Elsevier

The Lancet

Volume 373, Issue 9674, 2–8 May 2009, Pages 1550-1561
The Lancet

Seminar
Graft-versus-host disease

https://doi.org/10.1016/S0140-6736(09)60237-3Get rights and content

Summary

Haemopoietic-cell transplantation (HCT) is an intensive therapy used to treat high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. The main complication of HCT is graft-versus-host disease (GVHD), an immunological disorder that affects many organ systems, including the gastrointestinal tract, liver, skin, and lungs. The number of patients with this complication continues to grow, and many return home from transplant centres after HCT requiring continued treatment with immunosuppressive drugs that increases their risks for serious infections and other complications. In this Seminar, we review our understanding of the risk factors and causes of GHVD, the cellular and cytokine networks implicated in its pathophysiology, and current strategies to prevent and treat the disease. We also summarise supportive-care measures that are essential for management of this medically fragile population.

Introduction

The number of allogeneic haemopoietic-cell transplantations (HCTs) continues to rise, with more than 25 000 procedures undertaken annually. The graft-versus-leukaemia or graft-versus-tumour effect during this procedure effectively eradicates many haematological malignant diseases.1 Development of novel strategies that use donor leucocyte infusions, non-myeloablative conditioning, and umbilical-cord blood transplantation has helped expand the indications for allogeneic HCT over the past few years, especially for older patients.2 Improvements in infectious prophylaxis, immunosuppressive treatments, supportive care, and DNA-based tissue typing have also contributed to enhanced outcomes after the technique.1 Yet, the major complication of allogeneic HCT—graft-versus-host disease (GVHD)—remains lethal and limits use of this important procedure.2 In view of current trends, the number of transplants from unrelated donors is expected to double within the next 5 years, substantially increasing the population of patients with GVHD. In this Seminar, we review advances made in identification of genetic risk factors and pathophysiology of this major HCT complication and its prevention, diagnosis, and treatment.

Section snippets

Cause and clinical features

50 years ago, Billingham formulated three requirements for development of GVHD: (1) the graft must contain immunologically competent cells; (2) the recipient must express tissue antigens that are not present in the transplant donor; and (3) the patient must be incapable of mounting an effective response to eliminate the transplanted cells.3 We know now that the immunologically competent cells are T cells and that GVHD can develop in various clinical settings when tissues containing T cells

Clinical features of acute GVHD

On the basis of early work, acute GVHD was defined as arising before day 100 post-transplant, whereas chronic disease happened after that time.23, 24, 25 This definition is far from satisfactory, and a National Institutes of Health classification includes late-onset acute GVHD (after day 100) and an overlap syndrome with features of both acute and chronic disorder.26, 27 Late-onset acute GVHD and the overlap syndrome arise with greater frequency after reduced-intensity conditioning, an

Clinical features of chronic GVHD

Chronic GVHD is the major cause of late non-relapse death after HCT.40 Its presentation can be progressive (active or acute GVHD merging into chronic), quiescent (acute disease that resolves completely but is followed later by chronic), or de novo. Older recipient age and a history of acute GVHD are the greatest risk factors for chronic disease.41 Therefore, strategies for acute GVHD prevention could help to prevent chronic disease. Panel 2 shows that manifestations of chronic GVHD are somewhat

Pathophysiology of acute GVHD

Two important principles should be considered with respect to the pathophysiology of acute GVHD. First, the disease is indicative of exaggerated but typical inflammatory mechanisms mediated by donor lymphocytes infused into the recipient, in whom they function appropriately in view of the foreign environment they encounter. Second, the recipient's tissues that stimulate donor lymphocytes have usually been damaged by underlying disease, previous infections, and the transplant conditioning

Prevention of GVHD

On the basis of evidence from animal models for the central role of T cells in initiation of GVHD, many clinical studies of T-cell depletion as prophylaxis for the disease were undertaken in the 1980s and 1990s. Three main depletion strategies were studied: (1) negative selection of T cells ex vivo; (2) positive selection of CD34+ stem cells ex vivo; and (3) antibodies against T cells in vivo.82 Most approaches showed substantial limitation of both acute and chronic GVHD.83, 84, 85

Treatment of acute GVHD

GVHD first develops, generally, in the second month after HCT during calcineurin-based prophylaxis.114 Steroids, with their potent anti-lymphocyte and anti-inflammatory activity, are the gold standard for treatment of GVHD. Many centres treat mild GVHD of the skin (grade I) with topical steroids alone, but for more severe disease and any degree of visceral GVHD involvement high-dose systemic steroids are usually initiated. Administration of steroids results in complete remission in less than

Treatment of chronic GVHD

By contrast with acute GVHD, the pathophysiology of chronic GVHD remains poorly understood and the disease is treated with various immunosuppressive agents. The response of chronic GVHD to treatment is unpredictable, and mixed responses in different organs can take place in the same patient. Confounding variables such as infection and comorbidities also make responses hard to measure. Use of corticosteroids (with or without a calcineurin inhibitor) is the standard of care, but findings of a

Essential supportive care in GVHD patients

Meticulous supportive care is vital for patients with both acute and chronic GVHD owing to the extended duration of immunosuppressive regimens and because the many drugs administered could have synergistic toxic effects. Such care includes extensive infectious prophylaxis, early interventions in cases of suspected infections, and prophylaxis against non-infectious side-effects of drugs (table). These complications usually need rapid responses to prevent serious or irreversible damage and are

Future directions

As allogeneic transplantation becomes an increasingly attractive therapeutic option, need for novel approaches to GVHD has accelerated. The number of patients receiving transplants from unrelated donors is expected to double in the next 5 years, substantially boosting the population of patients with GVHD.

The advent of reduced-intensity conditioning regimens has diminished transplant-related mortality and lengthened the period during which acute GVHD can develop (many new cases present up to day

Search strategy and selection criteria

We searched PubMed and Medline with the term “GVHD” and cross-referenced it with the following words: “clinical”, “cytokines”, “MHC”, “HLA antigens”, “biology”, and “immunology”. We included mostly peer-reviewed original and review journal articles published within the past decade, except for seminal articles that initially described the clinical features. All non-peer-reviewed manuscripts, supplements, and textbooks were excluded.

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