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Review

Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease

, &
Pages 469-484 | Received 13 Jan 2016, Accepted 14 Mar 2016, Published online: 06 Apr 2016

References

  • Pasquini MC. Current use and outcomes of hematopoietic stem cell transplantation, CIBMTR summary slides, 2014. [Online] [2014]. Available from: http://www.cibmtr.org.
  • Ferrara JL, Levine JE, Reddy P, et al. Graft-versus-host disease. Lancet. 2009;373:1550–1561.
  • Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296–307.
  • Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.
  • Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–828.
  • MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21:761–767.
  • MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8:387–394.
  • Castilla-Llorente C, Martin PJ, McDonald GB, et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014;49:966–971.
  • Harris AC, Young R, Devine S, et al. International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium. Biol Blood Marrow Transplant. 2015 Sep 16. doi:10.1016/j.bbmt.2015.09.001.
  • Zeiser R, Penack O, Holler E, et al. Danger signals activating innate immunity in graft-versus-host disease. J Mol Med (Berl). 2011;89:833–845.
  • Hill GR, Crawford JM, Cooke KR, et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90:3204–3213.
  • Miura Y, Thoburn CJ, Bright EC, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood. 2004;104:2187–2193.
  • Dutt S, Ermann J, Tseng D, et al. L-selectin and beta7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease. Blood. 2005;106:4009–4015.
  • Palmer LA, Sale GE, Balogun JI, et al. Chemokine receptor CCR5 mediates alloimmune responses in graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:311–319.
  • Varona R, Cadenas V, Gómez L, et al. CCR6 regulates CD4+ T-cell-mediated acute graft-versus-host disease responses. Blood. 2005;106:18–26.
  • Braun MY, Lowin B, French L, et al. Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. J Exp Med. 1996;183:657–661.
  • Van Kraaij MG, Dekker AW, Verdonck LF, et al. Infectious gastro-enteritis: an uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients. Bone Marrow Tranplant. 2000;26:299–303.
  • Khan K, Schwarzenberg SJ, Sharp H, et al. Diagnostic endoscopy in children after hematopoietic stem cell transplantation. Gastrointest Endosc. 2006;64:379–385.
  • Johansson J-E, Nilsson O, Stotzer P-O. Colonoscopy and sigmoidoscopy are equally effective for the diagnosis of colonic acute graft-versus-host disease in patients with diarrhea after allogeneic stem cell transplantation: a prospective controlled trial. Biol Blood Marrow Transplant. 2015;21:2086–2090.
  • Aslanian H, Chander B, Robert M, et al. Prospective evaluation of acute graft-versus-host disease. Dig Dis Sci. 2012;57:720–725.
  • Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 2012;37:339–350.
  • Takashima S, Kadowaki M, Aoyama K, et al. The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. J Exp Med. 2011;208:285–294.
  • Selbst MK, Ahrens WA, Robert ME, et al. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Mod Pathol. 2009;22:737–743.
  • Lerner KG, Kao GF, Storb R, et al. Histopathology of graft-vs.-host reaction (GvHR) in human recipients of marrow from HL-A-matched sibling donors. Transplant Proc. 1974;6:367–371.
  • Washington K, Jagasia M. Pathology of graft-versus-host disease in the gastrointestinal tract. Hum Pathol. 2009;40:909–917.
  • Levine JE, Huber E, Hammer ST, et al. Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood. 2013;122:1505–1509.
  • Levine JE, Logan BR, Wu J, et al. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a blood and marrow transplant clinical trials network study. Blood. 2012;119:3854–3860.
  • Ranganathan P, Heaphy CE, Costinean S, et al. Regulation of acute graft-versus-host disease by microRNA-155. Blood. 2012;119:4786–4797.
  • Chien JW, Zhang XC, Fan W, et al. Evaluation of published single nucleotide polymorphisms associated with acute GVHD. Blood. 2012;119:5311–5319.
  • Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470–2475.
  • Choi SW, Kitko CL, Braun T, et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival. Blood. 2008;112:1539–1542.
  • Ferrara JL, Harris A, Greenson JK, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011;118:6702–6708.
  • Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.
  • Vander Lugt M, Braun TM, Hanash S, et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013;369:529–539.
  • Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute-graft-versus-host disease based on biomarkers: a multicenter study. Lancet Haematol. 2015;2:e21–e29.
  • Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate severe acute graft-versus-host disease after allogeneic bone marrow transplantation – an analysis of clinical risk features and outcome. Blood. 1990;75:1024–1030.
  • Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood. 1990;76:1464–1472.
  • Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:1504–1518.
  • Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Haematologica. 2015;100:842–848.
  • Hockenbery DM, Cruickshank S, Rodell TC. A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparin therapy for gastrointestinal graft-versus-host disease. Blood. 2007;109:4557–4563.
  • Van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood. 1998;92:2288–2293.
  • Frame DG, Markstrom D, Pogue J, et al. High budesonide bioavailability in patients with gastrointestinal (GI) graft versus host disease (GVHD) and/or Clostridium difficile infection. Biol Blood Marrow Transplant. 2009;15:133.
  • Bertz H, Afting M, Kreisel W, et al. Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transplant. 1999;24:1185–1189.
  • Castilla C, Pérez-Simón JA, Sanchez-Guijo FM, et al. Oral beclomethasone dipropionate for the treatment of gastrointestinal acute graft-versus-host disease (GVHD). Biol Blood Marrow Transplant. 2006;12:936–941.
  • Weintraub JL, Belanger AR, Sung CC, et al. Intra-arterial methylprednisolone infusion in treatment-resistant graft-versus-host disease. Cardiovasc Intervent Radiol. 2010;33:509–512.
  • Bürgler D, Medinger M, Passweg J, et al. Intra-arterial catheter guided steroid administration for the treatment of steroid-refractory intestinal GvHD. Leuk Res. 2014;38:184–187.
  • Nishimoto M, Koh H, Hirose A, et al. Efficacy and safety of intra-arterial steroid infusions in patients with steroid-resistant gastrointestinal acute graft-versus-host disease. Exp Hematol. 2015;43:995–1000.
  • Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation. 2001;72:1924–1929.
  • Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation. 2015;80:110–117.
  • Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124:1372–1377.
  • Wang L, Gu Z, Zhai R, et al. The efficacy and safety of sirolimus-based graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. Tranfusion. 2015;55:2134–2141.
  • Pidala J, Tomblyn M, Nishihori T, et al. Sirolimus demonstrates activity in the primary therapy of acute graft-versus-host disease without systemic glucocorticoids. Haematologica. 2011;96:1351–1356.
  • Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2010;45:1347–1351.
  • Furlong T, Martin P, Flowers ME, et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant. 2009;44:739–748.
  • Inagaki J, Kodama Y, Fukano R, et al. Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2015;19:652–658.
  • Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009;114:511–517.
  • Bolaños-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014;124:3221–3227.
  • Parfitt JR, Jayakumar S, Driman DK. Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes. Am J Surg Pathol. 2008;32:1367–1372.
  • Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia. N Engl J Med. 1994;330:691–697.
  • Alam N, Atenafu EG, Tse G, et al. Limited benefit of pentostatin salvage therapy for steroid-refractory grade III-IV acute graft-versus-host disease. Clin Transplant. 2013;27:930–937.
  • Pidala J, Kim J, Roman-Diaz J, et al. Pentostatin as rescue therapy for glucocorticoid-refractory acute and chronic graft-versus-host disease. Ann Transplant. 2010;15:21–29.
  • Schmitt T, Luft T, Hegenbart U, et al. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant. 2011;46:580–585.
  • Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomized, open-label, multicenter phase 3 trial. Lancet Oncol. 2009;10:855–864.
  • Soiffer RJ, Lerademacher J, Ho V, et al. Impact of immune modulation with anti-T cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood. 2011;117:6963–6970.
  • MacMillan ML, Weisdorf DJ, Davies SM, et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8:40–46.
  • Arai S, Margolis J, Zaburak M, et al. Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment. Biol Blood Marrow Transplant. 2002;8:155–160.
  • Van Lint MT, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin. Blood. 2006;107:4177–4181.
  • Nishimoto M, Nakamae H, Koh H, et al. Response-guided therapy for steroid-refractory acute GVHD starting with very-low-dose antithymocyte globulin. Exp Hematol. 2015;43:177–179.
  • Le G, Cobbold S, Novitzky N, et al. CAMPATH-1 antibodies in stem-cell transplantation. Cytotherapy. 2001;3:145–164.
  • Mead AJ, Thomson KJ, Morris EC, et al. HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning. Blood. 2010;115:5147–5153.
  • Gómez-Almaguer D, Ruiz-Argüelles GJ, et al. Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:10–15.
  • Meunier M, Bulabois CE, Thiebaut-Bertrand A, et al. Alemtuzumab for severe steroid-refractory gastrointestinal acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1451–1454.
  • Patriarca F, Sperotto A, Damiani D. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica. 2004;89:1352–1359.
  • Nogueira MC, Azevedo AM, Pereira SC, et al. Anti-tumor necrosis factor-a for the treatment of steroid-refractory acute graft-versus-host disease. Braz J Med Biol Res. 2007;40:1623–1629.
  • Pidala J, Kim J, Field T, et al. Infliximab for managing steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:1116–1121.
  • Couriel DR, Saliba R, De Lima M, et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:1555–1562.
  • Sieper J, Van Den Brande J. Diverse effects of infliximab and etanercept on T lymphocytes. Semin Arthritis Rheum. 2005;34:23–27.
  • Park JH, Lee HJ, Kim SR, et al. Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation. Korean J Intern Med. 2014;29:630–636.
  • Busca A, Locatelli F, Marmont F, et al. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2007;82:45–52.
  • Tawara I, Koyama M, Liu C, et al. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res. 2011;17:77–88.
  • Kennedy GA, Varelias A, Vuckovic S, et al. Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014;15:1451–1459.
  • Drobyski WR, Pasquini M, Kovatovic K, et al. Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant. 2011;17:1862–1868.
  • Roddy JV, Haverkos BM, McBride A, et al. Tocilizumab for steroid refractory acute graft-versus-host disease. Leuk Lymphoma. 2016;57(1):81–85.
  • Gatza E, Rogers CE, Clouthier SG, et al. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood. 2008;112:1515–1521.
  • Kitko CL, Levine JE. Extracorporeal photopheresis in prevention and treatment of acute GVHD. Transfus Apher Sci. 2015;52:151–156.
  • Rubegni P, Feci L, Poggiali S, et al. Extracorporeal photopheresis: a useful therapy for patients with steroid-refractory acute graft-versus-host disease but not for the prevention of the chronic form. Br J Dermatol. 2013;169:450–457.
  • Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. 2006;91:405–408.
  • Jagasia M, Greinix H, Robin M, et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant. 2013;18:1129–1133.
  • Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 2008;42:609–617.
  • Bay JO, Dhédin N, Goerner M, et al. Inolimomab in steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies. Transplantation. 2005;80:782–788.
  • García-Cadenas I, Valcárcel D, Martino R, et al. Updated experience with inolimomab as treatment for corticosteroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2013;19:435–439.
  • Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005;130:568–574.
  • Wang JZ, Liu KY, Xu LP, et al. Basiliximab for the treatment of steroid-refractory acute graft-versus-host disease after unmanipulated HLA-mismatched/haploidentical hematopoietic stem cell transplantation. Transplant Proc. 2011;43:1928–1933.
  • Bordigoni P, Dimicoli S, Clement L, et al. Daclizumab, an efficient treatment for steroid-refractory acute graft-versus-host disease. Br J Haematol. 2006;135:382–385.
  • Perales MA, Ishill N, Lomazow WA, et al. Long-term follow-up of patients treated with daclizumab for steroid-refractory acute graft-vs-host disease. Bone Marrow Transplant. 2007;40:481–486.
  • Shaughnessy PJ, Bachier C, Grimley M, et al. Denileukin diftitox for the treatment of steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant. 2005;11:188–193.
  • Ho VT, Zahrieh D, Hochberg E, et al. Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104:1224–1226.
  • Lee SJ, Zahrieh D, Agura E, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood. 2004;104:1559–1564.
  • Sawamukai N, Satake A, Schmidt AM, et al. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD. Blood. 2012;119:5575–5583.
  • Tao R, De Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007;13:1299–1307.
  • Reddy P, Sun Y, Toubai T, et al. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest. 2008;118:2562–2573.
  • Choi SW, Braun T, Chang L, et al. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014;15:87–95.
  • Perez L, Field T, Riches ML, et al. A phase I/II trial evaluating the use of a histone deacetylase inhibitor panobinostat (LBH589) in addition to glucocorticoids in patients with acute graft-versus-host disease. Blood. 2014;124:1167.
  • Schneidawind D, Pierini A, Negrin RS. Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood. 2013;122:3116–3121.
  • Brunstein CG, Miller JS, Cao Q, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117:1061–1070.
  • Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–3928.
  • Ringdén O, Erkers T, Nava S, et al. Fetal membrane cells for treatment of steroid-refractory acute graft-versus-host disease. Stem Cells. 2013;31:592–601.
  • Manochantr S, U-pratya Y, Kheolamai P, et al. Immunosuppressive properties of mesenchymal stromal cells derived from amnion, placenta, Wharton’s jelly and umbilical cord. Intern Med J. 2013;43:430–439.
  • Miura Y. Human bone marrow mesenchymal stromal/stem cells: current clinical applications and potential for hematology. Int J Hematol. 2016;103:122–128.
  • Fang B, Song Y, Liao L, et al. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc. 2007;39:3358–3362.
  • von Dalowski F, Kramer M, Wermke M, et al. Mesenchymal stromal cells for treatment of acute steroid-refractory GvHD: clinical responses and long-term outcome. Stem Cells. 2015; published online 13 October 2015. doi:10.1002/stem.2224.
  • Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–1586.
  • Kebriaei P, Isola L, Bahceci E, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:804–811.
  • Martin PJ, Uberti JP, Soiffer RJ, et al. Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease (SR-GVHD) involving the liver and gut: results of a randomized, placebo-controlled, multicenter phase III trial in GVHD. Biol Blood Marrow Transplant. 2010;16:S169–S170.
  • Hashmi S, Ahmed M, Murad MH, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol. 2016;3:e45–52.
  • Chen YB, McDonough S, Chen H, et al. Expression of α4β7 integrin on memory CD8(+) T cells at the presentation of acute intestinal GVHD. Bone Marrow Transplant. 2013;48:598–603.
  • Chen Y-B, Kim HT, McDonough S, et al. Up-Regulation of alpha4beta7 integrin on peripheral T cell subsets correlates with the development of acute intestinal graft-versus-host disease following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:1066–1076.
  • Engelhardt BG, Jagasia M, Savani BN, et al. Regulatory T cell expression of CLA or α(4)β(7) and skin or gut acute GVHD outcomes. Bone Marrow Transplant. 2011;46:436–442.
  • Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007;132:1672–1683.
  • Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–721.
  • Choi SW, Hildebrandt GC, Olkiewicz KM, et al. CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation. Blood. 2007;110:3447–3455.
  • Reshef R, Luger SM, Hexner EO, et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012;367:135–145.
  • Leonhardt F, Zirlik K, Buchner M, et al. Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels. Leukemia. 2012;26:1617–1629.
  • Kontzias A, Laurence A, Gadina M, et al. Kinase inhibitors in the treatment of immune-mediated disease. F1000 Med Rep. 2012;4:5.
  • Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123:3832–3842.
  • Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem. 2007;282:20059–20063.
  • Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29:2062–2068.
  • Tawara I, Sun Y, Lewis EC, et al. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A. 2012;109:564–569.
  • Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012;209:903–911.
  • Holler E, Butzhammer P, Schmid K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:640–645.
  • Van Bekkum DW, Roodenburg J, Heidt PJ, et al. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst. 1974;52:401–404.
  • Jenq RR, Taur Y, Devlin SM, et al. Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:1373–1383.
  • Weber D, Oefner PJ, Hiergeist A, et al. Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood. 2015;126:1723–1728.
  • Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14:282–289.
  • Bejaoui M, Sokol H, Marteau P. Targeting the microbiome in inflammatory bowel disease: critical evaluation of current concepts and moving to new horizons. Dig Dis. 2015;33:105–112.
  • Lindemans CA, Mertelsmann A, O’Connor MH, et al. IL-22 is an intestinal stem cell growth factor, and IL-22 administration in vivo reduces morbidity and mortality in murine GVHD. Blood. 2014;124:651.
  • Lindemans CA, Calafiore M, Mertelsmann AM, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature. 2015;528:560–564.
  • Dohi T, Borodovsky A, Wu P, et al. TWEAK/Fn14 pathway: a nonredundant role in intestinal damage in mice through a TWEAK/intestinal epithelial cell axis. Gastroenterology. 2009;136:912–923.
  • Chopra M, Brandl A, Siegmund D, et al. Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD. Blood. 2015;126:437–444.
  • Nencioni A, Schwarzenberg K, Brauer KM, et al. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood. 2006;108:551–558.
  • Blanco B, Pérez-Simón JA, Sánchez-Abarca LI, et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood. 2006;107:3575–3583.
  • Koreth J, Stevenson KE, Kim HT, et al. Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors. Blood. 2009;114:3956–3959.
  • Furlan SN, Watkins B, Tkachev V, et al. Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention. Sci Transl Med. 2015;7:315.
  • Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. 2012;4:a006957.
  • Florek M, Sega EI, Leveson-Gower DB, et al. Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models. Blood. 2014;124:1832–1842.
  • Mevorach D, Zuckerman T, Reiner I, et al. Single infusion of donor mononuclear early apoptotic cells as prophylaxis for graft-versus-host disease in myeloablative HLA-matched allogeneic bone marrow transplantation: a phase I/IIa clinical trial. Biol Blood Marrow Transplant. 2014;20:58–65.
  • Clark RB, Bishop-Bailey D, Estrada-Hernandez T, et al. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol. 2000;164:1364–1371.
  • Song EK, Yim JM, Yim JY, et al. Rosiglitazone prevents graft-versus-host disease (GVHD). Transpl Immunol. 2012;27:128–137.
  • Saubermann LJ, Nakajima A, Wada K, et al. Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. Inflamm Bowel Dis. 2002;8:330–339.
  • Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant. 2009;15:777–784.
  • Weisdorf DJ, Hurd D, Carter S, et al. Prospective grading of graft-versus-host disease after unrelated donor marrow transplantation: a grading algorithm versus blinded expert panel review. Biol Blood Marrow Transplant. 2003;9:512–518.

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