SFB 938:  Environment Specific Control of Immunological Reactivity

• Subject Area: Medicine
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 178696424

• Final Report Year: 2016

Final Report Abstract

In addition to a variety of immune competent cell types themselves, the CRC 938 has been studying molecular features that are characteristic for various (preferably human) micro-environments (blood, kidney, skin, lung intestine, tumor) with regard to their differential influences on local immune regulation. Such a comparative approach was taken to understand the nature of environment specific signals through which the immune system is programmed either to accept/tolerate or to attack/eliminate given antigens/organisms/altered self. We asked central questions such as: does a tolerogenic milieu towards foreign antigens as it exists physiologically at the body’s interfaces with the outside world share similarities with malignant environments where altered self i. e. malignantly transformed cells are tolerated? Can we identify means to manipulate environments in order to switch immune competent cells from a tolerogenic into an inflammatory state in which effector cells are induced to eliminate e.g. malignant tissue? Can we do the opposite in cases of chronically inflamed sites of autoimmunity in intestine, lung, kidney, skin etc. With this concept we, for the first time, move beyond studies of interactions among functional subpopulations of immune competent cells themselves to investigations of interactions of immune competent cells with their discrete environments. CRC 938 not only performed research in contemporary animal models and other high end experimental systems. We have, in addition, focused studying, despite the enormous efforts that are associated with this type of research, to investigate human tissues, isolated human immune competent cells, and organ culture models. It is clear that due to its unexpected early termination, a research program that was developed for a 12 years’ period could not arrive at all its goals. Nevertheless, CRC 938 has produced results that led to a substantial number of high level publications in international highly renownded scientific journals. The immunological community of Heidelberg,thus, perpetuates its worldwide visibility and impact on the progress in central questions of immunological research. In the coming two years additional contributions originating from the funding period of CRC 938 will be published and underline our research quality and international competitiveness.

Publications

• 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478: 197-203
  Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M
  
• 2011. Bevacizumab does not increase the risk of remote relapse in malignant glioma. Ann Neurol 69: 586-92
  Wick A, Dorner N, Schafer N, Hofer S, Heiland S, Schemmer D, Platten M, Weller M, Bendszus M, Wick W
  
• 2011. Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors. J Clin Invest 121: 703-14
  Schledzewski K, Geraud C, Arnold B, Wang S, Grone HJ, Kempf T, Wollert KC, Straub BK, Schirmacher P, Demory A, Schonhaber H, Gratchev A, Dietz L, Thierse HJ, Kzhyshkowska J, Goerdt S
  
• 2012. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18: 926-33
  Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnolzer M, Lasitschka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, Haberkorn U, Brownlee M, Reeh PW, Nawroth PP
  (See online at https://doi.org/10.1038/nm.2750)
• 2012. Myocardial infarction accelerates atherosclerosis. Nature 487: 325-9
  Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M
  (See online at https://doi.org/10.1038/nature11260)
• 2012. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med 18: 1682-7
  Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, Schenkova K, Ambiel I, Wabnitz G, Gramberg T, Panitz S, Flory E, Landau NR, Sertel S, Rutsch F, Lasitschka F, Kim B, Konig R, Fackler OT, Keppler OT
  (See online at https://doi.org/10.1038/nm.2964)
• 2013. A reducing milieu renders cofilin insensitive to phosphatidylinositol 4,5-bisphosphate (PIP2) inhibition. J Biol Chem 288: 29430-9
  Schulte B, John I, Simon B, Brockmann C, Oelmeier SA, Jahraus B, Kirchgessner H, Riplinger S, Carlomagno T, Wabnitz GH, Samstag Y
  (See online at https://doi.org/10.1074/jbc.M113.479766)
• 2013. Bifunctional oligodeoxynucleotide/antagomiR constructs: evaluation of a new tool for microRNA silencing. Nucleic Acid Ther 23: 427-34
  Ziegler S, Eberle ME, Wolfle SJ, Heeg K, Bekeredjian-Ding I
  (See online at https://doi.org/10.1089/nat.2013.0447)
• 2013. CD166/ALCAM mediates proinflammatory effects of S100B in delayed type hypersensitivity. J Immunol 191: 369-77
  von Bauer R, Oikonomou D, Sulaj A, Mohammed S, Hotz-Wagenblatt A, Grone HJ, Arnold B, Falk C, Luethje D, Erhardt A, Stern DM, Bierhaus A, Nawroth PP
  (See online at https://doi.org/10.4049/jimmunol.1201864)
• 2013. Cofilin: a redox sensitive mediator of actin dynamics during T-cell activation and migration. Immunol Rev 256: 30-47
  Samstag Y, John I, Wabnitz GH
  
• 2013. Depletion of the receptor for advanced glycation end products (RAGE) sensitizes towards apoptosis via p53 and p73 posttranslational regulation. Oncogene 32: 1460-8
  Brune M, Muller M, Melino G, Bierhaus A, Schilling T, Nawroth PP
  (See online at https://doi.org/10.1038/onc.2012.150)
• 2013. FcgammaRIII (CD16) equips immature 6-sulfo LacNAc-expressing dendritic cells (slanDCs) with a unique capacity to handle IgG-complexed antigens. Blood 121: 3609-18
  Dobel T, Kunze A, Babatz J, Trankner K, Ludwig A, Schmitz M, Enk A, Schakel K
  (See online at https://doi.org/10.1182/blood-2012-08-447045)
• 2013. Human 6-sulfo LacNAc (slan) dendritic cells have molecular and functional features of an important pro-inflammatory cell type in lupus erythematosus. J Autoimmun 40:1-8
  Hansel A, Gunther C, Baran W, Bidier M, Lorenz HM, Schmitz M, Bachmann M, Dobel T, Enk AH, Schakel K
  (See online at https://doi.org/10.1016/j.jaut.2012.07.005)
• 2013. Identification of the novel differentiation marker MS4A8B and its murine homolog MS4A8A in colonic epithelial cells lost during neoplastic transformation in human colon. Cell Death Dis 4: e469
  Michel J, Schonhaar K, Schledzewski K, Gkaniatsou C, Sticht C, Kellert B, Lasitschka F, Geraud C, Goerdt S, Schmieder A
  (See online at https://doi.org/10.1038/cddis.2012.215)
• 2013. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24: 589-602
  Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schakel K, Garbi N, Jager D, Weitz J, Schmitz-Winnenthal H, Hammerling GJ, Beckhove P
  (See online at https://doi.org/10.1016/j.ccr.2013.09.014)
• 2013. Multiple glutathione disulfide removal pathways mediate cytosolic redox homeostasis. Nat Chem Biol 9: 119-25
  Morgan B, Ezerina D, Amoako TN, Riemer J, Seedorf M, Dick TP
  (See online at https://doi.org/10.1038/NCHEMBIO.1142)
• 2013. Reduction of inflammatory slan (6-sulfo LacNAc) dendritic cells in psoriatic skin of patients treated with etanercept. Exp Dermatol 22: 535-40
  Gunther C, Blau K, Forster U, Viehweg A, Wozel G, Schakel K
  (See online at https://doi.org/10.1111/exd.12190)
• 2013. Sulfatides are required for renal adaptation to chronic metabolic acidosis. Proc Natl Acad Sci U S A 110: 9998-10003
  Stettner P, Bourgeois S, Marsching C, Traykova-Brauch M, Porubsky S, Nordstrom V, Hopf C, Koesters R, Sandhoff R, Wiegandt H, Wagner CA, Grone HJ, Jennemann R
  (See online at https://doi.org/10.1073/pnas.1217775110)
• 2014. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512: 324-7
  Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M, Keil M, Balss J, Rauschenbach K, Grabowska AK, Vogler I, Diekmann J, Trautwein N, Eichmuller SB, Okun J, Stevanovic S, Riemer AB, Sahin U, Friese MA, Beckhove P, von Deimling A, Wick W, Platten M
  (See online at https://doi.org/10.1038/nature13387)
• 2014. Adult thymus contains FoxN1(-) epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41: 257-69
  Ucar A, Ucar O, Klug P, Matt S, Brunk F, Hofmann TG, Kyewski B
  (See online at https://doi.org/10.1016/j.immuni.2014.07.005)
• 2014. Bronchial epithelial cells induce alternatively activated dendritic cells dependent on glucocorticoid receptor signaling. J Immunol 193: 1475-84
  Weitnauer M, Schmidt L, Ng Kuet Leong N, Muenchau S, Lasitschka F, Eckstein V, Hubner S, Tuckermann J, Dalpke AH
  (See online at https://doi.org/10.4049/jimmunol.1400446)
• 2014. Ca(2+) -related signaling events influence TLR9-induced IL-10 secretion in human B cells. Eur J Immunol 44: 1285-98
  Ziegler S, Gartner K, Scheuermann U, Zoeller T, Hantzschmann J, Over B, Foermer S, Heeg K, Bekeredjian-Ding I
  (See online at https://doi.org/10.1002/eji.201343994)
• 2014. Initiation of an inflammatory response in resident intestinal lamina propria cells -use of a human organ culture model. PLoS One 9: e97780
  Schroder-Braunstein J, Gras J, Brors B, Schwarz S, Szikszai T, Lasitschka F, Wabnitz G, Heidtmann A, Lee YS, Schiessling S, Leowardi C, Al-Saeedi M, Ulrich A, Engelke A, Winter J, Samstag Y, Giese T, Meuer S
  (See online at https://doi.org/10.1371/journal.pone.0097780)
• 2014. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41: 14-20
  Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA
  (See online at https://doi.org/10.1016/j.immuni.2014.06.008)
• 2014. Metastasis of prostate cancer and melanoma cells in a preclinical in vivo mouse model is enhanced by L-plastin expression and phosphorylation. Mol Cancer 13: 10
  Riplinger SM, Wabnitz GH, Kirchgessner H, Jahraus B, Lasitschka F, Schulte B, van der Pluijm G, van der Horst G, Hammerling GJ, Nakchbandi I, Samstag Y
  (See online at https://doi.org/10.1186/1476-4598-13-10)
• 2014. mTOR target NDRG1 confers MGMTdependent resistance to alkylating chemotherapy. Proc Natl Acad Sci USA 111: 409-14
  Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S, Bunse L, Solecki G, Eichwald V, Jugold M, Hodecker S, Osswald M, Meisner C, Hielscher T, Rubmann P, Pfenning PN, Ronellenfitsch M, Kempf T, Schnolzer M, Abdollahi A, Lang F, Bendszus M, von Deimling A, Winkler F, Weller M, Vajkoczy P, Platten M, Wick W
  (See online at https://doi.org/10.1073/pnas.1314469111)
• 2014. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14: 377-91
  Klein L, Kyewski B, Allen PM, Hogquist KA
  (See online at https://doi.org/10.1038/nri3667)
• 2014. Prognostic value of immune cell infiltration, tertiary lymphoid structures and PD-L1 expression in Merkel cell carcinomas. Int J Clin Exp Pathol 7: 7610-21
  Behr DS, Peitsch WK, Hametner C, Lasitschka F, Houben R, Schonhaar K, Michel J, Dollt C, Goebeler M, Marx A, Goerdt S, Schmieder A
  
• 2014. The 'mitoflash' probe cpYFP does not respond to superoxide. Nature 514: E12-4
  Schwarzlander M, Wagner S, Ermakova YG, Belousov VV, Radi R, Beckman JS, Buettner GR, Demaurex N, Duchen MR, Forman HJ, Fricker MD, Gems D, Halestrap AP, Halliwell B, Jakob U, Johnston IG, Jones NS, Logan DC, Morgan B, Muller FL, Nicholls DG, Remington SJ, Schumacker PT, Winterbourn CC, Sweetlove LJ, Meyer AJ, Dick TP, Murphy MP
  (See online at https://doi.org/10.1038/nature13858)
• 2015. A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation. Nat Chem Biol 11: 156-63
  Peralta D, Bronowska AK, Morgan B, Doka E, Van Laer K, Nagy P, Grater F, Dick TP
  (See online at https://doi.org/10.1038/NCHEMBIO.1720)
• 2015. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature 518: 542-6
  Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, Reth M, Hofer T, Rodewald HR
  (See online at https://doi.org/10.1038/nature14242)
• 2015. InFlow microscopy of human leukocytes: A tool for quantitative analysis of actin rearrangements in the immune synapse. J Immunol Methods 423: 29-39
  Wabnitz GH, Nessmann A, Kirchgessner H, Samstag Y
  (See online at https://doi.org/10.1016/j.jim.2015.03.003)
• 2015. Proximity ligation assay evaluates IDH1R132H presentation in gliomas. J Clin Invest 125: 593-606
  Bunse L, Schumacher T, Sahm F, Pusch S, Oezen I, Rauschenbach K, Gonzalez M, Solecki G, Osswald M, Capper D, Wiestler B, Winkler F, Herold-Mende C, von Deimling A, Wick W, Platten M
  (See online at https://doi.org/10.1172/JCI77780)
• 2015. Standardization of a human organ culture model of intestinal inflammation and its application for drug testing. J Immunol Methods 421: 96-103
  Szikszai T, Lasitschka F, Giese T, Greulich M, Lee YS, Ilse J, Schiessling S, Leowardi C, AlSaeedi M, Winter J, Meuer S, Schroder-Braunstein J
  (See online at https://doi.org/10.1016/j.jim.2014.12.014)
• 2015. The Origin of Tissue-Resident Macrophages: When an Erythro-myeloid Progenitor Is an Erythro-myeloid Progenitor. Immunity 43: 1023-4
  Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, de Bruijn M, Rodewald HR, Geissmann F
  (See online at https://doi.org/10.1016/j.immuni.2015.11.022)
• 2015. The renal microenvironment modifies dendritic cell phenotype. Kidney Int 2015 Oct 14. doi: 10.1038/ki.2015.292
  Chessa F, Mathow D, Wang S, Hielscher T, Atzberger A, Porubsky S, Gretz N, Burgdorf S, Grone HJ, Popovic ZV
  (See online at https://doi.org/10.1038/ki.2015.292)
• 2015. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518: 547-51
  Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR
  (See online at https://doi.org/10.1038/nature13989)
• 2015. Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. J Clin Invest 125: 739-51
  Reissfelder C, Stamova S, Gossmann C, Braun M, Bonertz A, Walliczek U, Grimm M, Rahbari NN, Koch M, Saadati M, Benner A, Buchler MW, Jager D, Halama N, Khazaie K, Weitz J, Beckhove P
  (See online at https://doi.org/10.1172/JCI74894)
• 2016. Control of local immunity by airway epithelial cells. Mucosal Immunol 9: 287-98
  Weitnauer M, Mijosek V, Dalpke AH
  (See online at https://doi.org/10.1038/mi.2015.126)
• 2016. Multilayered ancestry of arterial macrophages. Nat Immunol 17: 117-8
  Klapproth K, Lasitschka F, Rodewald HR
  (See online at https://doi.org/10.1038/ni.3374)