Review

Bone Marrow Transplantation (2008) 42, S66–S69; doi:10.1038/bmt.2008.119

Immune modulation and chronic graft-versus-host disease

R J Soiffer1

1Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA, USA

Correspondence: Dr RJ Soiffer, Division of Hematologic Malignancies, Dana Farber Cancer Institute, 44 Binney Street, Boston D3Q59, MA, USA. E-mail: robert_soiffer@dfci.harvard.edu

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Abstract

As more and more patients undergoing allogeneic hematopoietic SCT (HSCT) survive the early post-transplant period, the number of individuals at risk for chronic GVHD has grown. Treatment for established cGVHD remains unsatisfactory. No experimental agent has demonstrated superiority to steroids alone in a randomized clinical trial. Distinguishing chronic from acute graft-versus-host disease is a major issue. The importance of achieving clarity in cGVHD diagnosis is critical as efforts are undertaken to understand its pathogenesis and to design definitive trials that can target prevention and/or treatment. Immune tolerance to self-antigens may be broken in cGVHD, giving rise to the autoimmune manifestations of the disorder. Recent attention has focused on CD4+CD25 regulatory T cells and their relationship to cGVHD. Significant enthusiasm has emerged for manipulating Treg either ex vivo or in vivo for clinical benefit. Another immunomodulatory approach to cGVHD might be the targeting of B lymphocytes and the antibodies they produce. As efforts continue to devise strategies to treat and prevent chronic GVHD, it is important to acknowledge the link between cGVHD and freedom from relapse, at least for certain malignancies.

Keywords:

chronic GVHD, immune modulation, Tregs, B cells

Over the past 5 years, chronic graft-versus-host disease (cGVHD) has emerged as the most troublesome complication of allogeneic hematopoietic SCT (HSCT). Improvements in HLA typing for unrelated transplantation, adoption of new acute GVH prophylaxis measures, reductions in conditioning regimen intensity, introduction of new antimicrobial agents, and advances in supportive care have all helped to mitigate the early morbidity and mortality of allogeneic transplantation. As more and more patients survive the early post-transplant period, the number of individuals at risk for chronic GVHD has grown. This, in conjunction with the escalating trend toward the 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.1, 2, 3, 4, 5, 6 Unfortunately, treatment for established cGVHD remains unsatisfactory. Corticosteroids are the mainstay of therapy, but they are often not fully effective, and their long-term use leads to multiple complications.7, 8 Other agents, including calcineurin inhibitors, sirolimus, mycophenolate mofetil, thalidomide, pentostatin, 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.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19

The recognition of the impact cGVHD has upon the outcome and quality of life of transplanted survivors led to a recent consensus conference sponsored by the National Institutes of Health in part to revise definitions and scoring to assist with future clinical trials.20, 21, 22 Traditionally, any GVHD developing after Day +100 was considered chronic. Chronic GVHD is now characterized by its clinical manifestations rather than its temporal onset. Distinguishing chronic from acute graft-versus-host disease is a major issue. The consensus group identified two subcategories of acute and chronic GVHD. These include classic acute, persistent/late onset acute, classic chronic, and overlap syndrome.

The importance of achieving clarity in cGVHD diagnosis is critical as efforts are undertaken to understand its pathogenesis and to design definitive trials that can target prevention and/or treatment. Attempts to study cGVHD experimentally have been somewhat hampered by the absence of a reliable animal model that mimics the syndrome in humans. T cells most likely play a central role as effectors of cGVHD. Low rates of cGVHD have been reported after ex vivo T cell-depleted allogeneic marrow transplantation from HLA identical siblings.23, 24 In vivo T cell depletion with alemtuzumab or antithymocyte globulin has also been reported to produce low rates of chronic graft-versus-host disease.25, 26, 27 However, in a large randomized multicenter trial of unrelated bone marrow transplantation comparing T cell depletion plus cyclosporine to methotrexate and cyclosporine, there was no difference in the incidence of chronic GVHD disease despite a reduction in acute GVHD.28

It has been suggested that immune tolerance to self-antigens is broken in cGVHD, giving rise to the autoimmune manifestations of the disorder. Recent attention has focused on CD4+CD25 regulatory T cells and their relationship to cGVHD. Of note, patients with certain autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis exhibit deficiencies in Treg number and function.29, 30, 31 In several series, including our own, Treg number as measured by CD4+CD25+FoxP3+ staining was diminished in patients with cGVHD.32, 33, 34 Moreover, Treg number returned to normal in patients with resolved cGVHD. However, there have been conflicting data on Treg number and cGVHD. In one study, patients with chronic graft-versus-host disease had significantly increased Treg cells when compared to patients without cGVHD.35 When purified, these Treg demonstrated suppressive capabilities in vitro, which were hypothesized to account for the immune deficiency of patients with cGVHD. Ambiguity in the immunophenotypic identification of Treg (CD4+CD25+FoxP3+CD127− cells) makes it difficult to evaluate many of these reports. In addition, it remains unclear whether the blood compartment is representative of Treg content and activity in secondary lymphoid organs and target tissues.

The mechanism by which Tregs suppress graft-versus-host reactions remains uncertain, but there is evidence that suppression is mediated by cytokines such as transforming growth factor (TGF)-β and IL-10 or by contact with plasmacytoid dendritic cells through indoleamine 2,3-dioxygenase (IDO).36 Treg may also exert inhibitory influence directly in target tissues.37 A reduction in the number of mucosal Foxp3+ regulatory T cells has been documented in patients with acute and chronic GVHD compared to normal controls or patients without GVHD.38 In experimental models, the absence of regulatory T cell control of Th1 and Th17 cells has been associated with autoimmune-mediated pathology in chronic GVHD.39

Although the biologic control of Treg and their direct impact on GVHD remain incompletely defined, significant enthusiasm has emerged for manipulating Treg either ex vivo or in vivo for clinical benefit. Unfortunately, the ex vivo expansion of cells for human transplantation is still cumbersome and does not yet appear to yield reliably reproducible products for clinical use. Initial studies will be needed to determine how long expanded Treg survive and function in vivo to define the most appropriate schedule of infusions in treatment protocols for established chronic GVHD. An alternative approach for patients with established GVH could be directed toward in vivo expansion of Treg. It has also been suggested that current approaches, such as sirolimus, mycophenolate mofetil and extra-corporeal photopheresis (ECP), exert their effect through expansion of Treg.40, 41, 42, 43 A potentially intriguing strategy might be the use of interleukin-2 (IL-2). Interleukin-2 (IL-2) is essential to the generation and expansion of Treg in vitro and in vivo.44, 45 Laboratory studies from clinical trials of low dose recombinant IL-2 in patients with HIV infection or cancer have shown that Treg numbers were increased in these cancer patients receiving low dose IL-2 in vivo.46, 47 We demonstrated that prolonged low-dose IL-2 administration after allogeneic transplantation can preferentially expand Tregs compared to conventional T cells and does not induce GVHD.47 A study that evaluated the use of CD8-depleted donor lymphocyte infusion (DLI) followed by 8 weeks of low dose IL-2 designed to increase graft-versus-leukemia (GVL) activity resulted in a large expansion of CD4+CD25+Foxp3+ Treg with potent immune suppressive properties (Zorn et al., personal communication). A clinical trial evaluating the safety and efficacy of low dose IL-2 in patients with established chronic GVHD is now underway.

Another immunomodulatory approach to cGVHD might be the targeting of B lymphocytes and the antibodies they produce. There are numerous examples of auto-antibody formation in patients with cGVHD, though their role in its pathogenesis has not been elucidated.48 Of particular note is a study in which antibodies to platelet derived growth factor were observed in patients with cGVHD but not in those without it.49 These antibodies had the capacity to induce both tyrosine phosphorylation of PDGF receptor and type I collagen gene expression by fibroblasts. A murine study has suggested that depletion of donor B cells protected mice from cGVHD.50 The role of B cell activity in cGVHD is underscored by the observation that high plasma levels of BAFF (B cell activating factor), a cytokine that appears to drive B cell autoimmunity, were noted in patients with cGVHD.51 In fact, high plasma levels of BAFF 6 months post-transplant predicted for the subsequent development of cGVHD in asymptomatic patients. The development antibodies to minor histocompatibility antigens encoded on the Y chromosome in male patients receiving female grafts have been strongly associated with cGVHD incidence.52 The evidence supporting a role for B cells and antibodies in cGVHD has prompted trials of rituximab with responses documented in over 50% of subjects in phase 2 trials.53, 54 More definitive trials establishing rituximab efficacy are needed. Currently, we are exploring the use of rituximab in a prophylactic mode, beginning 3 months after transplantation, in hopes of preventing cGVHD development.

As efforts continue to devise strategies to treat and prevent chronic GVHD, it is important to acknowledge the link between cGVHD and freedom from relapse, at least for certain malignancies. If we are successful in completely preventing cGVHD, we may also dampen graft-versus-tumor (GVT) effects. This is of particular concern in nonmyeloablative transplantation where GVT, and not cytotoxic chemotherapy, is the primary mechanism of tumor eradication. In some studies, the development of limited cGVHD has been associated with optimal survival.1 Unraveling the cellular and molecular basis of cGVHD and GVT will be critical if we are able to provide our patients with safe and effective approaches to allogeneic transplantation in the future.

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Conflict of interest

The author declared no financial interests.

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