Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease

Mucosal Immunology

Volumn 8, Issue 4, 2015, Pages 720-730

  Nalle, S C ^a,b   Turner, J R ^b  

^a GENENTECH INC   (United States)

^b UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EPIDERMAL GROWTH FACTOR; PATTERN RECOGNITION RECEPTOR; TOLL LIKE RECEPTOR; VEDOLIZUMAB;

ADOPTIVE TRANSFER; DISEASE ASSOCIATION; DRUG TARGETING; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNE SYSTEM; IMMUNOPATHOGENESIS; INFLAMMATORY BOWEL DISEASE; INTESTINAL BARRIER LOSS; INTESTINE EPITHELIUM; INTESTINE INJURY; INTESTINE MUCOSA PERMEABILITY; LYMPHOCYTE MIGRATION; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TIGHT JUNCTION; TREATMENT PLANNING; ULCERATIVE COLITIS; ANIMAL; GRAFT VS HOST DISEASE; IMMUNOLOGY; INFLAMMATORY BOWEL DISEASES; INTESTINE MUCOSA; METABOLISM; MICROBIOLOGY; PATHOLOGY;

ANIMALS; GRAFT VS HOST DISEASE; HUMANS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA;

EID: 84932608065     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/mi.2015.40     Document Type: Review

References (180)

1. Pelaseyed T., et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8-20 (2014
2. Kostic A.D., Xavier R.J. & Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146, 1489-1499 (2014
3. Ursell L.K., et al. The intestinal metabolome: an intersection between microbiota and host. Gastroenterology 146, 1470-1476 (2014
4. Surana N.K. & Kasper D.L. Deciphering the tete-a-tete between the microbiota and the immune system. J. Clin. Invest. 124, 4197-4203 (2014
5. Elinav E., Henao-Mejia J. & Flavell R.A. Integrative inflammasome activity in the regulation of intestinal mucosal immune responses. Mucosal Immunol. 6, 4-13 (2013
6. Clevers H.C. & Bevins C.L. Paneth cells: maestros of the small intestinal crypts. Annu. Rev. Physiol. 75, 289-311 (2013
7. Cario E. Microbiota and innate immunity in intestinal inflammation and neoplasia. Curr. Opin. Gastroenterol. 29, 85-91 (2013
8. Manichanh C., Borruel N., Casellas F. & Guarner F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599-608 (2012
9. Hooper L.V., Littman D.R. & Macpherson A.J. Interactions between the microbiota and the immune system. Science 336, 1268-1273 (2012
10. Hollander D., et al. Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. Ann. Intern. Med. 105, 883-885 (1986
11. Odenwald M.A. & Turner J.R. Intestinal permeability defects: is it time to treat?. Clin. Gastroenterol. Hepatol. 11, 1075-1083 (2013
12. Hill G.R. & Ferrara J.L. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 95, 2754-2759 (2000
13. Penack O., Holler E. & van Den Brink M.R. Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Blood 115, 1865-1872 (2010
14. Nalle S.C. & Turner J.R. Endothelial and epithelial barriers in graft-versushost disease. Adv. Exp. Med. Biol. 763, 105-131 (2012
15. Johansson J.E. & Ekman T. Gut toxicity during hemopoietic stem cell transplantation may predict acute graft-versus-host disease severity in patients. Dig. Dis. Sci. 52, 2340-2345 (2007
16. Noth R., et al. Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model. BMC Gastroenterol. 11, 109 (2011
17. Hanash A.M., et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37, 339-350 (2012
18. Nalle S.C., et al. Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci. Transl. Med. 6, 243ra87 (2014
19. Heimesaat M.M., et al. MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 59, 1079-1087 (2010
20. Jenq R.R., et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209, 903-911 (2012
21. Eriguchi Y., et al. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood 120, 223-231 (2012
22. Heidegger S., van Den Brink M.R., Haas T. & Poeck H. The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation. Front. Immunol. 5, 337 (2014
23. Schwab L., et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat. Med. 20, 648-654 (2014
24. Koboziev I., Karlsson F., Zhang S. & Grisham M.B. Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies. Inflamm. Bowel Dis. 17, 1229-1245 (2011
25. Ostanin D.V., et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G135-G146 (2009
26. Turner J.R. in Robbins and Cotran Pathologic Basis of Disease. ed. (Kumar V. & Fausto A. & Aster J.814. Saunders Elsevier, Philadelphia, PA, USA, 2010
27. Ferrara J.L. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best. Pract. Res. Clin. Haematol. 20, 91-97 (2007
28. Jacobson P., Uberti J., Davis W. & Ratanatharathorn V. Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation. Bone Marrow Transplant. 22, 217-225 (1998
29. Nash R.A., et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versushost disease after marrow transplantation from unrelated donors. Blood 96, 2062-2068 (2000
30. Ng S.C. & Kamm M.A. Therapeutic strategies for the management of ulcerative colitis. Inflamm. Bowel Dis. 15, 935-950 (2009
31. Baumgart D.C., Pintoffl J.P., Sturm A., Wiedenmann B. & Dignass A.U. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease-a long-term follow-up. Am. J. Gastroenterol. 101, 1048-1056 (2006
32. Choi S.W. & Reddy P. Current and emerging strategies for the prevention of graft-versus-host disease. Nat. Rev. Clin. Oncol. 11, 536-547 (2014
33. Ngo B., et al. Tumor necrosis factor blockade for treatment of inflammatory bowel disease: efficacy and safety. Curr. Mol. Pharmacol. 3, 145-152 (2010
34. Kobayashi T. & Hibi T. Ulcerative colitis. Which makes patients happier, surgery or anti-TNF therapy?. Nat. Rev. Gastroenterol. Hepatol. 11, 272-273 (2014
35. Mozaffari S., Nikfar S., Abdolghaffari A.H. & Abdollahi M. New biologic therapeutics for ulcerative colitis and Crohn's disease. Expert Opin. Biol. Ther. 14, 583-600 (2014
36. Brown G.R., Lee E. & Thiele D.L. TNF-TNFR2 interactions are critical for the development of intestinal graft-versus-host disease in MHC class IIdisparate (C57BL/6J-4C57BL/6J x bm12)F1 mice. J. Immunol. 168, 3065-3071 (2002
37. Korngold R., Marini J.C., De Baca M.E., Murphy G.F. & Giles-Komar J. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol. BloodMarrow Transplant. 9, 292-303 (2003
38. Hill G.R., et al. Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia. J. Clin. Invest. 104, 459-467 (1999
39. Busca A., Locatelli F., Marmont F., Ceretto C. & Falda M. 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. 82, 45-52 (2007
40. Yanik G.A., et al. The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112, 3073-3081 (2008
41. Levine J.E., et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 111, 2470-2475 (2008
42. Couriel D.R., et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease. Biol. Blood Marrow Transplant. 15, 1555-1562 (2009
43. Gatza E., et al. Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 20, 1426-1434 (2014
44. Krijanovski O.I., et al. Keratinocyte growth factor separates graft-versusleukemia effects from graft-versus-host disease. Blood 94, 825-831 (1999
45. Ellison C.A., Gibson I.W., Hayglass K.T. & Gartner J.G. Effect of palifermin in a murine model of graft-versus-host disease (GVHD) associated with Th2 cytokine production, autoantibody production, and glomerulonephritis. J. Clin. Immunol. 26, 485-494 (2006
46. Nasilowska-Adamska B., et al. The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant. Bone Marrow Transplant. 40, 983-988 (2007
47. Levine J.E., Blazar B.R., DeFor T., Ferrara J.L. & Weisdorf D.J. Longterm follow-up of a phase I/II randomized, placebo-controlled trial of palifermin to prevent graft-versus-host disease (GVHD) after related donor allogeneic hematopoietic cell transplantation (HCT). Biol. Blood Marrow Transplant. 14, 1017-1021 (2008
48. Yamaoka T., Frey M.R., Dise R.S., Bernard J.K. & Polk D.B. Specific epidermal growth factor receptor autophosphorylation sites promote mouse colon epithelial cell chemotaxis and restitution. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G368-G376 (2011
49. Dube P.E., et al. Epidermal growth factor receptor inhibits colitisassociated cancer in mice. J. Clin. Invest. 122, 2780-2792 (2012
50. Zhao J., et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 132, 1331-1343 (2007
51. Takashima S., et al. The Wnt agonist R-spondin1 regulates systemic graftversus- host disease by protecting intestinal stem cells. J. Exp. Med. 208, 285-294 (2011
52. Takeuchi O. & Akira S. Pattern recognition receptors and inflammation. Cell 140, 805-820 (2010
53. Cooke K.R., et al. Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J. Clin. Invest. 102, 1882-1891 (1998
54. Cooke K.R., et al. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J. Clin. Invest. 107, 1581-1589 (2001
55. Zhao Y., et al. TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol. Immunol. 10, 165-175 (2013
56. Calcaterra C., et al. Critical role of TLR9 in acute graft-versus-host disease. J. Immunol. 181, 6132-6139 (2008
57. Hossain M.S., et al. Flagellin, a TLR5 agonist, reduces graft-versushost disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity. J. Immunol. 187, 5130-5140 (2011
58. Penack O., et al. NOD2regulates hematopoietic cell function during graftversus- host disease. J. Exp. Med. 206, 2101-2110 (2009
59. Ramanan D., Tang M.S., Bowcutt R., Loke P. & Cadwell K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 41, 311-324 (2014
60. Couturier-Maillard A., et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700-711 (2013
61. Lorenz E., et al. Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 7, 384-387 (2001
62. Elmaagacli A.H., et al. Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graftversus- host disease in patients who underwent an allogeneic transplantation. Transplantation 81, 247-254 (2006
63. Elmaagacli A.H., Koldehoff M. & Beelen D.W. Improved outcome of hematopoietic SCT in patients with homozygous gene variant of toll-like receptor 9. Bone Marrow Transplant. 44, 295-302 (2009
64. Elmaagacli A.H., et al. Toll-like receptor 9, NOD2 and IL23R gene polymorphisms influenced outcome in AML patients transplanted from HLA-identical sibling donors. Bone Marrow Transplant. 46, 702-708 (2011
65. Buhner S., et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?. Gut 55, 342-347 (2006
66. Cho J.H. & Abraham C. Inflammatory bowel disease genetics: Nod2. Annu. Rev. Med. 58, 401-416 (2007
67. Cooney R. & Jewell D. The genetic basis of inflammatory bowel disease. Digest. Dis. 27, 428-442 (2009
68. Strober W., Asano N., Fuss I., Kitani A. & Watanabe T. Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn's disease. Immunol. Rev. 260, 249-260 (2014
69. Holler E., et al. Both donor and recipient NOD2/CARD15 mutations associate with transplant-relatedmortality and GvHD following allogeneic stem cell transplantation. Blood 104, 889-894 (2004
70. Holler E., et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood 107, 4189-4193 (2006
71. van Der Velden W.J., et al. NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation. Bone Marrow Transplant. 44, 243-248 (2009
72. Fukata M., et al. The myeloid differentiation factor 88 (MyD88) is required for CD4+ Tcell effector function in a murine model of inflammatory bowel disease. J. Immunol. 180, 1886-1894 (2008
73. Tomita T., et al. MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ Tcells in chronic colitis. J. Immunol. 180, 5291-5299 (2008
74. Rakoff-Nahoum S., Hao L. & Medzhitov R. Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319-329 (2006
75. Petnicki-Ocwieja T., et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl Acad. Sci. USA 106, 15813-15818 (2009
76. Mondot S., et al. Altered gut microbiota composition in immune-impaired Nod2(-/-) mice. Gut 61, 634-635 (2012
77. Hedl M., Li J., Cho J.H. & Abraham C. Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc. Natl Acad. Sci. USA 104, 19440-19445 (2007
78. Wu X., Lahiri A., Haines G.K. 3rd, Flavell R.A. & Abraham C. NOD2 regulates CXCR3-dependent CD8+ T cell accumulation in intestinal tissues with acute injury. J. Immunol. 192, 3409-3418 (2014
79. Franchimont D., et al. Deficient host-bacteria interactions in inflammatory bowel disease?. The toll-like receptor (TLR)-4 Asp299gly polymorphismis associated with Crohn's disease and ulcerative colitis. Gut 53, 987-992 (2004
80. Henckaerts L., et al. Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patientswith inflammatory bowel disease. Gut 56, 1536-1542 (2007
81. Cario E. Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm. Bowel Dis. 16, 1583-1597 (2010
82. Hampe J., et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207-211 (2007
83. Gardet A. & Xavier R.J. Common alleles that influence autophagy and the risk for inflammatory bowel disease. Curr. Opin. Immunol. 24, 522-529 (2012
84. Holler E., Landfried K., Meier J., Hausmann M. & Rogler G. The role of bacteria and pattern recognition receptors in GVHD. Int. J. Inflam. 2010, 814326 (2010
85. Hubbard-Lucey V.M., et al. Autophagy gene atg16l1 prevents lethal Tcell alloreactivity mediated by dendritic cells. Immunity 41, 579-591 (2014
86. Shen L., Weber C.R., Raleigh D.R., Yu D. & Turner J.R. Tight junction pore and leak pathways: a dynamic duo. Annu. Rev. Physiol. 73, 283-309 (2011
87. Kalischuk L.D., Leggett F. & Inglis G.D. Campylobacter jejuni induces transcytosis of commensal bacteria across the intestinal epithelium through M-like cells. Gut. Pathog. 2, 14 (2010
88. Pravda J. Crohn's disease: evidence for involvement of unregulated transcytosis in disease etio-pathogenesis. World J. Gastroenterol. 17, 1416-1426 (2011
89. Tuma P. & Hubbard A.L. Transcytosis: crossing cellular barriers. Physiol. Rev. 83, 871-932 (2003
90. Johansen F.E. & Kaetzel C.S. Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol. 4, 598-602 (2011
91. Schulz O. & Pabst O. Antigen sampling in the small intestine. Trends Immunol. 34, 155-161 (2013
92. Farquhar M.G. & Palade G.E. Junctional complexes in various epithelia. J. Cell Biol. 17, 375-412 (1963
93. Weber C.R., et al. Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. J. Biol. Chem. 285, 12037-12046 (2010
94. Heller F., et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550-564 (2005
95. Jovani M., Fiorino G. & Danese S. Anti-IL-13 in inflammatory bowel disease: from the bench to the bedside. Curr. Drug Targets 14, 1444-1452 (2013
96. Jordan W.J., et al. IL-13 production by donor Tcells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation. Blood 103, 717-724 (2004
97. Clayburgh D.R., et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J. Clin. Invest. 115, 2702-2715 (2005
98. Clayburgh D.R., Musch M.W., Leitges M., Fu Y.X. & Turner J.R. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. J. Clin. Invest. 116, 2682-2694 (2006
99. Schwarz B.T., et al. LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology 132, 2383-2394 (2007
100. Al-Sadi R., Ye D., Dokladny K. & Ma T.Y. Mechanism of IL-1betainduced increase in intestinal epithelial tight junction permeability. J. Immunol. 180, 5653-5661 (2008
101. Marchiando A.M., et al. Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J. Cell Biol. 189, 111-126 (2010
102. Zeissig S., et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut 56, 61-72 (2007
103. Raleigh D.R., et al. Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. J. Cell Biol. 193, 565-582 (2011
104. Yu D., et al. MLCK-dependent exchange and actin binding regiondependent anchoring of ZO-1 regulate tight junction barrier function. Proc. Natl Acad. Sci. USA 107, 8237-8241 (2010
105. Su L., et al. TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology 145, 407-415 (2013
106. Gerlach K., et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol. 15, 676-686 (2014
107. Bird L. T cells: IL-9 breaks down barriers. Nat. Rev. Immunol. 14, 432 (2014
108. Gunzel D. & Yu A.S. Claudins and the modulation of tight junction permeability. Physiol. Rev. 93, 525-569 (2013
109. Clapper M.L., Cooper H.S. & Chang W.C. Dextran sulfate sodiuminduced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions. Acta. Pharmacol. Sin. 28, 1450-1459 (2007
110. Cooper H.S., Murthy S.N., Shah R.S. & Sedergran D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 69, 238-249 (1993
111. Hermiston M.L. & Gordon J.I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270, 1203-1207 (1995
112. Hermiston M.L. & Gordon J.I. In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death. J. Cell Biol. 129, 489-506 (1995
113. Leach M.W., Bean A.G., Mauze S., Coffman R.L. & Powrie F. Inflammatory bowel disease in C.B-17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T cells. Am. J. Pathol. 148, 1503-1515 (1996
114. Rennick D.M., Fort M.M. & Davidson N.J. Studies with IL-10-/- mice: an overview. J. Leukoc. Biol. 61, 389-396 (1997
115. Kontoyiannis D., Pasparakis M., Pizarro T.T., Cominelli F. & Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387-398 (1999
116. te Velde A.A., et al. Comparative analysis of colonic gene expression of three experimental colitis models mimicking inflammatory bowel disease. Inflamm. Bowel Dis. 13, 325-330 (2007
117. Turner J.R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799-809 (2009
118. Pastorelli L., De Salvo C., Mercado J.R., Vecchi M. & Pizarro T.T. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front. Immunol. 4, 280 (2013
119. Hill G.R., et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 90, 3204-3213 (1997
120. Powrie F., Mauze S. & Coffman R.L. CD4+ T-cells in the regulation of inflammatory responses in the intestine. Res. Immunol. 148, 576-581 (1997
121. Sellon R.K., et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 66, 5224-5231 (1998
122. Hoentjen F., et al. Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice. Gut 52, 1721-1727 (2003
123. Gkouskou K.K., Deligianni C., Tsatsanis C. & Eliopoulos A.G. The gut microbiota in mouse models of inflammatory bowel disease. Front Cell Infect Microbiol. 4, 28 (2014
124. Su L., et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology 136, 551-563 (2009
125. Zolotarevsky Y., et al. A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology 123, 163-172 (2002
126. Blair S.A., Kane S.V., Clayburgh D.R. & Turner J.R. Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab. Invest. 86, 191-201 (2006
127. Lazar V. & Garcia J.G. A single human myosin light chain kinase gene (MLCK; MYLK). Genomics 57, 256-267 (1999
128. Kamm K.E. & Stull J.T.Dedicated myosin light chain kinaseswith diverse cellular functions. J. Biol. Chem. 276, 4527-4530 (2001
129. Clayburgh D.R., et al. A differentiation-dependent splice variant of myosin light chain kinase, MLCK1, regulates epithelial tight junction permeability. J. Biol. Chem. 279, 55506-55513 (2004
130. Graham W.V., et al. Tumor necrosis factor-induced long myosin light chain kinase transcription is regulated by differentiationdependent signaling events. Characterization of the human long myosin light chain kinase promoter. J. Biol. Chem. 281, 26205-26215 (2006
131. Cao M., Wang P., Sun C., He W. & Wang F. Amelioration of IFN-gamma and TNF-alpha-induced intestinal epithelial barrier dysfunction by berberine via suppression of MLCK-MLC phosphorylation signaling pathway. PLoS One 8, e61944 (2013
132. Cooke K.R., et al. Tumor necrosis factor-alpha neutralization reduces lung injury after experimental allogeneic bone marrow transplantation. Transplantation 70, 272-279 (2000
133. Tamada K., et al. Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J. Clin. Invest. 109, 549-557 (2002
134. Xu Y., et al. Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease. Blood 109, 4097-4104 (2007
135. Jankovic D., et al. The Nlrp3 inflammasome regulates acute graft-versushost disease. J. Exp. Med. 210, 1899-1910 (2013
136. Noval Rivas M., et al. NK cell regulation of CD4 T cell-mediated graftversus- host disease. J. Immunol. 184, 6790-6798 (2010
137. Fort M.M., Leach M.W. & Rennick D.M. A role for NK cells as regulators ofCD4+ Tcells in a transfer model of colitis. J. Immunol. 161, 3256-3261 (1998
138. Hall L.J., et al. Natural killer cells protect mice from DSS-induced colitis by regulating neutrophil function via the NKG2A receptor. Mucosal Immunol. 6, 1016-1026 (2013
139. Olson J.A., et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 115, 4293-4301 (2010
140. Cella M., Miller H. & Song C. BeyondNKcells: the expanding universe of innate lymphoid cells. Front. Immunol. 5, 282 (2014
141. Passweg J.R., Stern M., Koehl U., Uharek L. & Tichelli A. Use of natural killer cells in hematopoetic stem cell transplantation. Bone Marrow Transplant. 35, 637-643 (2005
142. Velardi A., Ruggeri L., Alessandro, , Moretta, & Moretta L. NK cells: a lesson from mismatched hematopoietic transplantation. Trends Immunol. 23, 438-444 (2002
143. Blazar B.R., Murphy W.J. & Abedi M. Advances in graft-versus-host disease biology and therapy. Nat. Rev. Immunol. 12, 443-458 (2012
144. Murphy W.J., Kumar V. & Bennett M. Acute rejection of murine bone marrow allografts by natural killer cells and Tcells. Differences in kinetics and target antigens recognized. J. Exp. Med. 166, 1499-1509 (1987
145. Murphy W.J., Kumar V. & Bennett M. Rejection of bone marrow allografts by mice with severe combined immune deficiency (SCID). Evidence that natural killer cells can mediate the specificity of marrow graft rejection. J. Exp. Med. 165, 1212-1217 (1987
146. Ruggeri L., et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097-2100 (2002
147. Waggoner S.N., Taniguchi R.T., Mathew P.A., Kumar V. & Welsh R.M. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J. Clin. Invest. 120, 1925-1938 (2010
148. Rabinovich B.A., et al. Activated, but not resting, Tcells can be recognized and killed by syngeneic NK cells. J. Immunol. 170, 3572-3576 (2003
149. Yamaji O., et al. The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis. J. Immunol. 188, 2524-2536 (2012
150. Peppa D., et al. Up-regulation of a death receptor renders antiviral Tcells susceptible to NK cell-mediated deletion. J. Exp. Med. 210, 99-114 (2013
151. Diefenbach A., Jensen E.R., Jamieson A.M. & Raulet D.H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165-171 (2001
152. Spear P., Wu M.R., Sentman M.L. & Sentman C.L. NKG2D ligands as therapeutic targets. Cancer Immun. 13, 8 (2013
153. Hossain M.S., Ramachandiran S., Gewirtz A.T. & Waller E.K. Recombinant TLR5 agonist CBLB502 promotes NK cell-mediated anti-CMV immunity in mice. PLoS One 9, e96165 (2014
154. Zenewicz L.A., et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947-957 (2008
155. Cella M., et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722-725 (2009
156. Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15-23 (2009
157. Kumar P., Thakar M.S., Ouyang W. & Malarkannan S. IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol. 6, 69-82 (2013
158. Xu X., et al. Conventional NK cells can produce IL-22 and promote host defense in Klebsiella pneumoniae pneumonia. J. Immunol. 192, 1778-1786 (2014
159. Aujla S.J. & Kolls J.K. IL-22: a criticalmediator in mucosal host defense. J. Mol. Med. 87, 451-454 (2009
160. Sabat R., Ouyang W. & Wolk K. Therapeutic opportunities of the IL-22- IL-22R1 system. Nat. Rev. Drug Discov. 13, 21-38 (2014
161. Zenewicz L.A. & Flavell R.A. Recent advances in IL-22 biology. Int. Immunol. 23, 159-163 (2011
162. Rutz S., Eidenschenk C. & Ouyang W. IL-22, not simply a Th17 cytokine. Immunol. Rev. 252, 116-132 (2013
163. Sugimoto K., et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534-544 (2008
164. Zeeh J.M., et al. Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats. Gastroenterology 110, 1077-1083 (1996
165. Panoskaltsis-Mortari A., Lacey D.L., Vallera D.A. & Blazar B.R. Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice. Blood 92, 3960-3967 (1998
166. Egger B., et al. Keratinocyte growth factor ameliorates dextran sodium sulfate colitis in mice. Dig. Dis. Sci. 44, 836-844 (1999
167. Yamaoka T., et al. Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis. Proc. Natl Acad. Sci. USA 105, 11772-11777 (2008
168. Frey M.R., Hilliard V.C., Mullane M.T. & Polk D.B. ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Lab. Invest. 90, 1415-1424 (2010
169. Blazar B.R., et al. Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Blood 108, 3216-3222 (2006
170. Sandborn W.J., et al. Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Aliment Pharmacol. Ther. 17, 1355-1364 (2003
171. Gorfu G., Rivera-Nieves J. & Ley K. Role of beta7 integrins in intestinal lymphocyte homing and retention. Curr. Mol. Med. 9, 836-850 (2009
172. Sandborn W.J., et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N. Engl. J. Med. 369, 711-721 (2013
173. Feagan B.G., et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699-710 (2013
174. Haddley K. Vedolizumab for the treatment of inflammatory bowel disease. Drugs Today 50, 309-319 (2014
175. Petrovic A., et al. LPAM (alpha 4 beta 7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graftversus- host disease. Blood 103, 1542-1547 (2004
176. Ueha S., et al. Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects. J. Leukoc. Biol. 81, 176-185 (2007
177. Chen Y.B., et al. Up-regulation of alpha4beta7 integrin on peripheral Tcell subsets correlates with the development of acute intestinal graft-versushost disease following allogeneic stem cell transplantation. Biol. Blood Marrow Transplant. 15, 1066-1076 (2009
178. Van Itallie C.M., Fanning A.S., Holmes J. & Anderson J.M. Occludin is required for cytokine-induced regulation of tight junction barriers. J. Cell Sci. 123, 2844-2852 (2010
179. Chouaib S., et al. Improving the outcome of leukemia by natural killer cell-based immunotherapeutic strategies. Front. Immunol. 5, 95 (2014
180. Cooper M.A., Fehniger T.A. & Caligiuri M.A. The biology of human natural killer-cell subsets. Trends Immunol. 22, 633-640 (2001