VOLUME 31 䡠 NUMBER 35 䡠 DECEMBER 10 2013
JOURNAL OF CLINICAL ONCOLOGY
UNDERSTANDING THE PATHWAY
Pleiotropic Approach to Graft-Versus-Host Disease Areej El-Jawahri and Yi-Bin Chen, Massachusetts General Hospital, and Dana-Farber Cancer Institute, Boston MA See accompanying article on page 4416
Acute graft-versus-host disease (GVHD) is one of the main complications of allogeneic hematopoietic stem-cell transplantation (HSCT).1 Acute GVHD is thought to occur as a result of alloreactivity arising from mismatches in major or minor histocompatibility antigens between donor and recipient.1,2 The immunologic sequence of events leading to acute GVHD is initiated with the activation of antigen-presenting cells (APCs) and their presentation of host antigens to alloreactive donor lymphocytes in secondary lymphoid tissue.3 This is followed by activation, proliferation, and differentiation of these lymphocytes into T-helper type 1 (Th1) effector cells.4 These
Conditioning injury
effector cells then migrate to host target tissues where direct cytotoxicity along with locally and systemically released cytokines result in end-organ damage (Figure 1).1,5 Traditionally, prophylactic and therapeutic strategies for GVHD have relied on generalized immunosuppression.6 Given the lack of specificity, these methods often resulted in infectious complications as well as possible disease relapse due to suppression of the potentially curative graft-versus-malignancy effect.7 Certainly, better targeted and more effective therapies for the prevention and treatment of acute GVHD are needed.
Acetyl-CoA HMG-CoA Mevalonate GTP binding protein modification
TH2
Statin
STAT-6
TNF-α IL-1
Statin
APC (I) Host APC Activation
FOXP3
Donor T-Cell (II) Donor T-Cell Activation
TH1
LFA-1
TNF-α IL-1
T-cell trafficking
Treg
Target Cell Apoptosis TNF-α IL-1
CD4 CTL
(III) Cellular & Inflammatory Effectors
CD8 CTL
CD8 CTL
Fig 1. The immunomodulatory effects of statins on the pathophysiology of acute graft-versus-host disease (GVHD). The sequence of events leading to acute GVHD can be summarized by the following processes: (1) the activation of antigen-presenting cells (APCs) and the presentation of host antigens, a process exacerbated by tissue damage from conditioning chemotherapy and radiation; (2) donor T-cell activation occurs via direct interaction with APC costimulatory molecules, which results in T-cell proliferation and differentiation into T-helper type 1 (TH1) cells. T cells then use various adhesion molecules including leukocyte function-associated antigen 1 (LFA-1) to migrate to target tissues.3 Activated effector T cells (CD4 and CD8 cytotoxic T lymphocytes) in the presence of a local and systemic inflammatory milieu results in target cell apoptosis and end-organ damage. Conversely, regulatory T cells (Tregs) limit the proliferation of activated donor T cells. Statins may have an impact on many processes involved in acute GVHD. By blocking mevalonate biosynthesis, statins modulate intracellular signaling cascades by inhibiting post-translational modification of GTP-binding proteins. This results in statin-mediated suppression of T-cell activation (by inhibiting APC-dependent T-cell activation), polarization toward a T-helper type 2 (TH2) response (via STAT6 signaling), and upregulation of Tregs (via FOXP3 upregulation). Statins can also directly bind to LFA-1 and block T-cell migration and trafficking into target organs. CoA, coenzyme A; CTL, cytotoxic T-cell lymphocyte; GTP, guanosine triphosphate; HMG-CoA, 3-hydroxy-3-methyl-glutarylcoenzyme A; IL-1, interleukin-1; TNF-␣, tumor necrosis factor-␣. 4462
© 2013 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 31, No 35 (December 10), 2013: pp 4462-4464
Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on November 17, Copyright © 2013 American of Clinical Oncology. All rights reserved. 2015Society from 128.122.230.132
Pleiotropic Approach to GVHD
The class of agents called statins (3-hydroxy-3-methyl-glutarylcoenzyme A [HMG-CoA] reductase inhibitors) are commonly used medications for the treatment of hyperlipidemia and atherosclerotic vascular disease.8 Statins inhibit HMG-CoA reductase by displacing its natural substrate HMG-CoA, leading to inhibition of mevalonate and cholesterol biosynthesis.8,9 In addition to their impact on cholesterol synthesis, statins possess a multitude of anti-inflammatory effects, commonly referred to as “the pleiotropic effect of statins.”10-12 By inhibiting mevalonate biosynthesis, statins suppress production of isoprenoid intermediates that are necessary for the post-translation modifications of guanosine triphosphate (GTP) – binding cell signaling proteins such as Ras, Rho, and Rac.12,13 In doing so, statins affect intracellular signaling pathways that are critical for cellular proliferation, migration, differentiation, and secretion with resulting modulation of immune function.12,13 These immunomodulatory effects include suppression of T-cell activation and trafficking, polarization toward a T-helper type 2 (Th2) cytokine profile, and modulation of regulatory T cells, all of which may serve to suppress acute GVHD (Fig 1).9 T-cell activation is a critical step in any immunologic response, including acute GVHD. Statins can impair T-cell activation by preventing the expression of major histocompatibility complex (MHC) class II antigens on APCs.14,15 In addition, statins inhibit the APC surface expression of CD40, CD80, and CD86, all of which are important costimulatory molecules for T-cell activation.9 Furthermore, statins have been shown to modulate T-cell migration by binding to a lovastatin-binding site on the extracellular domain of leukocyte function-associated antigen 1, an adhesion molecule that functions in T-cell trafficking to target organs.16,17 Statins also play a role in T-cell differentiation and inducing a Th2-type immunologic response.10,18 Analysis of cytokines before HSCT has shown that an increased Th2-type cytokine profile is associated with less acute GVHD.19-21 Via their inhibition of Ras signaling, statins inhibit the secretion of proinflammatory Th1 cytokines such as interferon-␥, tumor necrosis factor-␣, interleukin-1 (IL-1), and IL6.10,15 Furthermore, statins appear to induce the production of Th2 cytokines such as IL-4, IL-5, and IL-10.10 This polarization toward Th2 cytokines involves activation of signal transducer and activator transcription 6 (STAT6).2 STAT6 is required for IL-4 – dependent Th2-lineage commitment.22,23 In a murine model, atorvastatintreated T cells had higher expression of phosphorylated STAT6 with resulting increased expression of c-MAF and GATA-3, which are important for Th2 commitment.2 Statin-mediated changes in intracellular signaling can also have an impact on the development of regulatory T cells (Tregs), which have been shown to play a protective role against GVHD.24 Treg differentiation is promoted by statin use in a protein geranylgeranylation-dependent mechanism.25 Statin induced inhibition of protein geranylgeranylation (a post-translational modification) is associated with demethylation and activation of the FOXP3 promoter, a transcription factor that is critical for Treg differentiation.25,26 Given the array of immunologic changes affected by statins, it is possible that their administration to either host or donor can modulate acute GVHD. In MHC-mismatched murine models, treating either donor or recipient mice with atorvastatin afforded protection from acute GVHD with an additive effect seen when treating both parties.2 The atorvastatin effect was partially reversed in STAT6–/– www.jco.org
donors, illustrating the importance of STAT6 signaling. Donor pretreatment with atorvastatin led to inhibition of T-cell expansion and higher expression of IL-10, a Th2 cytokine, and placebo treatment showed increased levels of interferon-␥ and tumor necrosis factor-␣ (Th1 cytokines) after transplantation. Host APCs isolated from the liver and spleen of atorvastatin-treated recipient mice showed reduction in expression of MHC II, CD80, CD86, and CD40 on their cell surfaces, and an increase in the number of Tregs was also noted.2 Importantly, treatment with atorvastatin did not interfere with perforin-mediated cytolysis or Fas-Fas ligand interactions, pathways which are thought to mediate the graft-versus-malignancy effect.2 These promising preclinical data led investigators to assess the impact of statins on acute GVHD in the human clinical setting. In retrospective studies, statin use by donors and/or recipients appeared to decrease the risk of grade 3 to 4 acute GVHD, with no difference in treatment-related mortality or disease relapse.27-29 In the report accompanying our article in Journal of Clinical Oncology, Hamadani et al30 conducted a phase II trial evaluating the safety and efficacy of atorvastatin (40 mg per day orally) use in both donors and recipients of matched sibling allogeneic HSCT in addition to standard tacrolimus-based prophylaxis. Rates of grade 2 to 4 acute GVHD at days ⫹100 and ⫹180 were 3.3% and 11.1%, respectively, which were lower than historical rates in this population with standard prophylaxis approaches. Importantly, atorvastatin appeared to be safe in this clinical setting, with no significant adverse events. Interestingly, the rate of chronic GVHD in this study was 43.5% at 1 year, although atorvastatin use was continued in recipients for the duration of immunosuppression. These findings contrast with the results of a large retrospective study, which suggested a reduction in chronic GVHD with recipient statin use.29 In addition, in a study in a murine model with some features resembling chronic GVHD, the use of statins was associated with significant attenuation of skin and pulmonary chronic GVHD, reduction in lung fibrosis, and reduction in chemokine concentration and number of inflammatory cells in bronchoalveolar lavage samples.31 In fact, pravastatin has been used in a small prospective study for the treatment of chronic GVHD with some improvements noted in severity of disease and a bias toward a Th2 cytokine profile.32 Statins are an attractive class of agents that merit further investigation, given their reassuring safety profile and widespread availability. Because of their more targeted effects on immunologic pathways, statins are less likely to cause generalized immunosuppression and, thus, can potentially spare significant morbidity. Future studies should focus on validating the clinical efficacy of statins in preventing acute GVHD, and the next appropriate step would be a large collaborative phase III randomized trial. Correlative studies will be vital to further delineate and understand the mechanisms behind any effect observed. This developing story exemplifies an increasingly popular strategy of using readily available and cost-effective agents that have been developed and approved for other indications for the therapy of a rare disease with a limited market, such as acute GVHD. We hope other advances will follow. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a © 2013 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on November 17, Copyright © 2013 American of Clinical Oncology. All rights reserved. 2015Society from 128.122.230.132
4463
El-Jawahri and Chen
financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Yi-Bin Chen, Seattle Genetics (C) Stock Ownership: None
REFERENCES 1. Ferrara JL, Cooke KR, Teshima T: The pathophysiology of acute graft-versus-host disease. Int J Hematol 78:181-187, 2003 2. Zeiser R, Youssef S, Baker J, et al: Preemptive HMG-CoA reductase inhibition provides graftversus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity. Blood 110:4588-4598, 2007 3. Xun CQ, Thompson JS, Jennings CD, et al: Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood 83:2360-2367, 1994 4. Shlomchik WD, Couzens MS, Tang CB, et al: Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285: 412-415, 1999 5. Nestel FP, Greene RN, Kichian K, et al: Activation of macrophage cytostatic effector mechanisms during acute graft-versus-host disease: Release of intracellular iron and nitric oxidemediated cytostasis. Blood 96:1836-1843, 2000 6. Vogelsang GB, Hess AD: Graft-versus-host disease: New directions for a persistent problem. Blood 84:2061-2067, 1994 7. Reshef R, Luger SM, Hexner EO, et al: Blockade of lymphocyte chemotaxis in visceral graftversus-host disease. N Engl J Med 367:135-145, 2012 8. Liao JK, Laufs U: Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89-118, 2005 9. Hamadani M, Craig MD, Gibson LF, et al: The evolving role of statins in hematopoietic stem and progenitor cell transplantation. Am J Blood Res 1:57-64, 2011 10. Youssef S, Stu¨ve O, Patarroyo JC, et al: The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78-84, 2002 11. Leung BP, Sattar N, Crilly A, et al: A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170:1524-1530, 2003
Honoraria: None Research Funding: Yi-Bin Chen, Genentech, Seattle Genetics, Otsuka Pharmaceutical, Onyx/Bayer Expert Testimony: None Patents: None Other Remuneration: None
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
12. Greenwood J, Steinman L, Zamvil SS: Statin therapy and autoimmune disease: From protein prenylation to immunomodulation. Nat Rev Immunol 6:358-370, 2006 13. Greenwood J, Walters CE, Pryce G, et al: Lovastatin inhibits brain endothelial cell Rhomediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 17:905-907, 2003 14. Sadeghi MM, Tiglio A, Sadigh K, et al: Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocompatibility complex class II gene activation by HMG-CoA reductase inhibitors. Transplantation 71:1262-1268, 2001 15. Kuipers HF, van den Elsen PJ: Immunomodulation by statins: Inhibition of cholesterol vs. isoprenoid biosynthesis. Biomed Pharmacother 61: 400-407, 2007 16. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7:687-692, 2001 17. Wang Y, Li D, Jones D, et al: Blocking LFA-1 activation with lovastatin prevents graft-versushost disease in mouse bone marrow transplantation. Biol Blood Marrow Transplant 15:1513-1522, 2009 18. Dunn SE, Youssef S, Goldstein MJ, et al: Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med 203:401-412, 2006 19. Lin MT, Storer B, Martin PJ, et al: Relation of an interleukin-10 promoter polymorphism to graft-versushost disease and survival after hematopoietic-cell transplantation. N Engl J Med 349:2201-2210, 2003 20. Holler E, Roncarolo MG, Hintermeier-Knabe R, et al: Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation. Bone Marrow Transplant 25: 237-241, 2000 21. Baker KS, Roncarolo MG, Peters C, et al: High spontaneous IL-10 production in unrelated bone marrow transplant recipients is associated with fewer transplantrelated complications and early deaths. Bone Marrow Transplant 23:1123-1129, 1999 22. Kaplan MH, Schindler U, Smiley ST, et al: Stat6 is required for mediating responses to IL-4 and
for development of Th2 cells. Immunity 4:313-319, 1996 23. Darnell JE Jr: STATs and gene regulation. Science 277:1630-1635, 1997 24. Mausner-Fainberg K, Luboshits G, Mor A, et al: The effect of HMG-CoA reductase inhibitors on naturally occurring CD4⫹CD25⫹ T cells. Atherosclerosis 197:829-839, 2008 25. Kagami S, Owada T, Kanari H, et al: Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3⫹ regulatory T cells. Int Immunol 21:679-689, 2009 26. Bu DX, Griffin G, Lichtman AH: Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol 22:165-170, 2011 27. Hamadani M, Awan FT, Devine SM: The impact of HMG-CoA reductase inhibition on the incidence and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic transplantation. Blood 111:3901-3902, 2008 28. Rotta M, Storer BE, Storb RF, et al: Donor statin treatment protects against severe acute graftversus-host disease after related allogeneic hematopoietic cell transplantation. Blood 115:1288-1295, 2010 29. Rotta M, Storer BE, Storb R, et al: Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 16:1463-1466, 2010 30. Hamadani M, Gibson L, Remick S, et al: Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graftversus-host disease. J Clin Oncol 31:4416-4423, 2013 31. Yoon HK, Lim JY, Kim TJ, et al: Effects of pravastatin on murine chronic graft-versus-host disease. Transplantation 90:853-860, 2010 32. Hori A, Kanda Y, Goyama S, et al: A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease. Transplantation 79:372374, 2005
DOI: 10.1200/JCO.2013.52.8182; published online ahead of print at www.jco.org on October 28, 2013
■ ■ ■
4464
© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on November 17, Copyright © 2013 American of Clinical Oncology. All rights reserved. 2015Society from 128.122.230.132
JOURNAL OF CLINICAL ONCOLOGY
UNDERSTANDING THE PATHWAY
Pleiotropic Approach to Graft-Versus-Host Disease Areej El-Jawahri and Yi-Bin Chen, Massachusetts General Hospital, and Dana-Farber Cancer Institute, Boston MA See accompanying article on page 4416
Acute graft-versus-host disease (GVHD) is one of the main complications of allogeneic hematopoietic stem-cell transplantation (HSCT).1 Acute GVHD is thought to occur as a result of alloreactivity arising from mismatches in major or minor histocompatibility antigens between donor and recipient.1,2 The immunologic sequence of events leading to acute GVHD is initiated with the activation of antigen-presenting cells (APCs) and their presentation of host antigens to alloreactive donor lymphocytes in secondary lymphoid tissue.3 This is followed by activation, proliferation, and differentiation of these lymphocytes into T-helper type 1 (Th1) effector cells.4 These
Conditioning injury
effector cells then migrate to host target tissues where direct cytotoxicity along with locally and systemically released cytokines result in end-organ damage (Figure 1).1,5 Traditionally, prophylactic and therapeutic strategies for GVHD have relied on generalized immunosuppression.6 Given the lack of specificity, these methods often resulted in infectious complications as well as possible disease relapse due to suppression of the potentially curative graft-versus-malignancy effect.7 Certainly, better targeted and more effective therapies for the prevention and treatment of acute GVHD are needed.
Acetyl-CoA HMG-CoA Mevalonate GTP binding protein modification
TH2
Statin
STAT-6
TNF-α IL-1
Statin
APC (I) Host APC Activation
FOXP3
Donor T-Cell (II) Donor T-Cell Activation
TH1
LFA-1
TNF-α IL-1
T-cell trafficking
Treg
Target Cell Apoptosis TNF-α IL-1
CD4 CTL
(III) Cellular & Inflammatory Effectors
CD8 CTL
CD8 CTL
Fig 1. The immunomodulatory effects of statins on the pathophysiology of acute graft-versus-host disease (GVHD). The sequence of events leading to acute GVHD can be summarized by the following processes: (1) the activation of antigen-presenting cells (APCs) and the presentation of host antigens, a process exacerbated by tissue damage from conditioning chemotherapy and radiation; (2) donor T-cell activation occurs via direct interaction with APC costimulatory molecules, which results in T-cell proliferation and differentiation into T-helper type 1 (TH1) cells. T cells then use various adhesion molecules including leukocyte function-associated antigen 1 (LFA-1) to migrate to target tissues.3 Activated effector T cells (CD4 and CD8 cytotoxic T lymphocytes) in the presence of a local and systemic inflammatory milieu results in target cell apoptosis and end-organ damage. Conversely, regulatory T cells (Tregs) limit the proliferation of activated donor T cells. Statins may have an impact on many processes involved in acute GVHD. By blocking mevalonate biosynthesis, statins modulate intracellular signaling cascades by inhibiting post-translational modification of GTP-binding proteins. This results in statin-mediated suppression of T-cell activation (by inhibiting APC-dependent T-cell activation), polarization toward a T-helper type 2 (TH2) response (via STAT6 signaling), and upregulation of Tregs (via FOXP3 upregulation). Statins can also directly bind to LFA-1 and block T-cell migration and trafficking into target organs. CoA, coenzyme A; CTL, cytotoxic T-cell lymphocyte; GTP, guanosine triphosphate; HMG-CoA, 3-hydroxy-3-methyl-glutarylcoenzyme A; IL-1, interleukin-1; TNF-␣, tumor necrosis factor-␣. 4462
© 2013 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 31, No 35 (December 10), 2013: pp 4462-4464
Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on November 17, Copyright © 2013 American of Clinical Oncology. All rights reserved. 2015Society from 128.122.230.132
Pleiotropic Approach to GVHD
The class of agents called statins (3-hydroxy-3-methyl-glutarylcoenzyme A [HMG-CoA] reductase inhibitors) are commonly used medications for the treatment of hyperlipidemia and atherosclerotic vascular disease.8 Statins inhibit HMG-CoA reductase by displacing its natural substrate HMG-CoA, leading to inhibition of mevalonate and cholesterol biosynthesis.8,9 In addition to their impact on cholesterol synthesis, statins possess a multitude of anti-inflammatory effects, commonly referred to as “the pleiotropic effect of statins.”10-12 By inhibiting mevalonate biosynthesis, statins suppress production of isoprenoid intermediates that are necessary for the post-translation modifications of guanosine triphosphate (GTP) – binding cell signaling proteins such as Ras, Rho, and Rac.12,13 In doing so, statins affect intracellular signaling pathways that are critical for cellular proliferation, migration, differentiation, and secretion with resulting modulation of immune function.12,13 These immunomodulatory effects include suppression of T-cell activation and trafficking, polarization toward a T-helper type 2 (Th2) cytokine profile, and modulation of regulatory T cells, all of which may serve to suppress acute GVHD (Fig 1).9 T-cell activation is a critical step in any immunologic response, including acute GVHD. Statins can impair T-cell activation by preventing the expression of major histocompatibility complex (MHC) class II antigens on APCs.14,15 In addition, statins inhibit the APC surface expression of CD40, CD80, and CD86, all of which are important costimulatory molecules for T-cell activation.9 Furthermore, statins have been shown to modulate T-cell migration by binding to a lovastatin-binding site on the extracellular domain of leukocyte function-associated antigen 1, an adhesion molecule that functions in T-cell trafficking to target organs.16,17 Statins also play a role in T-cell differentiation and inducing a Th2-type immunologic response.10,18 Analysis of cytokines before HSCT has shown that an increased Th2-type cytokine profile is associated with less acute GVHD.19-21 Via their inhibition of Ras signaling, statins inhibit the secretion of proinflammatory Th1 cytokines such as interferon-␥, tumor necrosis factor-␣, interleukin-1 (IL-1), and IL6.10,15 Furthermore, statins appear to induce the production of Th2 cytokines such as IL-4, IL-5, and IL-10.10 This polarization toward Th2 cytokines involves activation of signal transducer and activator transcription 6 (STAT6).2 STAT6 is required for IL-4 – dependent Th2-lineage commitment.22,23 In a murine model, atorvastatintreated T cells had higher expression of phosphorylated STAT6 with resulting increased expression of c-MAF and GATA-3, which are important for Th2 commitment.2 Statin-mediated changes in intracellular signaling can also have an impact on the development of regulatory T cells (Tregs), which have been shown to play a protective role against GVHD.24 Treg differentiation is promoted by statin use in a protein geranylgeranylation-dependent mechanism.25 Statin induced inhibition of protein geranylgeranylation (a post-translational modification) is associated with demethylation and activation of the FOXP3 promoter, a transcription factor that is critical for Treg differentiation.25,26 Given the array of immunologic changes affected by statins, it is possible that their administration to either host or donor can modulate acute GVHD. In MHC-mismatched murine models, treating either donor or recipient mice with atorvastatin afforded protection from acute GVHD with an additive effect seen when treating both parties.2 The atorvastatin effect was partially reversed in STAT6–/– www.jco.org
donors, illustrating the importance of STAT6 signaling. Donor pretreatment with atorvastatin led to inhibition of T-cell expansion and higher expression of IL-10, a Th2 cytokine, and placebo treatment showed increased levels of interferon-␥ and tumor necrosis factor-␣ (Th1 cytokines) after transplantation. Host APCs isolated from the liver and spleen of atorvastatin-treated recipient mice showed reduction in expression of MHC II, CD80, CD86, and CD40 on their cell surfaces, and an increase in the number of Tregs was also noted.2 Importantly, treatment with atorvastatin did not interfere with perforin-mediated cytolysis or Fas-Fas ligand interactions, pathways which are thought to mediate the graft-versus-malignancy effect.2 These promising preclinical data led investigators to assess the impact of statins on acute GVHD in the human clinical setting. In retrospective studies, statin use by donors and/or recipients appeared to decrease the risk of grade 3 to 4 acute GVHD, with no difference in treatment-related mortality or disease relapse.27-29 In the report accompanying our article in Journal of Clinical Oncology, Hamadani et al30 conducted a phase II trial evaluating the safety and efficacy of atorvastatin (40 mg per day orally) use in both donors and recipients of matched sibling allogeneic HSCT in addition to standard tacrolimus-based prophylaxis. Rates of grade 2 to 4 acute GVHD at days ⫹100 and ⫹180 were 3.3% and 11.1%, respectively, which were lower than historical rates in this population with standard prophylaxis approaches. Importantly, atorvastatin appeared to be safe in this clinical setting, with no significant adverse events. Interestingly, the rate of chronic GVHD in this study was 43.5% at 1 year, although atorvastatin use was continued in recipients for the duration of immunosuppression. These findings contrast with the results of a large retrospective study, which suggested a reduction in chronic GVHD with recipient statin use.29 In addition, in a study in a murine model with some features resembling chronic GVHD, the use of statins was associated with significant attenuation of skin and pulmonary chronic GVHD, reduction in lung fibrosis, and reduction in chemokine concentration and number of inflammatory cells in bronchoalveolar lavage samples.31 In fact, pravastatin has been used in a small prospective study for the treatment of chronic GVHD with some improvements noted in severity of disease and a bias toward a Th2 cytokine profile.32 Statins are an attractive class of agents that merit further investigation, given their reassuring safety profile and widespread availability. Because of their more targeted effects on immunologic pathways, statins are less likely to cause generalized immunosuppression and, thus, can potentially spare significant morbidity. Future studies should focus on validating the clinical efficacy of statins in preventing acute GVHD, and the next appropriate step would be a large collaborative phase III randomized trial. Correlative studies will be vital to further delineate and understand the mechanisms behind any effect observed. This developing story exemplifies an increasingly popular strategy of using readily available and cost-effective agents that have been developed and approved for other indications for the therapy of a rare disease with a limited market, such as acute GVHD. We hope other advances will follow. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a © 2013 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on November 17, Copyright © 2013 American of Clinical Oncology. All rights reserved. 2015Society from 128.122.230.132
4463
El-Jawahri and Chen
financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Yi-Bin Chen, Seattle Genetics (C) Stock Ownership: None
REFERENCES 1. Ferrara JL, Cooke KR, Teshima T: The pathophysiology of acute graft-versus-host disease. Int J Hematol 78:181-187, 2003 2. Zeiser R, Youssef S, Baker J, et al: Preemptive HMG-CoA reductase inhibition provides graftversus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity. Blood 110:4588-4598, 2007 3. Xun CQ, Thompson JS, Jennings CD, et al: Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood 83:2360-2367, 1994 4. Shlomchik WD, Couzens MS, Tang CB, et al: Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285: 412-415, 1999 5. Nestel FP, Greene RN, Kichian K, et al: Activation of macrophage cytostatic effector mechanisms during acute graft-versus-host disease: Release of intracellular iron and nitric oxidemediated cytostasis. Blood 96:1836-1843, 2000 6. Vogelsang GB, Hess AD: Graft-versus-host disease: New directions for a persistent problem. Blood 84:2061-2067, 1994 7. Reshef R, Luger SM, Hexner EO, et al: Blockade of lymphocyte chemotaxis in visceral graftversus-host disease. N Engl J Med 367:135-145, 2012 8. Liao JK, Laufs U: Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89-118, 2005 9. Hamadani M, Craig MD, Gibson LF, et al: The evolving role of statins in hematopoietic stem and progenitor cell transplantation. Am J Blood Res 1:57-64, 2011 10. Youssef S, Stu¨ve O, Patarroyo JC, et al: The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78-84, 2002 11. Leung BP, Sattar N, Crilly A, et al: A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170:1524-1530, 2003
Honoraria: None Research Funding: Yi-Bin Chen, Genentech, Seattle Genetics, Otsuka Pharmaceutical, Onyx/Bayer Expert Testimony: None Patents: None Other Remuneration: None
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
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DOI: 10.1200/JCO.2013.52.8182; published online ahead of print at www.jco.org on October 28, 2013
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