colleagues reported the use of MMF as second-line therapy in 24 patients, with five demonstrating CR and 13 partial response [ Lopez et al. 2005 ]. An earlier retrospective study reported an overall response rate of 72% in 18 patients treated with MMF for refractory cGVHD [ Busca et al. 2003 ]. Common side effects include infections, cytopenias and gastrointestinal toxicity, with the latter potentially mimicking the effects of gut GVHD both clinically and histologically, and thus complicating diagnosis and assessment of response.

Methotrexate

Low-dose methotrexate is well established as an anti-inflammatory agent in the management of autoimmune disease. It has been shown to be well tolerated and potentially efficacious in a number of smaller studies of patients with steroid-refractory cGVHD [ Huang et al. 2005 ; Inagaki et al. 2008 ]. More recently, Wang and colleagues evaluated the role of methotrexate as a first-line therapy in 86 patients with cGVHD in combination with other immunosuppressive agents. The overall response rate was 86%, with most marked benefit in cutaneous disease [ Wang et al. 2009 ].

Rituximab

Based on the hypothesis that B cells play a role in cGVHD pathogenesis, the anti-CD20 monoclonal antibody rituximab has been trialled in cGVHD management and shown some benefit. Cutler and colleagues reported a 70% response rate in 21 patients with steroid-refractory cGVHD treated with 38 cycles of rituximab [ Cutler et al. 2006 ]. Notably, responses were limited to patients with skin or musculoskeletal manifestations and many responses were partial. Similarly, in a meta-analysis of seven studies involving 111 patients, the pooled response rate to rituximab therapy was 66%, although the varying criteria for reporting organ response and dosage reduction of steroids limited interpretation [ Kharfan-Dabaja et al. 2009 ].

Sirolimus

Sirolimus has been evaluated in the second-line treatment of cGVHD, mainly in combination with other immunosuppressive agents. Johnston and colleagues showed an initial clinical response to sirolimus therapy in 15 of 16 patients with cGVHD, although documented adverse events included renal impairment, TAM and disease relapse, leading to discontinuation of treatment in six patients [ Johnston et al. 2005 ]. Similarly, Couriel and colleagues reported an overall response rate of 63% in 35 patients with steroid-resistant cGVHD treated with sirolimus, tacrolimus and methylprednisolone [ Couriel et al. 2005 ]. Notably, four patients developed TAM requiring cessation of therapy and there was a high rate of infectious complications. It is suggested that patients treated with sirolimus should be carefully monitored for renal complications and hyperlipidaemia. Interactions with other medications, especially calcineurin inhibitors and azoles, should be avoided if possible.

Pentostatin

Following its successful use in steroid-refractory aGVHD, pentostatin has also been trialled in the second-line treatment of cGVHD. One phase II study of 58 patients with refractory cGVHD who were given pentostatin every second week for a median of 12 doses reported an overall response rate of 55%, although it should be noted that most patients were heavily pretreated [ Jacobsohn et al. 2007 ]. Similar results were seen in a number of retrospective series. Infections appear to be a frequent complication of pentostatin treatment in cGVHD.

Thalidomide

Thalidomide demonstrates diverse immunomodulatory activities, inhibiting cytokines such as IL-6 and IL-12, reducing TNFα expression, downregulating surface adhesion molecules and suppressing angiogenesis. In 1992, Vogelsang and colleagues reported complete or partial response in 14 of 44 and 12 of 44 patients with refractory cGVHD treated with thalidomide therapy and subsequent studies have produced broadly similar results [ Vogelsang et al. 1992 ]. Thalidomide is, however, associated with numerous side effects, including neurotoxicity, sedation, constipation and thrombosis. Indeed, in a randomized, placebo-controlled trial of thalidomide as first-line therapy for cGVHD, treatment with the study drug was discontinued before resolution of cGVHD in 23 of the 25 patients taking thalidomide due to an unacceptable side-effect profile [ Koc et al. 2000 ].

Imatinib

In recent years, an adjuvant role for the tyrosine kinase inhibitor (TKI) imatinib in the treatment of refractory cGVHD has emerged, thought to act by inhibiting the TGFβ and platelet-derived growth factor pathways and thus reducing fibrosis. In 2009, Magro and colleagues evaluated the use of imatinib for the treatment of refractory sclerotic cGVHD in 14 patients, demonstrating a 50% response rate and reduction in corticosteroid requirement [ Magro et al. 2009 ]. Interestingly, in nine patients with lung GVHD, some benefit was suggested from imatinib therapy in mild–moderate disease, but only minor improvement was noted in more severe conditions, raising the question of whether established fibrosis can be reversed [ Stadler et al. 2009 ]. Side effects of imatinib include myelosuppression, shortness of breath and fluid retention.

Supportive care

Despite improvements in diagnosis and supportive care, cGVHD remains the major cause of late nonrelapse morbidity and mortality following HSCT, with deaths primarily resulting from infections related to the immunosuppressive effect of cGVHD or its treatments [ Socie et al. 1999 ]. Appropriate antimicrobial prophylaxis is of great importance, with adequate protection against Pneumocystis jiroveci, Streptococcus pneumoniae, viral and fungal infections according to local protocol (see Dignan and colleagues for a review) [ Dignan et al. 2012b ]. Patients should be educated as to the risk of sepsis and advised to seek medical attention at an early stage.

The heterogenous nature of disease manifestations in cGVHD means that a multidisciplinary approach to patient management is highly beneficial, with appropriate subspecialty opinion, early dietary review and a consideration of the impact of therapy on growth and development in younger patients. Long-term systemic steroid use is associated with a wide range of adverse effects, including infection, hyperglycaemia, hypertension, osteoporosis and dyspepsia. When steroid therapy cannot be avoided, patients should be monitored closely, with prescription of gastric protection, consideration of bone protection, and regular monitoring of blood glucose and blood pressure. It is also recognized that patient quality of life after HSCT may be compromised by cGVHD [ Pidala et al. 2011 ] and this should be acknowledged and formally assessed.

Novel therapies and further directions

Clearly there remains an urgent clinical need to optimize current therapies and to develop novel treatments for GVHD. Each of the therapeutic agents currently in use is associated with a significant risk of failure. Rather than developing universal treatment algorithms, it may be that we need to consider individualized therapy based on better characterization of GVHD subtypes, stages and the pathophysiological mechanisms involved.

Promising new directions include the inhibition of histone acetylation by vorinostat leading to a reduction in proinflammatory cytokine production, modulation of APC function and enhancement of regulatory T-cell number and activity [ Choi et al. 2012 ]. Similarly, administration of daily low-dose IL-2 to patients with cGVHD was associated with sustained expansion of these cells and amelioration of GVHD [ Koreth et al. 2011 ]. In a clinical study of haploidentical transplantation, investigators in Perugia demonstrated that adoptive transfer of regulatory T cells prevented GVHD in the absence of any post-transplantation immunosuppression [ Di Ianni et al. 2011 ]. Equally, blockage of the chemokine receptor CCR5 by maraviroc inhibited lymphocyte chemotaxis and prevented development of GVHD in an early clinical study [ Reshef et al. 2012 ]. Bortezomib has been shown to induce apoptosis in activated T cells via caspase activation and cleavage of the antiapoptotic bcl-2 protein and has recently entered early clinical trials [ Koreth et al. 2012 ]. Targeting inflamasome and danger signalling pathways may have a potential role in influencing the early stages of GVHD development (reviewed by Wolf and colleagues) [ Wolf et al. 2012 ].

Conclusion

The treatment and management of GVHD is continually changing as new therapies are proposed, trialled and validated. Although there is good evidence for the first-line management of both aGVHD and cGVHD with steroids and steroid-sparing agents, the most appropriate second-line treatment in both conditions remains unclear. Clearly there is a need for large systematic randomized studies to assess the efficacy and side effects of second-line therapies in GVHD management. By standardizing assessment tools for disease severity, outcome and quality of life, it is hoped that some of the variability seen in previous studies may be overcome. These trials should be conducted in conjunction with detailed laboratory analysis in an attempt to identify potential biomarkers predicting therapeutic responses with individual drugs as both aGVHD and cGVHD are biologically and clinically heterogeneous. Exciting prospects are on the horizon, in particular a role for MSCs in aGVHD management, and TKIs for the treatment of cGVHD. However, these remain to be validated in clinical practice. As our understanding of the pathophysiology underlying GVHD increases it seems likely that further therapeutic targets will continue to be identified.

Footnotes

Funding: The authors are grateful for support from the National Institute for Health Research Biomedical Research Centre funding scheme.

Conflict of interest statement: The authors have no potential conflicts of interest relevant to this article.

Contributor Information

Catherine Garnett, Imperial College London at Hammersmith Hospital, London, UK.

Jane F. Apperley, Imperial College London at Hammersmith Hospital, London, UK.

Jiří Pavlů, Department of Haematology, Imperial College Healthcare NHS Trust, Room 2.20 Catherine Lewis Centre, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK.

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Graft-versus-host disease

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Graft-versus-host disease
Specialty Emergency medicine   Edit this on Wikidata

Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person . GvHD is commonly associated with stem cell transplants such as those that occur with bone marrow transplants. GvHD also applies to other forms of transplanted tissues such as solid organ transplants.

White blood cells of the donor’s immune system which remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non-self). The white blood cells present within the transplanted tissue then attack the recipient’s body’s cells, which leads to GvHD. This should not be confused with a transplant rejection , which occurs when the immune system of the transplant recipient rejects the transplanted tissue; GvHD occurs when the donor’s immune system’s white blood cells reject the recipient. The underlying principle ( alloimmunity ) is the same, but the details and course may differ. GvHD can also occur after a blood transfusion if the blood products used have not been irradiated or treated with an approved pathogen reduction system.

Contents

  • 1 Signs and symptoms
    • 1.1 Types
  • 2 Causes
    • 2.1 Transfusion-associated GvHD
    • 2.2 Thymus transplantation
    • 2.3 Thymoma-associated multiorgan autoimmunity (TAMA)
  • 3 Mechanism
  • 4 Prevention
  • 5 Treatment
  • 6 Clinical research
  • 7 HIV elimination
  • 8 See also
  • 9 References
  • 10 Further reading
  • 11 External links

Signs and symptoms[ edit ]

In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the liver , skin (rash), mucosa , and the gastrointestinal tract . Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic system , e.g., the bone marrow and the thymus ) itself, and the lungs in the form of immune-mediated pneumonitis . Biomarkers can be used to identify specific causes of GvHD, such as elafin in the skin. [1] Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue and exocrine glands .[ citation needed ]

Acute GvHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GvHD is measured by the bilirubin level in acute patients. Skin GvHD results in a diffuse red maculopapular rash , sometimes in a lacy pattern.[ citation needed ]

Mucosal damage to the vagina can result in severe pain and scarring , and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse . [2]

Acute GvHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GvHD usually have a poor prognosis. If the GvHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection.[ citation needed ]

In the oral cavity , chronic graft-versus-host-disease manifests as lichen planus with a higher risk of malignant transformation to oral squamous cell carcinoma in comparison to the classical oral lichen planus. Graft-versus-host-disease-associated oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients. [3]

Types[ edit ]

In the clinical setting, graft-versus-host-disease is divided into acute and chronic forms, and scored or graded on the basis of the tissue affected and the severity of the reaction.

[4] [5]

  • The acute or fulminant form of the disease (aGvHD) is normally observed within the first 100 days post-transplant, [6] and is a major challenge to transplants owing to associated morbidity and mortality. [7]
  • The chronic form of graft-versus-host-disease (cGvHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival. [8]

Causes[ edit ]

GVHD pathology

Billingham Criteria : 3 criteria must be met in order for GvHD to occur. [2]

  • An immuno-competent graft is administered, with viable and functional immune cells.
  • The recipient is immunologically different from the donor – histo-incompatible .
  • The recipient is immuno-compromised and therefore cannot destroy or inactivate the transplanted cells.

After bone marrow transplantation, T cells present in the graft , either as contaminants or intentionally introduced into the host, attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokines , including TNF-α and interferon-gamma (IFNγ). A wide range of host antigens can initiate graft-versus-host-disease, among them the human leukocyte antigens (HLA). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different proteins (called minor histocompatibility antigens ) that can be presented by Major histocompatibility complex (MHC) molecules to the donor’s T-cells, which see these antigens as foreign and so mount an immune response. [9]

Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival). [10]

While donor T-cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient’s residual immune system from rejecting the bone marrow graft ( host-versus-graft ). In addition, as bone marrow transplantation is frequently used to treat cancer , mainly leukemias , donor T-cells have proven to have a valuable graft-versus- tumor effect. A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor effect.[ citation needed ]

Transfusion-associated GvHD[ edit ]

Main article: Transfusion-associated graft versus host disease

This type of GvHD is associated with transfusion of un-irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype . It is associated with higher mortality (80-90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GvHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within. [11]

Thymus transplantation[ edit ]

Thymus transplantation may be said to be able to cause a special type of GvHD because the recipient’s thymocytes would use the donor thymus cells as models when going through the negative selection to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GvHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient’s T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation experiments of the thymus between different species. [12] Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over 1 year post transplantation. [13] However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome , increases the risk of autoimmune disease. [14]

Thymoma-associated multiorgan autoimmunity (TAMA)[ edit ]

A GVHD-like disease called thymoma-associated multiorgan autoimmunity (TAMA) can occur in patients with thymoma. In these patients rather than a donor being a source of pathogenic T cells, the patient’s own malignant thymus produces self-directed T cells. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The end result is a disease virtually indistinguishable from GVHD. [15]

Mechanism[ edit ]

The pathophysiology of GVHD includes three phases:

  1. Activation of APC (antigen presenting cells)
  2. Activation, proliferation, differentiation and migration of effector cells
  3. Target tissue destruction

Activation of APC occurs in the first stage of GvHD. Prior to haematopoietic stem cell transplantation, radiation or chemotherapy results in damage and activation of host tissues, especially intestinal mucosa. This allows the microbial products to enter and stimulate pro-inflammatory cytokines such as IL-1 and TNF-α. These proinflammatory cytokines increase the expression of MHC and adhesion molecules on APCs, thereby increasing the ability of APC to present antigen. [16]
The second phase is characterized by the activation of effector cells. Activation of donor T-cells further enhances the expression of MHC and adhesion molecules, chemokines and the expansion of CD8 + and CD4 + T-cells and guest B-cells.
In the final phase, these effector cells migrate to target organs and mediate tissue damage, resulting in multiorgan failure. [17]

Prevention[ edit ]

  • DNA -based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GvHD and to increase long-term survival. [18]
  • The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity, [19] and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD. [20] The use of liver-derived hematopoietic stem cells to reconstitute bone marrow has the highest success rate according to recent studies.[ citation needed ]
  • Methotrexate , cyclosporin and tacrolimus are common drugs used for GVHD prophylaxis.[ citation needed ]
  • Graft-versus-host-disease can largely be avoided by performing a T-cell-depleted bone marrow transplant. However, these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure, or cancer relapse, [21] and general immunodeficiency , resulting in a patient more susceptible to viral , bacterial , and fungal infection . In a multi-center study, disease-free survival at 3 years was not different between T cell-depleted and T cell-replete transplants. [22]

Treatment[ edit ]

Intravenously administered glucocorticoids , such as prednisone , are the standard of care in acute GvHD [7] and chronic GVHD. [23] The use of these glucocorticoids is designed to suppress the T-cell-mediated immune onslaught on the host tissues; however, in high doses, this immune-suppression raises the risk of infections and cancer relapse. Therefore, it is desirable to taper off the post-transplant high-level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effect.[ citation needed ]. Cyclosporine and tacrolimus are calcineurin inhibitors . Both substances are structurally different but have the same mechanism of action. Cyclosporin binds to the cytosolic protein Peptidyl-prolyl cis-trans isomerase A (known as cyclophilin), while tacrolimus binds to the cytosolic protein Peptidyl-prolyl cis-trans isomerase FKBP12. These complexes inhibit calcineurin, block dephosphorylation of the transcription factor NFAT of activated T-cells and its translocation into the nucleus. [24] Standard prophylaxis involves the use of cyclosporine for six months with methotrexate. Cyclosporin levels should be maintained above 200 ng/ml. [25]
Other substances that have been studied for GvHD treatment include, for example: sirolimus , pentostatin , etanercept , and alemtuzamab . [25]

In August 2017 the US FDA approved ibrutinib to treat chronic GvHD after failure of one or more other systemic treatments. [26]

Clinical research[ edit ]

There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention. [27]

On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal , its drug for acute graft-versus host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved for a systemic disease. [28]

In January 2016, Mesoblast released results of a Phase2 clinical trial on 241 children with acute Graft-versus-host disease, that was not responsive to steroids. [29] The trial was of a mesenchymal stem cell therapy known as remestemcel-L or MSC-100-IV. Survival rate was 82% (vs 39% of controls) for those who showed some improvement after 1 month, and in the long term 72% (vs 18% of controls) for those that showed little effect after 1 month. [29]

HIV elimination[ edit ]

Graft versus host disease has been implicated in eliminating several cases of HIV, including the The Berlin Patient and 6 others in Spain.
[30]

See also[ edit ]

  • Graft-versus-tumor effect
  • Immunosuppression
  • Transplant rejection

References[ edit ]

  1. ^ Paczesny, S.; Levine, J.E.; Hogan, J.; Crawford, J.; Braun, T.M.; Wang, H.; Faca, V.; Zhang, Q.; et al. (2009). “Elafin is a Biomarker of Graft Versus Host Disease of the Skin”. Biology of Blood and Marrow Transplantation. 15 (2): 13–4. doi : 10.1016/j.bbmt.2008.12.039 .

  2. ^ a b Spiryda, L; Laufer, MR; Soiffer, RJ; Antin, JA (2003). “Graft-versus-host disease of the vulva and/or vagina: Diagnosis and treatment”. Biology of Blood and Marrow Transplantation. 9 (12): 760–5. doi : 10.1016/j.bbmt.2003.08.001 . PMID   14677115 .
  3. ^ Elad, Sharon; Zadik, Yehuda; Zeevi, Itai; Miyazaki, Akihiro; De Figueiredo, Maria A. Z.; Or, Reuven (2010). “Oral Cancer in Patients After Hematopoietic Stem-Cell Transplantation: Long-Term Follow-Up Suggests an Increased Risk for Recurrence”. Transplantation. 90 (11): 1243–4. doi : 10.1097/TP.0b013e3181f9caaa . PMID   21119507 .
  4. ^ Martino R, Romero P, Subirá M, Bellido M, Altés A, Sureda A, Brunet S, Badell I, Cubells J, Sierra J (1999). “Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry” . Bone Marrow Transplantation . 24 (3): 283–287. doi : 10.1038/sj.bmt.1701899 . PMID   10455367 .
  5. ^ Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME (2005). “National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report” . BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 11 (12): 945–956. doi : 10.1016/j.bbmt.2005.09.004 . PMID   16338616 .
  6. ^ “Improved Management of Graft-Versus-Host Disease” . National Marrow Donor Program .
  7. ^ a b Goker, H; Haznedaroglu, IC; Chao, NJ (2001). “Acute graft-vs-host disease Pathobiology and management”. Experimental Hematology. 29 (3): 259–77. doi : 10.1016/S0301-472X(00)00677-9 . PMID   11274753 .
  8. ^ Lee, Stephanie J.; Vogelsang, Georgia; Flowers, Mary E.D. (2003). “Chronic graft-versus-host disease”. Biology of Blood and Marrow Transplantation. 9 (4): 215–33. doi : 10.1053/bbmt.2003.50026 . PMID   12720215 .
  9. ^ Taylor CJ, Bolton EM, Bradley JA (2011). “Immunological considerations for embryonic and induced pluripotent stem cell banking” . Philosophical Transactions of the Royal Society B . 366 (1575): 2312–2322. doi : 10.1098/rstb.2011.0030 . PMC   3130422 . PMID   21727137 .
  10. ^ Solomon S, Pitossi F, Rao MS (2015). “Banking on iPSC–is it doable and is it worthwhile” . STEM CELL REVIEWS. 11 (1): 1–10. doi : 10.1007/s12015-014-9574-4 . PMC   4333229 . PMID   25516409 .
  11. ^ Moroff, G; Leitman, SF; Luban, NL (1997). “Principles of blood irradiation, dose validation, and quality control”. Transfusion. 37 (10): 1084–92. doi : 10.1046/j.1537-2995.1997.371098016450.x . PMID   9354830 .
  12. ^ Xia, G; Goebels, J; Rutgeerts, O; Vandeputte, M; Waer, M (2001). “Transplantation tolerance and autoimmunity after xenogeneic thymus transplantation”. Journal of Immunology. 166 (3): 1843–54. doi : 10.4049/jimmunol.166.3.1843 . PMID   11160231 .
  13. ^ Markert, M. Louise; Devlin, Blythe H.; McCarthy, Elizabeth A.; Chinn, Ivan K.; Hale, Laura P. (2008). “Thymus Transplantation” . In Lavini, Corrado; Moran, Cesar A.; Morandi, Uliano; et al. Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. pp. 255–67. doi : 10.1007/978-88-470-0828-1_30 . ISBN   978-88-470-0827-4 .
  14. ^ Markert, M. L.; Devlin, B. H.; Alexieff, M. J.; Li, J.; McCarthy, E. A.; Gupton, S. E.; Chinn, I. K.; Hale, L. P.; et al. (2007). “Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: Outcome of 44 consecutive transplants” . Blood. 109 (10): 4539–47. doi : 10.1182/blood-2006-10-048652 . PMC   1885498 . PMID   17284531 .
  15. ^ Wadhera A, Maverakis E, Mitsiades N, Lara PN, Fung MA, Lynch PJ (Oct 2007). “Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease”. J Am Acad Dermatol. 57 (4): 683–9. doi : 10.1016/j.jaad.2007.02.027 . PMID   17433850 .
  16. ^ Roncarolo, Maria-Grazia; Battaglia, Manuela (August 2007). “Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans”. Nature Reviews Immunology. 7 (8): 585–598. doi : 10.1038/nri2138 .
  17. ^ Zhang, L.; Chu, J.; Yu, J.; Wei, W. (7 December 2015). “Cellular and molecular mechanisms in graft-versus-host disease”. Journal of Leukocyte Biology. 99 (2): 279–287. doi : 10.1189/jlb.4ru0615-254rr .
  18. ^ Morishima, Y.; Sasazuki, T; Inoko, H; Juji, T; Akaza, T; Yamamoto, K; Ishikawa, Y; Kato, S; et al. (2002). “The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors”. Blood. 99 (11): 4200–6. doi : 10.1182/blood.V99.11.4200 . PMID   12010826 .
  19. ^ Grewal, S. S.; Barker, JN; Davies, SM; Wagner, JE (2003). “Unrelated donor hematopoietic cell transplantation: Marrow or umbilical cord blood?”. Blood. 101 (11): 4233–44. doi : 10.1182/blood-2002-08-2510 . PMID   12522002 .
  20. ^ Laughlin, Mary J.; Barker, Juliet; Bambach, Barbara; Koc, Omer N.; Rizzieri, David A.; Wagner, John E.; Gerson, Stanton L.; Lazarus, Hillard M.; et al. (2001). “Hematopoietic Engraftment and Survival in Adult Recipients of Umbilical-Cord Blood from Unrelated Donors”. New England Journal of Medicine. 344 (24): 1815–22. doi : 10.1056/NEJM200106143442402 . PMID   11407342 .
  21. ^ Hale, G; Waldmann, H (1994). “Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases”. Bone marrow transplantation. 13 (5): 597–611. PMID   8054913 .
  22. ^ Wagner, John E; Thompson, John S; Carter, Shelly L; Kernan, Nancy A; Unrelated Donor Marrow Transplantation Trial (2005). “Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): A multi-centre, randomised phase II–III trial”. The Lancet. 366 (9487): 733–41. doi : 10.1016/S0140-6736(05)66996-6 . PMID   16125590 .
  23. ^ Menillo, S A; Goldberg, S L; McKiernan, P; Pecora, A L (2001). “Intraoral psoralen ultraviolet a irradiation (PUVA) treatment of refractory oral chronic graft-versus-host disease following allogeneic stem cell transplantation”. Bone Marrow Transplantation. 28 (8): 807–8. doi : 10.1038/sj.bmt.1703231 . PMID   11781637 .
  24. ^ Liu, J; Farmer JD, Jr; Lane, WS; Friedman, J; Weissman, I; Schreiber, SL (23 August 1991). “Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes”. Cell. 66 (4): 807–15. doi : 10.1016/0092-8674(91)90124-h . PMID   1715244 .
  25. ^ a b Mandanas, Romeo A. “Graft Versus Host Disease Treatment & Management: Medical Care” . Medscape. Retrieved 30 August 2017.
  26. ^ FDA expands ibrutinib indications to chronic GVHD. Aug 2017
  27. ^ search of clinicaltrials.gov for Graft-versus-host disease
  28. ^ “World’s First Stem-Cell Drug Approval Achieved in Canada” . The National Law Review. Drinker Biddle & Reath LLP. 2012-06-12. Retrieved 2012-07-01.
  29. ^ a b “Increased Survival Using MSB Cells In Children With aGVHD” . Retrieved 22 Feb 2016.
  30. ^ “Immune war with donor cells after transplant may wipe out HIV” . ?. NewScientist. 2017-05-03. Retrieved 2018-11-23.

Further reading[ edit ]

  • Ferrara JLM, Deeg HJ, Burakoff SJ . Graft-Vs.-Host Disease: Immunology, Pathophysiology, and Treatment. Marcel Dekker, 1990 ISBN   0-8247-9728-0
  • Polsdorfer, JR Gale Encyclopedia of Medicine: Graft-vs.-host disease

External links[ edit ]

Classification
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