Seminars in Immunopathology

, Volume 41, Issue 6, pp 655–664 | Cite as

Resolution of acute intestinal graft-versus-host disease

  • Sindhu Thiagarajan
  • Markus F. Neurath
  • Kai HildnerEmail author


Allogeneic transplantation of hematopoietic stem cells (allo-HCT) represents an increasingly employed therapeutic approach to potentially cure patients suffering from life-threatening malignant and autoimmune disorders. Despite its lifesaving potential, immune-mediated allo-reactivity inherent to the allogeneic transplantation can be observed within up to 50% of all allo-HCT patients regularly resulting in the manifestation of acute and/or chronic graft-versus-host disease (GvHD). Mechanistically, especially donor T cells are assumed to chiefly drive inflammation that can occur in virtually all organs, with the skin, liver, and gut representing as the most frequently affected anatomic sites. Especially in the presence of intestinal manifestations of GvHD, the risk that the disease takes a life-threatening, potentially fatal course is significantly increased. In the light of a rapid gain of knowledge in respect to decode innate and adaptive immunity related mechanisms as, e.g., cytokine networks, intracellular signaling pathways or environmental triggers as, e.g., the intestinal microbiota and the development of novel therapeutic approaches, detailed insight into endogenous mechanisms seeking to counterbalance the proinflammatory machinery or to proactively foster signals promoting the resolution of allo-driven intestinal inflammation is emerging. Here, we seek to highlight the key aspects of those mechanisms involved in and contributing to the resolution of GvHD-associated intestinal inflammation. Concomitantly, we would like to briefly outline and discuss promising future experimental targets suitable to be therapeutically employed to directionally deflect the tissue response from a proinflammatory to an inflammation-resolving type of intestinal GvHD after allo-HCT.


Allogeneic hematopoietic stem cell transplantation Intestinal graft-versus-host disease T cells resolution of intestinal GvHD 


Funding information

This study was supported by the Collaborative Research Center 1181 (DFG-CRC1181, project B05), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (to K.H) and the Collaborative Research Center 221 (DFG-CRC221, project B03 [K.H.].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373(9674):1550–1561PubMedPubMedCentralGoogle Scholar
  2. 2.
    Blazar BR, Murphy WJ, Abedi M (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12(6):443–458PubMedPubMedCentralGoogle Scholar
  3. 3.
    Vadakekolathu J, Rutella S (2017) T-cell manipulation strategies to prevent graft-versus-host disease in haploidentical stem cell transplantation. Biomedicines 5(2):33PubMedCentralGoogle Scholar
  4. 4.
    Ferrara JL (2000) Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res 9(3):299–306PubMedGoogle Scholar
  5. 5.
    Zeiser R, Blazar BR (2017) Acute graft-versus-host disease — biologic process, prevention, and therapy. N Engl J Med 377(22):2167–2179PubMedGoogle Scholar
  6. 6.
    Holtan SG, Pasquini M, Weisdorf DJ (2014) Acute graft-versus-host disease: a bench-to-bedside update. Blood advances 124(3):363–373PubMedPubMedCentralGoogle Scholar
  7. 7.
    Ferrara JLM, Chaudhry MS (2018) GVHD: biology matters. Blood Advances 2(22):3411PubMedCentralGoogle Scholar
  8. 8.
    Markey KA, MacDonald KP, Hill GR (2014) The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood 124(3):354–362PubMedPubMedCentralGoogle Scholar
  9. 9.
    Burman AC, Banovic T, Kuns RD, Clouston AD, Stanley AC, Morris ES, Rowe V, Bofinger H, Skoczylas R, Raffelt N, Fahy O, McColl S, Engwerda CR, McDonald K, Hill GR (2007) IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood 110(3):1064–1072Google Scholar
  10. 10.
    Zeiser R (2015) Activation of innate immunity in graft-versus-host disease: implications for novel targets? Oncol Research and Treatment 38(5):239–243Google Scholar
  11. 11.
    Jenq RR et al (2012) Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med 209(5):903–911Google Scholar
  12. 12.
    Elgaz S, Kuçi Z, Kuçi S, Bönig H, Bader P (2019) Clinical use of mesenchymal stromal cells in the treatment of acute graft-versus-host disease. Transfus Med Hemother 46(1):27–34PubMedPubMedCentralGoogle Scholar
  13. 13.
    Zindl CL et al (2013) IL-22–producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci USA 110(31):12768–12773Google Scholar
  14. 14.
    Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov II, Littman DR, O'Shea JJ (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206(1):35–41PubMedPubMedCentralGoogle Scholar
  15. 15.
    Aparicio-Domingo P et al (2015) Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J Exp Med 212(11):1783–1791PubMedPubMedCentralGoogle Scholar
  16. 16.
    Basu R, O'Quinn DB, Silberger DJ, Schoeb TR, Fouser L, Ouyang W, Hatton RD, Weaver CT (2012) Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37(6):1061–1075PubMedPubMedCentralGoogle Scholar
  17. 17.
    Pickert G et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206(7):1465–1472PubMedPubMedCentralGoogle Scholar
  18. 18.
    Couturier M et al (2013) IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect. Leukemia 27(7):1527–1537PubMedGoogle Scholar
  19. 19.
    Pan B, Xia F, Wu Y, Zhang F, Lu Z, Fu R, Shang L, Li L, Sun Z, Zeng L, Xu K (2018) Recipient-derived IL-22 alleviates murine acute graft-versus-host disease in association with reduced activation of antigen presenting cells. Cytokine 111:33–40PubMedGoogle Scholar
  20. 20.
    Hülsdünker J (2018) et al, Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset. Blood 131(16):1858–1869PubMedPubMedCentralGoogle Scholar
  21. 21.
    Schwab L et al (2014) Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med 20:648PubMedGoogle Scholar
  22. 22.
    Buron F, Perrin H, Malcus C, Héquet O, Thaunat O, Kholopp-Sarda MN, Moulin FT, Morelon E (2009) Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneic responses: an in vitro study using human cells. Transplant Proc 41(8):3347–3352PubMedGoogle Scholar
  23. 23.
    Prasad VK, Lucas KG, Kleiner GI, Talano JA, Jacobsohn D, Broadwater G, Monroy R, Kurtzberg J (2011) Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal™) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol of Blood and Marrow Transplant 17(4):534–541Google Scholar
  24. 24.
    Le Blanc K et al (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363(9419):1439–1441PubMedPubMedCentralGoogle Scholar
  25. 25.
    Holler E, Weber D (2016) Fit for cure? Microbiota and GVHD. Blood 128(16):2004–2005PubMedGoogle Scholar
  26. 26.
    van Bekkum DW et al (1974) Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst 52(2):401–404PubMedGoogle Scholar
  27. 27.
    Shono Y, van den Brink MRM (2018) Gut microbiota injury in allogeneic haematopoietic stem cell transplantation. Nat Rev Cancer 18:283PubMedGoogle Scholar
  28. 28.
    Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink M, Holler E (2017) Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 23(5):845–852PubMedPubMedCentralGoogle Scholar
  29. 29.
    Jenq RR et al (2015) Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant 21(8):1373–1383PubMedPubMedCentralGoogle Scholar
  30. 30.
    Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire A, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C (2015) MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 349(6251):993–997PubMedPubMedCentralGoogle Scholar
  31. 31.
    Ohnmacht C et al (2015) MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science 349(6251):989–993PubMedGoogle Scholar
  32. 32.
    Atarashi K et al (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341PubMedGoogle Scholar
  33. 33.
    Taur Y et al (2018) Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci transl med 10(460):eaap9489PubMedPubMedCentralGoogle Scholar
  34. 34.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol 4(4):330–336PubMedGoogle Scholar
  35. 35.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061PubMedGoogle Scholar
  36. 36.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21Google Scholar
  37. 37.
    Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4 + CD25+ regulatory T cells. J Immunol 170(8):3939–3943Google Scholar
  38. 38.
    Edinger M, Powrie F, Chakraverty R (2009) Regulatory mechanisms in graft-versus-host responses. Biology of Blood and Marrow Transplantation 15(1, Supplement):2–6Google Scholar
  39. 39.
    Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S (2002) Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 196(3):389–399PubMedCentralGoogle Scholar
  40. 40.
    Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99(10):3493–3499PubMedGoogle Scholar
  41. 41.
    Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS (2003) CD4 + CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9(9):1144–1150PubMedGoogle Scholar
  42. 42.
    Panduro M, Benoist C, Mathis D (2016) Tissue Tregs. Annu Rev Immunol 34:609–633PubMedPubMedCentralGoogle Scholar
  43. 43.
    Schiering C, Krausgruber T, Chomka A, Fröhlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN, Harrison OJ, Owens BMJ, Löhning M, Belkaid Y, Fallon PG, Powrie F (2014) The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513(7519):564–568PubMedPubMedCentralGoogle Scholar
  44. 44.
    Coghill JM, Sarantopoulos S, Moran TP, Murphy WJ, Blazar BR, Serody JS (2011) Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new. Blood 117(12):3268–3276PubMedPubMedCentralGoogle Scholar
  45. 45.
    Feagan BG et al (2013) Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 369(8):699–710PubMedGoogle Scholar
  46. 46.
    Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, Lukas M, Fedorak RN, Lee S, Bressler B, Fox I, Rosario M, Sankoh S, Xu J, Stephens K, Milch C, Parikh A, GEMINI 2 Study Group (2013) Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 369(8):711–721PubMedGoogle Scholar
  47. 47.
    Beilhack A et al (2008) Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 111(5):2919–2928PubMedPubMedCentralGoogle Scholar
  48. 48.
    Schreder A, Moschovakis GL, Halle S, Schlue J, Lee CW, Schippers A, David S, Bernhardt G, Ganser A, Pabst O, Förster R, Koenecke C (2015) Differential effects of gut-homing molecules CC chemokine receptor 9 and integrin-β7 during acute graft-versus-host disease of the liver. Biology of Blood and Marrow Transplantation 21(12):2069–2078PubMedGoogle Scholar
  49. 49.
    Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD, Goldstein SC, Stadtmauer EA, Smith J, Bailey S, Mick R, Heitjan DF, Emerson SG, Hoxie JA, Vonderheide RH, Porter DL (2012) Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med 367(2):135–145PubMedPubMedCentralGoogle Scholar
  50. 50.
    O’Shea JJ (2004) Targeting the Jak/STAT pathway for immunosuppression. Ann Rheum Dis 63(suppl 2):ii67–ii71PubMedPubMedCentralGoogle Scholar
  51. 51.
    Panés J et al (2017) Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut 66(6):1049–1059PubMedPubMedCentralGoogle Scholar
  52. 52.
    Spoerl S et al (2014) Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 123PubMedGoogle Scholar
  53. 53.
    Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P (2013) The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 122(7):1192–1202PubMedGoogle Scholar
  54. 54.
    Imamura M, Hashino S, Kobayashi H, Kubayashi S, Hirano S, Minagawa T, Tanaka J, Fujii Y, Kobayashi M, Kasai M (1994) Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. Bone Marrow Transplant 13(6):745–751PubMedGoogle Scholar
  55. 55.
    Holler E et al (1995) Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F). Blood 86(3):890–899PubMedGoogle Scholar
  56. 56.
    Remberger M, Ringden O, Markling L (1995) TNF alpha levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD. Bone Marrow Transplant 15(1):99–104Google Scholar
  57. 57.
    Yalniz FF, Hefazi M, McCullough K, Litzow MR, Hogan WJ, Wolf R, Alkhateeb H, Kansagra A, Damlaj M, Patnaik MM (2017) Safety and efficacy of infliximab therapy in the setting of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 23(9):1478–1484PubMedGoogle Scholar
  58. 58.
    Leclerc M et al (2016) Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells. Blood 128(12):1651–1659PubMedGoogle Scholar
  59. 59.
    Pierini A et al (2016) TNF-α priming enhances CD4 < sup > +</sup > FoxP3 < sup > +</sup > regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128(6):866–871PubMedPubMedCentralGoogle Scholar
  60. 60.
    Ivanov II, McKenzie B, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133PubMedGoogle Scholar
  61. 61.
    Leppkes M et al (2009) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136(1):257–267PubMedGoogle Scholar
  62. 62.
    Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12(6):560–567PubMedGoogle Scholar
  63. 63.
    Becher B, Tugues S, Greter M (2016) GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45(5):963–973PubMedGoogle Scholar
  64. 64.
    Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I, LeBon T, Kandeel F, Forman S, Zeng D (2008) Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 112(5):2101–2110PubMedPubMedCentralGoogle Scholar
  65. 65.
    Yu Y, Wang D, Liu C, Kaosaard K, Semple K, Anasetti C, Yu XZ (2011) Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORgammat in mice. Blood 118(18):5011–5020PubMedPubMedCentralGoogle Scholar
  66. 66.
    Kappel LW, Goldberg GL, King CG, Suh DY, Smith OM, Ligh C, Holland AM, Grubin J, Mark NM, Liu C, Iwakura Y, Heller G, van den Brink M (2009) IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 113(4):945–952PubMedPubMedCentralGoogle Scholar
  67. 67.
    Iclozan C et al (2010) T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol of blood and marrow transplant 16(2):170–178Google Scholar
  68. 68.
    Fulton LM et al (2012) Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORgammat. J Immunol 189(4):1765–1772PubMedCentralGoogle Scholar
  69. 69.
    Ullrich E et al (2018) BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease. J Clin Invest 128(3):916–930PubMedPubMedCentralGoogle Scholar
  70. 70.
    Buchele V et al (2018) Targeting inflammatory T helper cells via retinoic acid-related orphan receptor gamma t is ineffective to prevent allo-response-driven colitis. Front Immunol 9:1138PubMedPubMedCentralGoogle Scholar
  71. 71.
    Tugues S et al (2018) Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF–licensed myeloid cells. Sci Trans M 10(469):eaat8410PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicine 1, University Hospital ErlangenUniversity of Erlangen-Nuremberg, Kussmaul Campus for Medical ResearchErlangenGermany
  2. 2.University Hospital ErlangenDeutsches Zentrum Immuntherapie (DZI)ErlangenGermany

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