The role of beta-defensins in allogeneic transplantation
Final Report Abstract
Based on our initial hypothesis that antimicrobial peptides (AMPs) play a crucial role in the development of GvHD we have shown that AMPs namely beta-defensins are indicators of enhanced inflammatory and pro-angiogenic reactions. Furthermore, when expressed systemically AMPs perpetuate pro-inflammatory signalling pathways both in vitro and in vivo. We have elucidated the molecular mechanisms how beta-defensins enhance these inflammatory and pro-angiogenic reactions and further identified the respective host receptors which belong to the Gi-protein coupled receptor family. Based on the identification of Reg3α, another AMP produced by Paneth cells of the small intestine, as a specific biomarker of intestinal GvHD we have generated Reg3 transgenic mice in order to characterize Reg3α functions in our experimental models. Interestingly, the analysis of Reg3α transgenic mice revealed that these mice have a strongly altered gut microbial composition accompanied by a loss of microbial diversity compared to wildtype control mice. The alterations of the gut microbial composition is further depicted by strongly reduced levels of short chain fatty acids (e.g. acetate and butyrate). In order to test whether the composition/diversity of the intestinal microbiota plays a major role in the pathophysiology of GvHD we determined in a translational approach the composition of the intestinal microbiome in patients receiving allogeneic SCT. The results revealed a loss of bacterial diversity and an increase in enterococci after initiation of antibiotic prophylaxis; however, these changes were significantly stronger in those patients who developed or actually suffered from gastrointestinal GvHD. In addition, the levels of the bacterial metabolite 3-indoxylsulfate are strongly reduced in patients with active GvHD as a consequence of the loss of bacterial diversity. A possible role of the urinary metabolite 3-indoxyl-sulfate as an indirect biomarker for the loss of microbial diversity in patients undergoing allogeneic SCT is currently under investigation. Furthermore, we have extended our translational studies by analyzing the local induction of Reg3α in samples from patients after allogeneic SCT. The relative expression of endogenous Paneth cell-derived AMPs, as well as Reg3α serum levels were analyzed in relation to acute gastrointestinal GvHD in 200 patients undergoing allogeneic SCT. Our results demonstrate that the relative expression of Paneth cell-derived AMPs is significantly higher in the small intestine in the absence of GvHD. Acute stages of GvHD was associated with reduced expression of endogenousAMPs. Severe GvHD also correlated with higher serum concentrations of Reg3α and low levels of 3-indoxyl-sulphate as an indirect marker of reduced microbial diversity. In conclusion acute GvHD correlates with intestinal expression of Paneth cell defensins as well as Reg3α serum levels, both associated with intestinal dysbiosis.
Publications
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(2011) Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn's disease is affected by NOD2/CARD15 genotype. Inflamm Bowel Disease 17:1641-1650
Gutiérrez A, Holler E, Zapater P, Sempere L, Jover R, Pérez-Mateo M,Schoelmerich J, Such J, Wiest R, Francés R
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(2011) Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graftversus-host disease. Blood 118:6702-6708
Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Huber E, Landfried K, Akashi K, Vander Lugt M, Reddy P, Chin A, Zhang Q, Hanash S, Paczesny S
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(2011) Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase. Blood 118:6971-6974
Landfried K, Zhu W, Waldhier MC, Schulz U, Ammer J, Holler B, Wolff D, Edinger M, Peter K, Kreutz M, Andreesen R, Oefner PJ, Holler E
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(2012) Friend or foe: A novel role of β-defensins in tumor development. Oncoimmunology 8:1159-1160
Röhrl J, Geissler EK, Hehlgans T
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(2012) Mouse β-defensin 14 (Defb14) promotes tumor growth by inducing angiogenesis in a CCR6-dependent manner. J Immunol. 188:4931-4939
Röhrl J, Huber B, Koehl GE, Geissler EK, Hehlgans T
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(2012) Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood 119:2960-2963
Harris AC, Ferrara JL, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Landfried K, Akashi K, Vander Lugt M, Couriel DR, Reddy P, Paczesny S
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(2013) Beta-defensins activate macrophages and synergize in proinflammatory cytokine expression induced by TLR ligands. Immunobiology 218(7):1005-1011
Barabas N, Röhrl J, Holler E, Hehlgans T
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(2013) LTβR expression on hematopoietic cells regulates acute inflammation and influences maturation of myeloid subpopulations. Innate Immun. 20(5):461-470
Wege AK, Huber B, Wimmer N, Männel DN, Hehlgans T.
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(2013) Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity. Immunity. 38(5):1013-1024
Chai Q, Onder L, Scandella E, Gil-Cruz C, Perez-Shibayama C, Cupovic J, Danuser R, Sparwasser T, Luther SA, Thiel V, Rülicke T, Stein JV, Hehlgans T, Ludewig B
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(2014) 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. 20(5):640-645
Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, Zhu W, Sporrer D, Hehlgans T, Kreutz M, Holler B, Wolff D, Edinger M, Andreesen R, Levine JE, Ferrara JL, Gessner A, Spang R, Oefner PJ
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(2015) A prognostic score for acute graftversus-host disease based on biomarkers: A multicenter study. Lancet Haematol. 2:21-29
Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, Magenau J, Weisdorf DJ, Ho VT, Bolanos-Meade J, Alousi AM, Ferrara JL
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(2015) The microbiome and allogeneic stem cell transplantation, Curr Stem Cell Rep. 1: 53-59
Sporrer D, Gessner A, Hehlgans T, Oefner P, Holler E.
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(2016) Human beta-defensin-2 and-3 enhance proinflammatory cytokine expression induced by TLR ligands via ATP release in a P2X7R dependent manner. Immunobiology. 221:1259-65
Wanke D, Mauch-Mücke K, Holler E, Hehlgans T
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(2016) IL10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol. Lett.170:52-63
Lal G, Kulkarni N, Nakayama Y, Singh AK, Sethi A, Burrell BE, Brinkman CC, Iwami D, Zhang T, Hehlgans T, and Jonathan S. Bromberg
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(2017) An early-biomarker algorithm predicts lethal graftversus-host disease and survival. JCI insight. 2(3):e89798
Hartwell MJ, Özbeck U, Holler E, Renteria AS, Major-Monfried H, Reddy P, Aziz M, Hogan WK, Ayuk F, Efebera YA, Hexner EO, Bunworasate U, Qayed M, Ordemann R, Wölfl M, Mielke S, Pawarode A, Chen YB, Devine S, Harris AC, Jagasia M, Kitko CL, Litzow MR, Kröger N, Locatelli F, Morales G, Nakamura R, Reshef R, Rössler W, Weber D, Wudhikarn K, Yanik GA, Levine JE, Ferrara JL
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(2017) The association between acute graft-versus-host disease and antimicrobial peptide expression in the gastrointestinal tract after allogeneic stem cell transplantation. PLoS One. 12(9):e0185265
Weber D, Frauenschläger K, Ghimire S, Peter K, Panzer I, Hiergeist A, Weber M, Kutny D, Wolff D, Grube M, Huber E, Oefner P, Gessner A, Hehlgans T, Herr W, Holler E
