Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 6/2019

01-11-2019 | Graft-Versus-Host Disease | Review

Resolution of acute intestinal graft-versus-host disease

Authors: Sindhu Thiagarajan, Markus F. Neurath, Kai Hildner

Published in: Seminars in Immunopathology | Issue 6/2019

Login to get access

Abstract

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.
Literature
1.
2.
Blazar BR, Murphy WJ, Abedi M (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12(6):443–458PubMedPubMedCentral
3.
Vadakekolathu J, Rutella S (2017) T-cell manipulation strategies to prevent graft-versus-host disease in haploidentical stem cell transplantation. Biomedicines 5(2):33PubMedCentral
4.
Ferrara JL (2000) Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res 9(3):299–306PubMed
5.
Zeiser R, Blazar BR (2017) Acute graft-versus-host disease — biologic process, prevention, and therapy. N Engl J Med 377(22):2167–2179
6.
Holtan SG, Pasquini M, Weisdorf DJ (2014) Acute graft-versus-host disease: a bench-to-bedside update. Blood advances 124(3):363–373PubMedPubMedCentral
7.
8.
Markey KA, MacDonald KP, Hill GR (2014) The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood 124(3):354–362PubMedPubMedCentral
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):1064–1072PubMed
10.
Zeiser R (2015) Activation of innate immunity in graft-versus-host disease: implications for novel targets? Oncol Research and Treatment 38(5):239–243
11.
Jenq RR et al (2012) Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med 209(5):903–911
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):27–34PubMedPubMedCentral
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):12768–12773
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):35–41PubMedPubMedCentral
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):1783–1791PubMedPubMedCentral
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):1061–1075PubMedPubMedCentral
17.
Pickert G et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206(7):1465–1472PubMedPubMedCentral
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):1527–1537PubMed
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 111:33–40PubMed
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):1858–1869PubMedPubMedCentral
21.
Schwab L et al (2014) Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med 20:648PubMed
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):3347–3352PubMed
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):534–541
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):1439–1441PubMed
25.
Holler E, Weber D (2016) Fit for cure? Microbiota and GVHD. Blood 128(16):2004–2005PubMed
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):401–404PubMed
27.
Shono Y, van den Brink MRM (2018) Gut microbiota injury in allogeneic haematopoietic stem cell transplantation. Nat Rev Cancer 18:283PubMedPubMedCentral
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):845–852PubMedPubMedCentral
29.
Jenq RR et al (2015) Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant 21(8):1373–1383PubMedPubMedCentral
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):993–997PubMedPubMedCentral
31.
Ohnmacht C et al (2015) MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science 349(6251):989–993PubMed
32.
Atarashi K et al (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341PubMed
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):eaap9489PubMedPubMedCentral
34.
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol 4(4):330–336PubMed
35.
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061PubMed
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):20–21PubMed
37.
Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4 + CD25+ regulatory T cells. J Immunol 170(8):3939–3943PubMed
38.
Edinger M, Powrie F, Chakraverty R (2009) Regulatory mechanisms in graft-versus-host responses. Biology of Blood and Marrow Transplantation 15(1, Supplement):2–6PubMed
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):389–399PubMedCentralPubMed
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):3493–3499PubMed
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):1144–1150PubMed
42.
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):564–568PubMedPubMedCentral
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):3268–3276PubMedPubMedCentral
45.
Feagan BG et al (2013) Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 369(8):699–710
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):711–721PubMed
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):2919–2928PubMedPubMedCentral
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):2069–2078PubMed
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):135–145PubMedPubMedCentral
50.
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):1049–1059PubMed
52.
Spoerl S et al (2014) Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 123PubMed
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):1192–1202PubMed
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):745–751PubMed
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):890–899PubMed
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):99–104PubMed
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):1478–1484PubMed
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):1651–1659PubMed
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):866–871PubMedPubMedCentral
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):1121–1133PubMed
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):257–267PubMed
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):560–567PubMed
63.
Becher B, Tugues S, Greter M (2016) GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45(5):963–973PubMed
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):2101–2110PubMedPubMedCentral
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):5011–5020PubMedPubMedCentral
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):945–952PubMedPubMedCentral
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):170–178
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):1765–1772PubMed
69.
Ullrich E et al (2018) BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease. J Clin Invest 128(3):916–930PubMedPubMedCentral
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 9:1138PubMedPubMedCentral
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):eaat8410PubMed
Metadata
Title
Resolution of acute intestinal graft-versus-host disease
Authors
Sindhu Thiagarajan
Markus F. Neurath
Kai Hildner
Publication date
01-11-2019
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 6/2019
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-019-00769-w

Other articles of this Issue 6/2019

Seminars in Immunopathology 6/2019 Go to the issue

Review

Resolution in bullous pemphigoid

Review

The resolution of inflammation through omega-3 fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification

Review

Resolution of Crohn’s disease

Review

Resolution of inflammation during multiple sclerosis

Review

Resolution of allergic asthma

Review

Towards a pro-resolving concept in systemic lupus erythematosus

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits