Interplay between receptors of innate immunity and vitamin D3 for the induction of alloreactions through antigen-presenting cells
Final Report Abstract
The main findings of this project are that SNPs of NOD2 seem to affect monocyte differentiation as the blood cell composition is changed in healthy donors with NOD2 SNP12 & SNP13 mutations. These healthy donors show lower levels of monocytes but these monocytes have a higher expression level of CD16. CD14+/CD16+ monocytes are discussed as “inflammatory monocyte” population and could partially explain the association of NOD2 SNPs with inflammatory diseases such as Crohn’s disease and GvHD. Furthermore healthy donors with NOD2 SNP12/13 had lower numbers of myeloid DCs. Based on these data we speculated that monocyte differentiation may be disturbed as a consequence of NOD2 mutations. Accordingly we found differences in the in vitro differentiation of monocytes into DCs. Interestingly, inhibition of DC differentiation regarding surface markers was detected only in a special fast protocol with mononuclear cells indicating that NOD2/CARD15 expression in human lymphocytes is in part responsible for the NOD2-mediated immune regulation. Problematic is the frequency of NOD2 SNPs in healthy donors. It took a long time to get a reasonable number of mutated donors and we still need to confirm the data with more donors. We tried to circumvent this problem by using a mouse model, however, could not reproduce the findings in mice, most likely based on the fact that murine monocytes are characterized by other markers and do not express CD16. In the second part of the project we analysed the interplay between NOD2 and vitamin D3. We investigated the impact of NOD2 SNPs on vitamin D levels in patients undergoing stem cell transplantation; here we did not find differences indicating that NOD2 is not involved in vitamin D3 metabolism in patients. However, analyses of gut biopsies showed that the expression of the vitamin D receptor VDR and the vitamin D3 metabolizing enzyme CYP27A1 seem to be related to GvHD development and TRM. We suggest that these findings may be linked to our in vitro data showing that the active metabolite of vitamin D3 can induce FOXP3 expression in vitro and may support Treg differentiation in the gut.
Publications
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(2015). A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015 Jan;2(1):e21-9
Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, Magenau J, Weisdorf DJ, Ho VT, Bolaños-Meade J, Alousi AM, Ferrara JL; Blood and Marrow Transplant Clinical Trials Network
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(2011) Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 401(10):3249-3261
Zhu W, Stevens AP, Dettmer K, Gottfried E, Hoves S, Kreutz M, Holler E, Canelas AB, Kema I, Oefner PJ
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(2011) Tryptophan catabolism is associated with acute GvHD following human allogeneic stem cell transplantation and indicates activation of indole-amine-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) MIP-3α expression in macrophages is NOD dependent. Digestion 85:192-201
Hausmann M, Zeitler C, Weber A, Krebs M, Kellermeier S, Rosenstiel P, de Vallière C, Kosovac K, Fried M, Holler E, Rogler G
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(2012) STAT5b as molecular target in pancreatic cancer-inhibition of tumor growth, angiogenesis, and metastases. Neoplasia 14(10):915-925
Moser C, Ruemmele P, Gehmert S, Schenk H, Kreutz MP, Mycielska ME, Hackl C, Kroemer A, Schnitzbauer AA, Stoeltzing O, Schlitt HJ, Geissler EK, Lang SA
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(2012) Whole-body UVB irradiation during allogeneic hematopoietic cell transplantation is safe and decreases acute graft-versus-host disease. J Invest Dermatol. 132:179-187
Kreutz M, Karrer S, Hoffmann P, Gottfried E, Szeimies RM, Hahn J, Edinger M, Landthaler M, Andreesen R, Merad M, Holler E
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(2014) Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease. Gut 63(2):272-280
Gutiérrez A, Scharl M, Sempere L, Holler E, Zapater P, Almenta I, González-Navajas JM, Such J, Wiest R, Rogler G, Francés R
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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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(2014).Cytostatic conditioning in experimental allogeneic bone marrow transplantation: Busulfan causes less early gastrointestinal toxicity but Treosulfan results in improved immune reconstitution. Immunopharmacol Immunotoxicol Apr;36(2):158-64
Bouazzaoui A, Dickhöfer S, Kreutz M, Huber E, Holler E, Wolff D
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(2015) Lactic acid delays the inflammatory response of human monocytes. Biochem Biophys Res Commun. 13;457(3):412- 418
Peter K, Rehli M, Singer K, Renner-Sattler K, Kreutz M
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(2015). Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood. Oct 1;126(14):1723-8
Weber D, Oefner PJ, Hiergeist A, Koestler J, Gessner A, Weber M, Hahn J, Wolff D, Stämmler F, Spang R, Herr W, Dettmer K, Holler E
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(2016) Antithymocyte globulin induces a tolerogenic phenotype in human dendritic cells. Int J Mol Sci. Dec 11;17(12)
Roider T, Katzfuß M, Matos C, Singer K, Renner K, Oefner PJ, Dettmer-Wilde K, Herr W, Holler E, Kreutz M, Peter K
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(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. May;23(5):845-852
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 MR, Holler E
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(2017). An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight. Feb 9;2(3):e89798
Hartwell MJ, Özbek U, Holler E, Renteria AS, Major-Monfried H, Reddy P, Aziz M, Hogan WJ, 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, Rösler W, Weber D, Wudhikarn K, Yanik GA, Levine JE, Ferrara JL
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(2018) Indoxyl 3-sulfate inhibits maturation and activation of human monocyte-derived dendritic cells. Immunobiology. Feb;223(2):239-245
Ghimire S, Matos C, Caioni M, Weber D, Peter K, Holler E, Kreutz M, Renner K
