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5. Abstract

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Mache, Ch., Urban, Ch., Sauer, H., Brandesky, G., Meßner, H., Grienberger, H., Becker, H., Slave, I., Hauer, Ch., Pakisch, B., Oberbauer, R., Mokry, M., Ebner, F., Kleinert, R., Schiller, D., Kasparu, H., Schneider, G., Sega, W., Lutz, D., Mader, R. M., Steger, G. G., Sieder, A. E., Ovissi, L., Roth, E., Hamilton, G., Jakesz, R., Rainer, H., Schenk, T., Kornek, G., Schulz, F., Depisch, D., Rosen, H., Sebesta, Ch., Scheithauer, W., Locker, G. J., Czernin, J., Derfler, K., Gnant, M., Schiessel, R., Petru, E., Pickel, H., Heydarfadai, M., Lahousen, M., Haas, J., Sagaster, P., Flamm, J., Umek, H., Essl, R., Teich, G., Micksche, M., Ludwig, H., Ambros, P. F., Lestou, V., Strehl, S., Mann, G., Gadner, H., Eibl, B., Greiter, E., Grünewald, K., Gastl, G., Thaler, J., Aulitzky, W., Lion, T., Henn, T., Gaiger, A., Hofmann, J., Wolf, A., Spitaler, M., Ludescher, Christof, Grunicke, H., Mitterbauer, G., Stangl, E., Geissler, K., Jäger, U., Lechner, K., Mannhalter, C., Haas, Oskar A., Tirita, Anthi, Kahls, P., Haas, O., Hinterberger, W., Linkesch, W., Pober, Michael, Fae, Ingrid, Kyrle, Alexander, Neumeister, Andrea, Panzer, Simon, Kandioler, D., End, A., Grill, R., Karlic, H., Inhauser, T., Chott, A., Pirc-Danoewinata, H., Klepetko, W., Heinz, R., Hopfinger-Limberger, G., Koller, E., Schneider, B., Pittermann, E., Lorber, C., Eichinger, S., Neumann, E., Weidinger, J., Gisslinger, H., Bedford P., Jones D., Cawley J., Catovsky D., Bevan P., Scherrer, R., Bettelheim, P., Knöbl, P., Kyrie, P. A., Lazcika, K., Schwarzinger, I., Sillaber, C., Watzke, H., Dávid, M., Losonczy, H., Matolcsy, A., Papp, M., Prischl, F. C., Schwarzmeier, J. D., Zoubek, Andreas, Harbott, Jochen, Ritterbach, Jutta, Ritter, Jörg, Sillaber, Ch., Agis, H., Spanblöchl, E., Sperr, W. R., Valent, P., Czerwenka, K., Virgolini, I., Li, S. R., Müller, M., Wrann, M., Gaggl, S., Fasching, B., Herold, M., Geissler, D., Nachbaur, D., Huber, Ch., Schwaighofer, H., Pichl, M., Niederwieser, D., Gilly, B., Weissel, H., Lorber, Ch., Schwarzmeier, J., Gasché, C., Reinisch, W., Hilgarth, M., Keil, F., Thomssen, C., Kolb, H. J., Holler, E., Wilmanns, W., Tilg, H., Gächter, A., Panzer-Grümayer, E. R., Majdic, O., Kersey, J. H., Petzer, A. L., Bilgeri, R., Zilian, U., Geisen, F. H., Haun, M., Konwalinka, G., Fuchs, D., Zangerle, R., Artner-Dworzak, E., Weiss, G., Fritsch, P., Tilz, G. P., Dierich, M. P., Wachter, H., Schüller, J., Czejka, M. J., Jäger, W., Meyer, B., Weiss, C., Schernthaner, G., Marosi, Ch., Onderka, E., Schlögl, B., Maca, T., Hanak, R., Mannhalter, Ch., Brenner, B., Mayer, R., Langmann, A., Langmann, G., Slave, J., Poier, E., Stücklschweiger, G., Hackl, A., Fritz, A., Pabinger, I., Willfort, A., Groiss, E., Bernhart, M., Waldner, R., Krieger, O., Nowotny, H., Strobl, H., Michlmayr, G., Mistrik, M., lstvan, L., Kapiotis, S., Laczika, K., Speiser, W., Granena, A., Hermans, J., Zwaan, F., Gratwohl, A., Labar B., Mrsić M., Nemet D., Bogdanić V., Radman I., Zupančić-Šalek Silva, Kovačević-Metelko Jasna, Aurer I., Forstinger, C., Scholten, C., Kier, P., Kalhs, P., Schwinger, W., Slavc, I., Lackner, H., Nussbaumer, W., Fritsch, E., Fink, M., Zechner, O., Kührer, I., Kletter, V., Frey, S., Leitgeb, C., Fritz, E., Silly, H., Brezinschek, R., Kuss, I., Stöger, H., Schmid, M., Samonigg, H., Wilders-Truschnig, M., Schmidt, F., Bauernhofer, T., Kasparek, A. K., Ploner, F., Stoeger, H., Moser, R., Leikauf, W., Klemm, F., Pfeffel, F., Niessner, H., Poschauko, H., Pojer, E., Locker, G. J., Braun, J., Gnant, M. F. X., Michl, I., Pirker, R., Liebhard, A., Zielinski, C., Dittrich, C., Bernát, S. I., Pongrácz, E., Kastner, J., Raderer, M., Jorbenyi, Z., Yilmaz, A., Suardet, L., Lahm, H., Odartchenko, N., Varga, Gy., Sréter, L. A., Oberberg, D., Berdel, W. E., Budiman, R., Brand, C., Berkessy, S., Radványi, G., Pauker, Zs., Nagy, Zs., Karádi, Å., Serti, S., Hainz, R., Kirchweger, P., Prager, C., Prada, J., Neifer, S., Bienzle, U., Kremsner, P., Kämmerer, B., Vetterlein, M., Pohl, W., Letnansky, K., Imre, S. G., Parkas, T., Lakos, Zs., Kiss, A., Telek, B., Felszeghy, E., Kelemen, E., Rak, K., Pfeilstöcker, M., Reisner, R., Salamon, J., Georgopoulos, A., Feistauer, S., Georgopoulos, M., Graninger, W., Klinda, F., Hrubisko, M., Sakalova, A., Weißmann, A., Röhle, R., Fortelny, R., Gutierrez, F., Fritsch, G., Printz, D., Buchinger, P., Buchinger, P., Hoecker, P., Peters, C., Gebauer, E., Katanić, D., Nagy, Á., Szomor, Á., Med. J., Batinić D., Užaervić B., Marušić M., Kovačoević-Metelko Jasminka, Jakić-Razumović Jasminka, Kovačević-Metelko Jasminka, Zuoancić-Šalek Silva, Ihra, G. C., Reinisch, W. W., Hilgarth, M. F., Schwarzmeier, I. D., Várady, E., Molnár, Z. S., Fleischmann, T., Borbényi, Z., Bérczi, M., István, L., Szerafin, L., Jakó, J., Bányai, A., Dankó, K., Szegedi, Gy., Neubauer, M., Frudinger, A., Scholten, Ch., Forstinger, Ch., Dobrić I., Willheim, M., Szépfalusi, Z., Mader, R., Boltz, G., Schwarzmeier, J. D., Nahajevszky, S., Téri, N., Póth, I., Nagy, P., Smanykó, D., Babicz, T., Ujj, Gy., Iványi, J. L., Tóth, F. D., Kiss, J., Konja, J., Petković, I., Kardum, I., Kaštelan, M., Kelečić, J., Feminić, R., Djermanović, M., Bilić, E., Jakovljević, G., Peter, B., Gredelj, G., Senji, P., Thalhammer, F., Floth, A., Etele-Hainz, A., Kainberger, F., Radaszkiewicz, T., Kierner, H., Mód, Anna, Pitlik, E., Gottesman, M., Magócsi, Mária, Sarkadi, B., Knapp, S., Purtscher, B., DelleKarth, G., Jaeger, U., Krieger, O., Berger, W., Elbling, L., Ludescher, C., Hilbe, W., Eisterer, W., Preuß, E., Izraeli, S., Janssen, J. W. G., Walther, J. U., Kovar, H., Ludwig, W. D., Rechavi, G., Bartram, C. R., Rehberger, A., Mittermayer, F., Schauer, E., Kokoschka, E. M., Kammerer, B., Kokron, E., Desser, L., Abdul-Hamid, G., Kroschinksky, F., Luther, Th., Fischer, H., Nowak, R., Wolf, H., Fleischer, J., Wichmann, G., Albercht, S., Adorf, D., Kaboth, W., Nerl, C., Aman, J., Rudolf, G., Peschel, C., Anders, O., Burstein, Ch., Ernst, B., Steiner, H., Konrad, H., Annaloro, U. P., Mozzana, C., Butti, R., Della, C., Volpe A., Soligo D., Uderzo M., Lambertenghi-Deliliers G., Ansari, H., Dickson, D., Hasford, J., Hehlmann, R., Anyanwu, E., Krysa, S., Bülzebrück, H., Vogt-Moykopf, I., Arning, M., Südhoff, Th., Kliche, K. O., Wehmeier, A., Schneider, W., Arnold, R., Bunjes, D., Hertenstein, B., Hueske, D., Stefanic, M., Theobald, M., Wiesneth, M., Heimpel, H., Waldmann, H., Arseniev, L., Bokemeyer, C., Andres, J., Könneke, A., Papageorgiou, E., Kleine, H. -D., Battmer, K., Südmeyer, I., Zaki, M., Schmoll, H. -J., Stangel, W., Poliwoda, H., Link, H., Aul, C., Runde, V., Heyll, A., Germing, U., Gattermann, N., Ebert, A., Feinendegen, L. E., Huhn, D., Bergmann, L., Dönner, H., Hartlapp, J. H., Kreiter, H., Schuhmacher, K., Schalk T., Sparwasser C., Peschel U., Fraaß C. Huber, HIadik, F., Kolbe, K., Irschick, E., Bajko, G., Wozny, T., Hansz, J., Bares, R., Buell, U., Baumann, I., Harms, H., Kuse, R., Wilms, K., Müller-Hermelink, H. K., Baurmann, H., Cherif, D., Berger, R., Becker, K., Zeller, W., Helmchen, U., Hossfeld, D. K., Bentrup, I., Plusczyk, T., Kemkes-Matthes, B., Matthes, K., Bentz, M., Speicher, M., Schröder, M., Moos, M., Döhner, H., Lichter, P., Stilgenbauer, S., Korfel, A., Harnoss, B. -M., Boese-Landgraf, J., May, E., Kreuser, E. -D., Thiel, E., Karacas, T., Jahn, B., Lautenschläger, G., Szepes, S., Fenchel, K., Mitrou, P. S., Hoelzer, D., Heil, G., Lengfelder, E., Puzicha, E., Martin, H., Beyer, J., Kleiner, S., Strohscheer, I., Schwerdtfeger, R., Schwella, N., Schmidt-Wolf, I., Siegert, W., Weyer, C., arzen, G., Risse, G., Miksits, K., Farshidfar, G., Birken, R., Schilling, C. v., Brugger, W., Holldack, J., Mertelsmann, R., Kanz, L., Blanz, J., Mewes, K., Ehninger, G., Zeller, K. -P., Böhme. A., Just G., Bergmann. L., Shah P., Hoelzer D., Stille W., Bohlen, H., Hopff, T., Kapp, U., Wolf, J., Engert, A., Diehl, V., Tesch, H., Schrader, A., van Rhee, J., Köhne-Wömpner, H., Bokemeyer', C., Gonnermann, D., Harstrick, A., Schöffski, P., van Rhee, J., Schuppert, F., Freund, M., Boos, J., Göring, M., Blaschke, G., Borstel, A., Franke, A., Hüller, G., Uhle, R., Weise, W., Brach, Marion A., Gruss, Hans-Jürgen, Herrmann, Friedhelm, deVos, Sven, Brennscheidt, Ulrich, Riedel, Detlev, Klch, Walter, Bonlfer, Renate, Mertelsmann, Roland, Brieaer, J., Appelhans, H., Brückner, S., Siemens, HJ., Wagner, T., Moecklin, W., Mertelsmann, R., Bertz, H., Hecht, T., Mertelsmann, R., Bühl, K., Eichelbaum, M. G., Ladda, E., Schumacher, K., Weimer, A., Bühling, F., Kunz, D., Lendeckel, U., Reinhold, D., Ulmer, A. J., Flad, H. -D., Ansorge, S., Bühring, Hans-Jörg, Broudy¶, Virginia C., Ashman§, Leonie K., Burk, M., Kunecke, H., Dumont, C., Meckenstock, G., Volmer, M., Bucher, M., Manegold, C., Krenpien, B., Fischer, J. R., Drings, P., Bückner, U., Donhuijsen-Ant, R., Eberhardt, B., Westerhausen, M., Busch, F. W., Jaschonek, K., Steinke, B., Calavrezos, A., Hausmann, K., Solbach, M., Woitowitz, H. -P., Hilierdal, G., Heilmann, H. -P., Chen, Z. J., Frickhofen, N., Ellbrück, D., Schwarz, T. F., Körner, K., Wiest, C., Kubanek, B., Seifried, E., Claudé, R., Brücher, J., Clemens, M. R., Bublitz, K., Bieger, O., Schmid, B., Clemetson, K. J., Clemm, Ch., Bamberg, M., Gerl, A., Weißbach, L., Danhauser-Riedl, S., Schick, H. D., Bender, R., Reuter, M., Dietzfelbinger, H., Rastetter, J., Hanauske, A. -R., Decker, Hans-Jochen, Klauck, Sabine, Seizinger, Bernd, Denfeld, Ralf, Pohl, Christoph, Renner, Christoph, Hombach, Andreas, Jung, Wolfram, Schwonzen, Martin, Pfreundschuh, Michael, Derigs, H. Günter, Boswell, H. Scott, Kühn, D., Zafferani, M., Ehrhardt, R., Fischer, K., Schmitt, M., Witt, B., Ho, A. D., Haas, R., Hunstein, W., Dölken, G., Finke, J., Lange, W., Held, M., Schalipp, E., Fauser, A. A., Mertelsmann, R., Donhuijsen, K., Nabavi, D., Leder, L. D., Haedicke, Ch., Freund, H., Hattenberger, S., Dreger, Peter, Grelle, Karen, Schmitz, Norbert, Suttorp, Meinolf, Müller-Ruchholtz, Wolfgang, Löffler, Helmut, Dumoulin, F. L., Jakschies, D., Walther, M., Hunger, P., Deicher, H., von Wussow, P., Dutcher, J. P., Ebell, W., Bender-Götze, C., Bettoni, C., Niethammer, D., Reiter, A., Sauter, S., Schrappe, M., Riehm, H., Niederle, N., Heidersdorf, H., Müller, M. R., Mengelkoch, B., Vanhoefer, U., Stahl, M., Budach, V., loehren, B., Alberti, W., Nowrousian, M. R., Seeber, S., Wilke, H., Stamatis, G., Greschuchna, D., Sack, H., Konietzko, N., Krause, B., Dopfer, R., Schmidt, H., Einsele, H., Müller, C. A., Goldmann, S. F., Grosse-Wilde, H., Waller, H. D., Libal, B., Hohaus, S., Gericke, G., von Eiff, M., Oehme, A., Roth, B., van de Loo, J., von Eiff, K., Pötter, R., Weiß, H., Suhr, B., Koch, P., Roos, H., van de Loo, J., Meuter, V., Heissig, B., Schick, F., Duda, S., Saal, J. G., Klein, R., Steidle, M., Eisner, S., Ganser, A., Seipelt, G., Leonhardt, M., Engelhard, M., Brittinger, G., Gerhartz, H., Meusers, P., Aydemir, Ü., Tintrup, W., Tiemann, H., Lennert, K., Esser, B., Hirsch, F. W., Evers, C., Riess, H., Lübbe, A., Greil, R., Köchling, A., Digel, D., Bross, K. J., Dölken, G., Mertelsmann, R., Gencic S., Ostermann, M., Baum, R. P., Fiebig, H. H., Berger, D. P., Dengler, W. A., Winterhalter, B. R., Hendriks, H., Schwartsmann, G., Pinedo, H. M., Ternes, P., Mertelsmann, R., Dölken, G., Fischbach, W., Zidianakis, Z., Lüke, G., Kirchner, Th., Mössner, J., Fischer, Thomas, Haque, Saikh J., Kumar, Aseem, Rutherford, Michael N., Williams, Bryan R. G., Flohr, T., Decker, T., Thews, A., Hild, F., Dohmen, M., von Wussow, P., Grote-Metke, A., Otremba, B., Fonatsch, C., Binder, T., Imhof, C., Feller, A. C., Fruehauf, S., Moehle, R., Hiddemann Th., Büchner M. Unterhalt, Wörmann, B., Ottmann, O. G., Verbeek, G. W., Seipelt A. Maurer, Geissler, G., Schardt, C., Reutzel, R., Hiddemann, W., Maurer, A., Hess, U., Lindemann, A., Frisch, J., Schulz, G., Mertelsmann, R., Hoelzer, P., Gassmann, W., Sperling, C., Uharek, L., Becher, R., Weh, H. J., Tirier, C., Hagemann, F. G., Fuhr, H. G., Wandt, H., Sauerland, M. C., Gause, A., Spickermann, D., Klein, S., Pfreund-schuh, M., Gebauer, W., Fallgren-Gebauer, E., Geissler, R. G., Mentzel, U., Kleiner, K., Rossol, R., Guba, P., Kojouharoff, G., Gerdau, St., Körholz, D., Klein-Vehne, A., Burdach, St., Gerdemann M., Maurer J., Gerhartz, H. H., Schmetzer, H., Mayer, P., Clemm, C., Hentrich, M., Hartenstein, R., Kohl, P., Gieseler, F., Boege, F., Enttmann, R., Meyer, P., Glass, B., Zeis, M., Loeffler, H., Mueller-Ruchholtz, W., Görg, C., Schwerk, W. B., Köppler, H., Havemann, K., Goldschmitt, J., Goldschmidt, H., Nicolai, M., Richter, Th., Blau, W., Hahn, U., Kappe, R., Leithäuser, F., Gottstein, Claudia, Schön, Gisela, Dünnebacke, Markus, Berthold, Frank, Gramatzki, M., Eger, G., Geiger, M., Burger, R., Zölch, A., Bair, H. J., Becker, W., Griesinger, F., Elfers, H., Griesser, H., Grundner-Culemann, E., Neubauer, V., Fricke, D., Shalitin, C., Benter, T., Mertelsmann, R., Dölken, Gottfried, Mertelsmann, Roland, Günther, W., Schunmm, M., Rieber, P., Thierfelder, S., Gunsilius, E., Kirstein, O., Bommer, M., Serve, H., Hülser, P. -J., Del Valle F., Fischer J. Th., Huberts H., Kaplan E., Haase, D., Halbmayer, W. -M., Feichtinger, Ch., Rubi, K., Fischer, M., Hallek, M., Lepislo, E. M., Griffin, J. D., Emst, T. J., Druker, B., Eder, M., Okuda, K., D.Griffin, J., Kozłowska-Skrzypczak, K., Meyer, B., Reile, D., Scharnofske, M., Hapke, G., Aulenbacher, P., Havemann, K., Becker, N., Scheller, S., Zugmaier, G., Pralle, H., Wahrendorf, J., Heide, Immo, Thiede, Christian, de Kant, Eric, Neubauer, Andreas, Herrmann, Richard, Rochlitz, Christoph, Heiden, B., Depenbrock, H., Block, T., Vogelsang, H., Schneider, P., Fellbaum, Ch., Heidtmann, H. -H., Blings, B., Havemann, K., Fackler-Schwalbe, E., Schlimok, G., Lösch, A., Queißer, W., Löffler, B., Kurrle, E., Chadid, L., Lindemann, A., Mertelsmann, R., Nicolay, U., Gaus, W., Heinemann, V., Jehn, U., Gleixner, B., Wachholz, W., Scholz, P., Plunkett, W., Heinze, B., Novotny, J., Hess, Georg, Gamm, Heinold, Seliger, Barbara, Heuft, H. G., Oettle, H., Zeiler, T., Eckstein, R., Heymanns, J., Havemann, K., Hladik, F., Hoang-Vu, C., Horn, R., Cetin, Y., Scheumann, G., Dralle, H., Köhrle, J., von zur Mühlen, A., Brabant, G., Hochhaus, A., Mende, S., Simon, M., Fonatsch, Ch., Heinze, B., Georgii, A., Hötzl, Ch., Hintermeier-Knabe, R., Kempeni, J., Kaul, M., Hoetzl, Ch., Clemm, Ch., Lauter, H., Hoffknecht, M. M., Eckardt, N., Hoffmann-Fezer, G., Gall, C., Kranz, B., Zengerle, U., Pfoersich, M., Birkenstock, U., Pittenann, E., Heinz, B., Hosten, N., Schörner, W., Kirsch, A., Neumann, K., Felix, R., Humpe, A., Kiss, T., Trümper, L. H., Messner, H. A., Hundt, M., Zielinska-Skowronek, M., Schubert, J., Schmidt, R. E., Huss, R., Storb, R., Deeg, H. J., Issels, R. D., Bosse, D., Abdel-Rahman, S., Jaeger, M., Söhngen, D., Weidmann, E., Schwulera, U., Jakab, I., Fodor, F., Pecze, K., Jaques, G., Schöneberger, H. -J., Wegmann, B., Grüber, A., Bust, K., Pflüger, K. -H., Havemann, K., Faul, C., Wannke, B., Scheurlen, M., Kirchner, M., Dahl, G., Schmits, R., Fohl, C., Kaiser, U., Tuohimaa, P., Wollmer, E., Aumüller, G., Havemann, K., Kolbabek, H., Schölten, C., Popov-Kraupp, B., Emminger, W., Hummel, M., Pawlita, M., v.Kalle, C., Dallenbach, F., Stein, H., Krueger, G. R. F., Müller-Lantzsch, N., Kath, R., Höffken, K., Horn, G., Brockmann, P., Keilholz, U., Stoelben, E., Scheibenbogen, C., Manasterski, M., Tilgen, W., Schlag, P., Görich, J., Kauffmann, G. W., Kempter, B., Rüth, S., Lohse, P., Khalil, R. M., Hültner, L., Mailhammer, R., Luz, A., Hasslinger, M. -A., Omran, S., Dörmer, P., Kienast, J., Kister, K. P., Seifarth, W., Klaassen, U., Werk, S., Reiter, W. W., Klein, G., Beck-Gessert, S., Timpl, R., Hinrichs, H., Lux, E., Döring, G., Scheinichen, D., Döring, G., Wernet, P., Vogeley, K. T., Richartz, G., Südhoff, T., Horstkotte, D., Klocker, J., Trotsenburg, M. v., Schumer, J., Kanatschnig, M., Henning, K., Knauf, W. U., Pottgießer, E., Raghavachar, A., Zeigmeister, B., Bollow, M., Schilling, A., König, H., Koch, M., Volkenandt, M., Seger, Andrea, Banerjee, D., Vogel, J., Bierhoff, E., Heidi, G., Neyses, L., Bertino, J., Kocki, J., Rozynkowa, D. M., M.Rupniewska, Z., Wojcierowski, J., König, V., Hopf, U., Koenigsmann, M., Streit, M., Koeppen, K. M., Martini, I., Poppy, U., Hardel, M., Havemann, K., Havemann, K., Clemm, Ch., Wendt, Th., Gauss, J., Kreienberg, R., Hohenfellner, R., Krieger, O., Istvan, L., Komarnicki, M., Kazmierczak, M., Haertle, D., Korossy, P., Haus, S. Kotlarek, Gabryś, K., Kuliszkiewicz-Janus, M., Krauter, J., Westphal, C., Werner, K., Lang, P., Preissner, K. T., Völler, H., Schröder, K., Uhrig, A., Behles, Ch., Seibt-Jung, H., Besserer, A., Kreutzmann, H., Kröning, H., Kähne, T., Eßbach, U., Kühne, W., Krüger, W. H., Krause, K., Nowicki, B., Stockschläder, M., Peters, S. O., Zander, A. R., Kurowski, V., Schüler, C., Höher, D., Montenarh, M., Lang, W., Schweiger, H., Dölken, Gottfried, Lege, H., Dölken, G., Wex, Th., Frank, K., Hastka, J., Bohrer, M., Leo, R., Peest, D., Tschechne, B., Atzpodien, J., Kirchner, H., Hein, R., Hoffmann, L., Stauch, M., Franks, C. R., Palmer, P. A., Licht, T., Mertelsmann, R., Liersch, T., Vehmeyer, K., Kaboth, U., Maschmeyer, G., Meyer, P., Helmerking, M., Schmitt, J., Adam, D., Prahst, A., Hübner, G., Meisner, M., Seifert, M., Richard, D., Yver, A., Spiekermann, K., Brinkmann, L., Battmer, K., Krainer, M., Löffel, J., Stahl, H., Wust, P., Lübbert, M., Schottelius, A., Mertelsmann, R., Henschler, R., Mertelsmann, R., Mapara, M. Y., Bargou, R., Zugck, C., Krammer, P. H., Dörken, B., Maschek, Hansjörg, Kaloutsi, Vassiliki, Maschek, Hansjörg, Gormitz, Ralf, Meyer, P., Kuntz, B. M. E., Mehl, B., Günther, I., Bülzebruck, H., Menssen, H. D., Mergenthaler, H. -G., Dörmer, P., Heusers, P., Zeller, K. -P., Enzinger, H. M., Neugebauer, T., Klippstein, T., Burkhardt, K. L., Putzicha, E., Möller, Peter, Henne, Christof, Eichelmann, Anette, Brüderlein, Silke, Dhein, Jens, Möstl, M., Krieger, O., Mucke, H., Schinkinger, M., Moiling, J., Daoud, A., Willgeroth, Ch., Mross K., Bewermeier P., Krüger W., Peters S., Berger C., Bohn, C., Edler, L., Jonat, W., Queisser, W., Heidemann, E., Goebel, M., Hamm, K., Markovic-Lipkovski, J., Bitzer, G., Müller, H., Oethinger, M., Grießhammer, M., Tuner, I., Musch E., Malek, M., Peter-Katalinic, J., Hügl, E., Helli, A., Slanicka, M., Filipowicz, A., Nissen, C., Speck, B., Nehls, M. C., Grass, H. -J., Dierbach, H., Mertelsmann, R., Thaller, J., Fiebeler, A., Schmidt, C. A., O'Bryan, J. P., Liu, E., Ritter, M., de Kant, E., Brendel, C., He, M., Dodge, R., George, S., Davey, F., Silver, R., Schiffer, C., Mayer, R., Ball, E., Bloomfield, C., Ramschak, H., Tiran, A., Truschnig-Wilders, M., Nizze, H., Bühring, U., Oelschlägel, U., Jermolow, M., Oertel, J., Weisbach, V., Zingsem, J., Wiens, M., Jessen, J., Osthoff, K., Timm, H., Wilborn, F., Bodak, K., Langmach, K., Bechstein, W., Blumhardt, G., Neuhaus, P., Olek, K., Ottinger, H., Kozole, G., Belka, C., Meusers, P., Hense, J., Papadileris, Stefan, Pasternak, G., Pasternak, L., Karsten, U., Pecherstorfer, M., Zimmer-Roth, I., Poloskey, A., Petrasch, S., Kühnemund, O., Uppenkamp, M., Lütticken, R., Kosco, M., Schmitz, J., Petrides, Petro E., Dittmann, Klaus H., Krieger, O., Pflueger, K. -H., Grueber, A., Schoeneberger, J., Wenzel, E., Havemann, K., Pies, A., Kneba, M., Edel, G., Pohl, S., Bulgay-Mörschel, M., Polzin, R., Issing, W., Clemm, Ch., Schorn, K., Ponta, H., Zöller, M., Hofmann, M., Arch, R., Heider, K. -H., Rudy, W., Tölg, C., Herrlich, P., Prümmer, O., Scherbaum, W. A., Porzsolt, F., Prümmer, O., Krüger, A., Schrezenmeier, H., Schlander, H., Pineo, G., Marin, P., Gluckman, E., Shahidi, N. T., Bacigalupo, A., Ratajczak, M. Z., Gewirtz, A. M., Ratei, R., Borner, K., Bank, U., Bühling, F., Reisbach, G., Bartke, L., Kempkes, B., Kostka, G., Ellwart, X., Birner, A., Bornkamm, G. W., Ullrich, A., Dörmer, P., Henze, G., Parwaresch, R., Müller-Weihrich, S. T., Klingebiel, Th., Odenwald, E., Brandhorst, D., Tsuruo, T., Wetter, O., Renner, C., Pohl, C., Sahin, U., Renner, U., Zeller, K. -P., Repp, R., Valerius, Th., Sendler, A., Kalden, J. R., PIatzer, E., Reuss-Borst, M. A., Bühring, H. J., Reuter, C., der Landwehr, II, U. Auf, der Landwehr, II, U. Auf, Schleyer, E., Rolf, C., Ridwelski, K., Matthias, M., Preiss, R., Riewald, M., Puzo, A., Serke, S., Rohrer, B., Pfeiffer, D., Hepp, H., Romanowski, R., Schött, C., Rüther, U., Rothe, B., Pöllmann, H., Nunnensiek, C., Schöllhammer, T., Ulshöfer, Th., Bader, H., Jipp, P., Müller, H. A. G., Rupp, W., Lüthgens, M., Eisenberger, F., Afflerbach, C., Höller, A., Schwamborn, J. S., Daus, H., Krämer, K., Pees, H., Salat, C., Reinhardt, B., Düll, T., Knabe, H., Hiller, E., Sawinski, K., Schalhorn, A., Kühl, M., Heil, K., Schardt, Ch., Drexler, H. G., Scharf, R. E., Suhijar, D., del Zoppo, G. J., Ruggeri, Z. M., Roll, T., Möhler, T., Giselinger, H., Knäbl, P., Kyrie, P. A., Lazcíka, K., Lechner, X., Scheulen, M. E., Beelen, D. W., Reithmayer, H., Daniels, R., Weiherich, A., Quabeck, K., Schaefer, U. W., Reinhardt J., Grimm M., Unterhalt M., Schliesser, G., Lohmeyer, J., Schlingheider, O., von Eiff, M., Schulze, F., Oehme, C., van de Loo, J., Schlögl E., Bemhart M., Schmeiser, Th., Rozdzinski, E., Kern, W., Reichle, A., Moritz, T., Merk, Bruno, Schmid, R. M., Perkins, N. D., Duckett, C. S., Leung, K., Nabel, G. J., Pawlaczyk-Peter, B., Kellermann-Kegreiß, Schmidt E., Steiert, I., Schmidt-Wolf, G., Schmidt-Wolf, I. G. H., Schlegel, P., Blume, K. G., Chao, N. J., Lefterova, P., Laser, J., Schmitz, G., Rothe, G., Schönfeld, S., Schulz, S., Nyce, J. W., Graf, N., Ludwig, R., Steinhauser, I., Brommer, A. E., Qui, H., Schroeder, M., Grote-Kiehn, J., Bückner, U., Rüger, I., Schröder, J., Meusers, P., Weimar, Ch., Schoch, C., Schröter, G., Stern, H., Buchwald, B., Schick, K., Avril, N., Flierdt, E. v. d., Langhammer, H. R., Pabst, H. W., Alvarado, M., Witte, T., Vogt, H., Schuler, U., Brammer, K., Klann, R. C., Schumm, M., Hahn, J., Günther, W., Wullich, B., Moringlane, J. R., Schöndorf, S., Schwartz, S., Bühring, H. -J., Notter, M., Böttcher, S., Martin, M., Schmid, H., Lübbe, A. S., Leib-Mösch C., Wankmüller, H., Eilbrück, D., Funke, I., Cardoso, M., Duranceyk, H., Seitz, R., Rappe, N., Kraus, H., Egbring, R., Haasberg, M., Havemann, K., Seibach, J., Wollscheid, Ursula, Serke, St., Zimmermann, R., Shirai, T., Umeda, M., Anno, S., Kosuge, T., Katoh, M., Moro, S., Su, C. -Y., Shikoshi, K., Arai, N., Schwieder, G., Silling-Engelhardt, G., Zühlsdorf, M., Aguion-Freire-Innig, E., van de Loo, J., Stockdreher, K., Gatsch, L., Tischler, H. -J., Ringe, B., Diedrich, H., Franzi, A., Kruse, E., Lück, R., Trenn, G., Sykora, J., Wen, T., Fung-Leung, W. P., Mak, T. W., Brady, G., Loke, S., Cossman, J., Gascoyne, R., Mak, T., Urasinski, I., Zdziarska, B., Usnarska-Zubkiewicz, L., Kotlarek-Haus, S., Sciborskl, R., Nowosad, H., Kummer, G., Schleucher, N., Preusser, P., Niebel, W., Achterrath, W., Pott, D., Eigler, F. -W., Venook, A., Stagg, R., Frye, J., Gordon, R., Ring, E., Verschuer, U. v., Baur, F., Heit, W., Corrons, J. L. L. Vives, Vogel, M., Nekarda, H., Remy, W., Bissery, M. C., Aapro, M., Buchwald-Pospiech, A., Kaltwasser, J. P., Jacobi, V., de Vos, Sven, Asano, Yoshinobu, Voss, Harald, Knuth, Alexander, Wiedemann, G., Komischke, B., Horisberger, R., Wussow, P. v., Wanders, L., Senekowitsch, R., Strohmeyer, S., Emmerich, B., Selbach, J., Gutensohn, K., Wacker-Backhaus, G., Winkeimann, M., Send, W., Rösche, J., Weide, R., Parviz, B., Havemann, K., Weidmann, B., Henss, H., Engelhardt, R., Bernards, P., Zeidler, D., Jägerbauer, E., Colajori, E., Kerpel-Fronius, S., Weiss, A., Buchheidt, D., Döring, A., D.Saeger, H., Weissbach, L., Emmler, J., Wermes, R., Meusers, P., Flasshove, M., Skorzec, M., Käding, J., Platow, S., Winkler, Ute, Thorpe, Philip, Winter, S. F., Minna, J. D., Nestor, P. J., Johnson, B. E., Gazdar, A. F., Havemann, K., Carbone, D. P., Wit, M. de, Bittner, S., Hossfeld, D., Wittmann, G., Borchelt, M., Steinhagen-Thiessen, E., Koch, K., Brosch, T., Haas, N., Wölfel, C., Knuth, A., Wölfel, T., Safford, M., Könemann, S., Zurlutter, K., Schreiber, K., Piechotka, K., Drescher, M., Toepker, S., Terstappen, L. W. M. M., Bullerdiek, J., Jox, A., zur Hausen, H., Wolters, B., Stenzinger, W., Woźny, T., Sawiński, K., Kozłowska-Skrzypczak, M., Wussow, P. v., Hochhaus, T., Ansarl, H., Prümmer, O., Zapf, H., Thorban, S., Präuer, H., Zeller, W., Stieglitz, J. v., Dürken, M., Greenshaw, C., Kabisch, H., Reuther, C., Knabbe, C., Lippman, M., Havemann, K., Wellstein, A., Degos, L., Castaigne, S., Fenaux, P., Chomienne, C., Raza, A., Preisler, H. D., PEG Interventional Antimicrobial Strategy Study Group, Interventional Antimicrobial Strategy Study Group of the Paul Ehrlich Society (PEG), and H. Riehm for the BFM study group

Published
1992
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6. Supplement II: Abstracts of the international symposium on Skin Carcinogenesis in man and in experimental models. Heidelberg, 29–31 October 1991 (pp S61–S88)

Author

Barrett, J. C., Afshari, C. A., Annab, L. A., Burkhart, B. A., Boyd, J. A., Owen, R. D., Futreal, P. A., Richter, K. H., Moses, H. L., Lavker, R. M., Miller, Stanley, Sun, T. -T., Stingl, G., Bianchi, A. B., Navone, N. M., Conti, C. J., Spencer, James M., Kahn, S., Weinstein, I. B., Silvers, D. S., DeLeo, V. A., Larcher, F., Bauluz, C., Quintanilla, M., Ballestin, C., Jorcano, J. L., Schön, M., Haas, M., Klein, C. E., Weber, L., Cerri, A., Tadini, G., Gitto, R., Berti, E., Cano, A., Caulín, C., Gómez, M., Gandarillas, A., Martín, M., Montes, A., Navarro, P., Bastian, B. C., Van der Piepen, U., Römisch, J., Pâques, E., Hartmann, A. A., Krieg, P., Schnapke, R., Feil, S., Fürstenberger, G., Marks, F., Missero, C., Cajal, S. Ramon y, Filvaroff, E., Dotto, G. P., Sherman, J., Albert, R. E., Baxter, C. S., Bauer, G., Höfler, P., Götschl, M., Viesel, E., Jürgensmeier, J., Schaefer, D., Picht, G., Grande, T., Real, A., Rünqer, T. M., Möller, K., Fuchs, P., Bauer, C., Epe' B., Gruner, S., Diezel, W., Macejewski, J., Weber, H., Eckert, R., Volk, H. D., Sönnichsen, N., Bavinck, Jan N. Bouwes, Vermeer, Bert J., Van Der Woude, Fokko J., Vandenbroucke, Jan P., Claas, Frans H. J., Griffin, E. F., Harris, H., Tilgen, W., Garbe, C., Østerlind, Anne, Weiss, J., Jung, E. G., Ruiter, D. J., Danen, E., Broecker, E. -B., Johnson, J. P., van Muijen, G. N. P., Halaban, R., Krüger-Krasagakes, S., Orfanos, C. E., Newton, J. A., Bataille, V., Cuzick, J., Bishop, T., Schwaaf, A., Azizi, E., Bröcker, E. B., Eberlein, B., Froschermaier, S., Gollhausen, R., Przybilla, B., Krasagakis, K., Abdel-Naser, M. B., Lopez-Bran, E., Robledo, A., Lopez-Bran, E., Heine, H., Hennig, B., Graf, G., Nährig, J., Niedner, R., Schöpf, E., Mailhammer, R., Reisbach, G., Kempkes, B., Hültner, L., Thalmeier, K., Anders, F., Zechel, C., Schleenbecker, U., Leers, J., Smith, A., Wagner, E., Burcin, U., Hug, H., Fiebich, B., Anders, A., Gröger, H., Schlatterer, B., Moll, I., Wollina, U., Leigh IM, Purkis PE, Markey A., Neill S., Proby C., Glover M., Lane EB, Klein-Szanto, A. J. P., Yaar, M., Garmyn, M., Gilani, A., Gilchrest, B. A., Bowden, G. T., Nelson, M., Levy, J., Tanooka, Hiroshi, Ootsuyama, Akira, Urbach, F., van der Leun, J. C., de Gruijl, F. R., Kripke, Margaret L., Yuspa, S. H., Glick, A., Lee, E., Diugosz, A., Balmain, A., Bums, P., Kemp, C. J., Stoler, A. B., Harks, F., Boukamp, P., Pascheberg, U., Breitkreutz, D., Hülsen, A., Altmeier, S., Tomakidi, P., Fusenig, N. E., Lowy, Douglas R., Sedman, Sylvia A., Cohen, Bruce D., Schiller, John T., Kricker, A., Armstrong, B. K., English, D., Heenan, P. J., Randell, P. L., de Gruijl, F. R., Kelfkens, G., van Weelden, H., van der Leun, J. C., Grabbe, S., Bruvers, S., Granstein, R. D., Albert, R., Miller, M., Cody, T., Baxter, C., Shukla, R., Ueda, M., Ichihashi, M., Yamamura, K., Hayashibe, K., Funasaka, Y., Mishima, Y., Fujiwara, Y., Ichihashi, M., Jimbo, T., Mishima, Y., Popanda, O., Thielmann, H. W., Jahrens, D., Edler, L., Ootsuyama, A., Tanooka, H., Sutter, C., Mukhtar, H., Strickland, P. T., Winter, H., Schweizer, J., Schmidt, R., Weber, E., Rippmann, F., Hecker, E., Kopp-Schneider, A., Lehmann, W. D., Stephan, M., Troll, W., Wei, H., Fujiki, H., Garte, S. J., Frenkel, K., Svetek, J., Schara, M., Pečar, S., Hergenhahn, M., Kinzel, V., Richards, J., Plein, P., Schiess, K., Kaszkin, M., Yamamoto, S., Wang, J. C., Kato, R., Kuroki, T., Hashimoto, Y., Osada, S., Ohno, S., Gilles, C., Piette, M., Foidart, J. -M., Ranki, A., Lassus, J., Lehmus, A., Niemi, K. -M., Friesel, H., Schneider, T., Steinbauer, B., Sorg, B., Winter, A., Krauter, G., Krauß, R., Roeser, H., Unger, Sylvia, Janiaud, Paul, Rueß, Doris, Mechler, Bernard M., Stanbridge, Eric J., Gross, Monika M., Buček, M., Klein-Bauernschmitt, P., Schlehofer, J. R., Kosters, R., Stark, H. -J., Okulov, V. B., Elgjo, K., Ushmorov, A. G., Danilov, A. O., Zubova, S. G., Furstenberger, G., and Faissner, A.

Published
1991
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8. Biodistribution and radioimmunotherapy of SCCHN in xenotransplantated SCID mice with a 131I-labelled anti-EpCAM monoclonal antibody

Author

Andratschke, M., Gildehaus, F.J., Johannson, V., Schmitt, B., Mack, B., Reisbach, G., Lang, S., Lindhofer, H., Zeidler, R., Wollenberg, B., and Luebbers, C.W.

Subjects
Hypopharyngeal Neoplasms, Immunotoxins, Transplantation, Heterologous, Antibodies, Monoclonal, Mice, SCID, Radioimmunotherapy, Epithelial Cell Adhesion Molecule, Iodine Radioisotopes, Mice, Antigens, Neoplasm, Immunoglobulin G, Carcinoma, Squamous Cell, Animals, Humans, Tissue Distribution, Cell Adhesion Molecules, Neoplasm Transplantation
Abstract

BACKGROUND: The mortality from squamous cell carcinoma of the head and neck (SCCHN) remains high and almost unchanged throughout the last decades. Therefore, new therapeutic strategies are urgently needed. One promising approach is the application of radio-labeled antibodies directed against tumor-associated antigens. EpCAM is a transmembrane protein, which is overexpressed on almost all SCCHN, making it a suitable anchor molecule for targeted radioimmunotherapy (RIT). The aim of this study was to establish an animal model to investigate the biodistribution and the therapeutic effect of a radio-labeled EpCAM-specific monoclonal antibody (mAb). MATERIALS AND METHODS: The mAb C215 was labeled with 131I and tested for its antitumor effect against established SCCHN xenografts in SCID mice. Initially, the biodistribution of the mAb in the tumor and different organs was determined with a gamma counter and was calculated as % injected dose/gram tissue. For therapeutic approaches 5, 15 or 25 MBq 131I-labeled mAb was injected as a single bolus into tumor-bearing mice. Control animals received either sodium chloride or the unlabeled mAb. The tumor growth and body weight of the animals were measured at various times after administration of the antibody. RESULTS: Initially, high activity was seen in all organs after systemic administration of 13I-C215. Over time general activity decreased whereas an accumulation of activity was seen in the tumor. Tumor growth was delayed in the groups receiving either 15 MBq or 25 MBq 131I-C215 relative to control groups and the 5 MBq group. However, animals in the high-dose groups suffered from treatment-related toxicity, which led to body weight loss of more than 20%. CONCLUSION: Our data demonstrate that the EpCAM-specific radio-labeled mAb C215 is a promising tool to target SCCHN leading to significant tumor control. Further studies are necessary to increase efficacy and reduce toxicity of this new therapeutic approach.

Published
2007

10. Latent membrane protein 1 is critical for efficient growth transformation of human B cells by epstein-barr virus

Author

Dirmeier, U., Neuhierl, B., Kilger, E., Reisbach, G., Sandberg, M. L., and Wolfgang Hammerschmidt

Subjects
Viral Matrix Proteins, B-Lymphocytes, Herpesvirus 4, Human, Mice, Mutation, Tumor Cells, Cultured, Animals, Humans, Mice, SCID, Cell Transformation, Viral, Burkitt Lymphoma, Alleles, Cell Division
Abstract

The EBV latent membrane protein 1 (LMP1) is an integral membrane protein that acts like a constitutively activated receptor. LMP1 interacts with members of the tumor necrosis factor receptor-associated factor family, as well as with tumor necrosis factor receptor-associated death domain, resulting in induction of nuclear factor-κB, the p38 mitogen-activated protein kinase pathway, and the c-Jun NH2-terminal kinase activator protein 1-signaling cascade. The binding of Janus kinase 3 results in activation of signal transducers and activators of transcription. The domain structure of LMP1 has been mapped extensively, but the quantitative contribution of distinct LMP1 domains to the efficiency of B-cell proliferation by EBV has not been determined. On the basis of the maxi-EBV system, which allows us to introduce and study mutations in the context of the complete EBV genome, a panel of 10 EBV mutants with alterations in the LMP1 gene locus was established. The mutant EBVs were tested for their efficiency to induce and maintain proliferation of clonal B-cell lines in vitro. Surprisingly and with reduced frequency, EBV mutants which deleted LMP1’s COOH terminus, transmembrane domains, or the entire open reading frame were able to generate proliferating B-cell clones that were dependent on the presence of human fibroblast feeder cells. A B-cell clone carrying the LMP1-null mutant EBV genome was also analyzed for oncogenicity in severe combined immunodeficiency mice. Our results demonstrate that LMP1 is critical but not mandatory for the generation of proliferating B cells in vitro. LMP1 functions greatly contribute to EBV’s transformation potential and appear essential for its oncogenicity in severe combined immunodeficiency mice.

Published
2003

13. Implications for the assay and biological properties of interleukin-3. Results of a WHO international collaborative study

Author

Mire-Sluis, A.R. (Anthony), Gaines Das, R. (Rose), Thorpe, H. (Helen), Thomas, S. (Siep), Maher, D., Valent, P. (Peter), Payer, E. (Elisabeth), Groote, de, Hayglass, K. (Kent), Ziltener, H. (H.), Poulsen, L.K., Miossec, P. (Pierre), Chomarat, P. (P.), Grassi, J. (Jacques), Pawelec, G. (G.), Fritzsche, U. (U.), Falk, M. (M.), Topp, H. (Heinrich), Reisbach, G. (G.), Sidiropoulos, J. (John), Ben-Sasson, S.Z. (S.), Even-Chen, Z. (Zeev), Pegoraro, L. (Luigi), Barboni, E., Sugimoto, M. (Masahiro), Tsuji, K. (K.), Matsumoto, T. (Tomoya), Arai, T. (Takashi), Yokota, T. (Takashi), Olobo, J. (J.), Wagemaker, G. (Gerard), Pouw Kraan, T.C. (Tineke) van der, Sheth, K.V. (Kirrikant), Gutierrez, C. (Carlos), Rivas, D. (Daniel), Lyeke, N. (Nils), Schön, K. (Karin), Bews, J.P.A. (John), Tullberg, K. (K.), Klotzbücher, R. (R.), Page, L. (L.), Bird, C. (Carolyne), McGuckin, C.P. (Colin), Gordon, J. (Jocelynne), Katira, A. (Anita), Openshaw, P. (Peter), Georgiou, A., Testa, N.G. (Nydia), Callard, R. (Robin), Paik, K. (K.), McKearn, J. (John), Rock, M. (Marie), Harper, K. (Kathleen), Swanson, S.J. (Steven), Siegel, J.P. (Jay), Spiegelberg, L. (Linda), Geigert, J. (John), Carter, K. (Kerri), Paul, W.E. (William), Watson, C. (Cynthia), Tsang, M. (Monica), Zhou, L. (Lili), Westreich, L. (Louis), Chao, C.C. (Chun), Riss, T.L. (Terry), Moravec, R. (Rich), Mire-Sluis, A.R. (Anthony), Gaines Das, R. (Rose), Thorpe, H. (Helen), Thomas, S. (Siep), Maher, D., Valent, P. (Peter), Payer, E. (Elisabeth), Groote, de, Hayglass, K. (Kent), Ziltener, H. (H.), Poulsen, L.K., Miossec, P. (Pierre), Chomarat, P. (P.), Grassi, J. (Jacques), Pawelec, G. (G.), Fritzsche, U. (U.), Falk, M. (M.), Topp, H. (Heinrich), Reisbach, G. (G.), Sidiropoulos, J. (John), Ben-Sasson, S.Z. (S.), Even-Chen, Z. (Zeev), Pegoraro, L. (Luigi), Barboni, E., Sugimoto, M. (Masahiro), Tsuji, K. (K.), Matsumoto, T. (Tomoya), Arai, T. (Takashi), Yokota, T. (Takashi), Olobo, J. (J.), Wagemaker, G. (Gerard), Pouw Kraan, T.C. (Tineke) van der, Sheth, K.V. (Kirrikant), Gutierrez, C. (Carlos), Rivas, D. (Daniel), Lyeke, N. (Nils), Schön, K. (Karin), Bews, J.P.A. (John), Tullberg, K. (K.), Klotzbücher, R. (R.), Page, L. (L.), Bird, C. (Carolyne), McGuckin, C.P. (Colin), Gordon, J. (Jocelynne), Katira, A. (Anita), Openshaw, P. (Peter), Georgiou, A., Testa, N.G. (Nydia), Callard, R. (Robin), Paik, K. (K.), McKearn, J. (John), Rock, M. (Marie), Harper, K. (Kathleen), Swanson, S.J. (Steven), Siegel, J.P. (Jay), Spiegelberg, L. (Linda), Geigert, J. (John), Carter, K. (Kerri), Paul, W.E. (William), Watson, C. (Cynthia), Tsang, M. (Monica), Zhou, L. (Lili), Westreich, L. (Louis), Chao, C.C. (Chun), Riss, T.L. (Terry), and Moravec, R. (Rich)

Published
1996
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14. Implications for the assay and biological properties of interleukin-3. Results of a WHO international collaborative study

Author

Mire-Sluis, Anthony R., Das, Rose Gaines, Thorpe, Robin, Thomas, Sandra, Maher, Darryl, Valent, Peter, Payer, Elisabeth, De Groote, Groote, Hayglass, Kent, Ziltener, H., Poulsen, Lars K., Miossec, Pierre, Chomarat, P., Grassi, Jacques, Pawelec, G., Fritzsche, U., Reisbach, G., Sidiropoulos, John, Ben-Sasson, S. Z., Even-Chen, Zeev, Pegoraro, Luigi, Barboni, Francesco, Sugimoto, Kenkichi, Tsuji, K., Matsumoto, Tomoaki, Arai, Kenrichi, Olobo, J., Wagemaker, G., Van Der Pouw-Kraan, T., Sheth, Kirrikant V., Gutierrez, C., Rivas, D., Lyeke, Nils, Schön, Karin, Bews, John P.A., Tullberg, K., Klotzbücher, R., Page, L., Bird, C., McGuckin, Colin P., Gordon, John, Katira, Anita, Openshaw, Peter, Georgiou, Andrew, Testa, Nydia G., Callard, Robin, Paik, K., McKearn, John, Rock, Marie, Harper, Kathleen, Swanson, Steven J., Siegel, Jay P., Spiegelberg, H. L., Geigert, John, Carter, Kerri, Paul, William E., Watson, Cynthia, Tsang, Monica, Zhou, Li, Westreich, Louis, Chao, Chun C., Riss, Terry L., Moravec, Rich, Mire-Sluis, Anthony R., Das, Rose Gaines, Thorpe, Robin, Thomas, Sandra, Maher, Darryl, Valent, Peter, Payer, Elisabeth, De Groote, Groote, Hayglass, Kent, Ziltener, H., Poulsen, Lars K., Miossec, Pierre, Chomarat, P., Grassi, Jacques, Pawelec, G., Fritzsche, U., Reisbach, G., Sidiropoulos, John, Ben-Sasson, S. Z., Even-Chen, Zeev, Pegoraro, Luigi, Barboni, Francesco, Sugimoto, Kenkichi, Tsuji, K., Matsumoto, Tomoaki, Arai, Kenrichi, Olobo, J., Wagemaker, G., Van Der Pouw-Kraan, T., Sheth, Kirrikant V., Gutierrez, C., Rivas, D., Lyeke, Nils, Schön, Karin, Bews, John P.A., Tullberg, K., Klotzbücher, R., Page, L., Bird, C., McGuckin, Colin P., Gordon, John, Katira, Anita, Openshaw, Peter, Georgiou, Andrew, Testa, Nydia G., Callard, Robin, Paik, K., McKearn, John, Rock, Marie, Harper, Kathleen, Swanson, Steven J., Siegel, Jay P., Spiegelberg, H. L., Geigert, John, Carter, Kerri, Paul, William E., Watson, Cynthia, Tsang, Monica, Zhou, Li, Westreich, Louis, Chao, Chun C., Riss, Terry L., and Moravec, Rich

Abstract

Five preparations of interleukin-3 (IL-3) have been evaluated by 28 laboratories in 12 countries for their suitability to serve as an international standard for this material in a joint international collaborative study for IL-3 and interleukin-4 (IL-4). The preparations were assayed in a wide range of in vitro bioassays and immunoassays. It is clear from the biological assays contributed to this study that different recombinant preparations of IL-3 can have very different biological specific activities, including those from the same source (i.e., E. coli). Biological assays of IL-3 were significantly more consistent in their estimates of levels of IL-3 than the immunoassays, suggesting an unusual pattern of epitome recognition amongst the antibodies in the immunoassays. This study also illustrates the point that the level of cytokine measured by immunoassays does not necessarily reflect the biological potency of the cytokine. On the basis of results reported here, with the agreement of the participants of the study and with the authorization of the Expert Committee on Biological Standardization (ECBS) of the World Health Organization (WHO) the preparation of IL-3 (91/510) was established as the international standard for interleukin-3 with an assigned unitage of 1700 IU/ampoule.

Published
1996

15. Implications for the assay and biological activity of interleukin-4. Results of a WHO international collaborative study

Author

Mire-Sluis, Anthony R., Das, Rose Gaines, Thorpe, Robin, Thomas, Sandra, Maher, Darryl, Valent, Peter, Payer, Elisabeth, De Groote, Groote, Hayglass, Kent, Ziltener, H., Poulsen, Lars K., Miossec, Pierre, Chomarat, P., Grassi, Jacques, Pawelec, G., Fritzsche, U., Reisbach, G., Sidiropoulos, John, Ben-Sasson, S. Z., Even-Chen, Zeev, Pegoraro, Luigi, Barboni, Francesco, Sugimoto, Kenkichi, Tsuji, K., Matsumoto, Tomoaki, Arai, Kenrichi, Yokota, Takashi, Olobo, J., Wagemaker, G., Van Der Pouw-Kraan, T., Sheth, Kirrikant V., Gutierrez, C., Rivas, D., Lyeke, Nils, Schön, Karin, Bews, John P.A., Tullberg, K., Klotzbücher, R., Page, L., Bird, C., McGuckin, Colin P., Gordon, John, Katira, Anita, Openshaw, Peter, Georgiou, Andrew, Testa, Nydia G., Callard, Robin, Paik, K., McKearn, John, Rock, Marie, Harper, Kathleen, Swanson, Steven J., Siegel, Jay P., Spiegelberg, H. L., Geigert, John, Carter, Kerri, Paul, William E., Watson, Cynthia, Tsang, Monica, Zhou, Li, Westreich, Louis, Chao, Chun C., Riss, Terry L., Moravec, Rich, Mire-Sluis, Anthony R., Das, Rose Gaines, Thorpe, Robin, Thomas, Sandra, Maher, Darryl, Valent, Peter, Payer, Elisabeth, De Groote, Groote, Hayglass, Kent, Ziltener, H., Poulsen, Lars K., Miossec, Pierre, Chomarat, P., Grassi, Jacques, Pawelec, G., Fritzsche, U., Reisbach, G., Sidiropoulos, John, Ben-Sasson, S. Z., Even-Chen, Zeev, Pegoraro, Luigi, Barboni, Francesco, Sugimoto, Kenkichi, Tsuji, K., Matsumoto, Tomoaki, Arai, Kenrichi, Yokota, Takashi, Olobo, J., Wagemaker, G., Van Der Pouw-Kraan, T., Sheth, Kirrikant V., Gutierrez, C., Rivas, D., Lyeke, Nils, Schön, Karin, Bews, John P.A., Tullberg, K., Klotzbücher, R., Page, L., Bird, C., McGuckin, Colin P., Gordon, John, Katira, Anita, Openshaw, Peter, Georgiou, Andrew, Testa, Nydia G., Callard, Robin, Paik, K., McKearn, John, Rock, Marie, Harper, Kathleen, Swanson, Steven J., Siegel, Jay P., Spiegelberg, H. L., Geigert, John, Carter, Kerri, Paul, William E., Watson, Cynthia, Tsang, Monica, Zhou, Li, Westreich, Louis, Chao, Chun C., Riss, Terry L., and Moravec, Rich

Abstract

Five ampouled preparations of interleukin-4 (IL-4) have been evaluated by 36 laboratories in 14 countries for their suitability to serve as an international standard for this material in a joint international collaborative study for interleukin-3 (IL-3) and IL-4. The preparations were assayed in a wide range of in vitro bioassays and immunoassays. It is clear from the study that different recombinant preparations of IL-4 can have very different biological specific activities, including those from the same source (i.e., E. coli). In addition, immunoassay estimates of IL-4 levels did not correlate with those of bioassays, illustrating the fact that immunoassays do not necessarily measure active cytokine. It is of interest that the estimates provided by the different bioassays were less variable than those produced by the immunoassays, suggesting that bioassays can be as accurate, if not more so, than immunoassays. The large reduction in the variability of estimates with the inclusion of a single reference preparation clearly illustrates the need for a single standard to assay IL-4. On the basis of the results reported here, with the agreement of the participants of the study with the authorization of the Expert Committee on Biological Standardization (ECBS) on the World Health Organization (WHO) the preparation of IL-4 (88/656) was established as the international standard for interleukin-4 with an assigned unitage of 1000 IU/ampoule.

Published
1996

22. Macrophage colony-stimulating factor (CSF-1) is expressed by spontaneously outgrown EBV-B cell lines and activated normal B lymphocytes

Author

Reisbach, G, Sindermann, J, Kremer, JP, Hultner, L, Wolf, H, and Dormer, P

Abstract

Human B lymphocytes activated by mitogens or infected by Epstein Barr virus (EBV) have previously been shown to release colony-stimulating activity (CSA) supporting the growth of normal human bone marrow progenitors. We established five different human EBV-B cell lines spontaneously outgrown from nonmalignant peripheral blood cells and long-term bone marrow cultures. CSA derived from all of these lines induces the growth of murine macrophage colonies, whereas virtually no human bone marrow cell progenitors were stimulated. As observed in the tumor cell line MIA PaCa-2, a 4.3-kilobase (kb) transcript was detected in all cases using a human colony-stimulating factor (CSF)-1 probe. Expression of this transcript can be further stimulated within three hours upon addition of phorbol myristate acetate (PMA). The highly purified native protein exerting macrophage colony-stimulating activity (M-CSA) exhibits a molecular size of approximately 75 to 97 Kd in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The identity of EBV-B cell derived M-CSA with human urinary CSF-1 was confirmed by a complete neutralization of macrophage CSA by an antihuman urinary CSF-1 antiserum. Normal human B lymphocytes purified from tonsils or from mononuclear blood cells also express CSF-1 upon stimulation with Staphylococcus aureus Cowan I. No CSF-1 expression, however, could be detected in normal resting B lymphocytes or in the Burkitt lymphoma cell line RAJI.

Published
1989
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28. A virus-like particle-based Epstein-Barr virus vaccine.

Author

Ruiss R, Jochum S, Wanner G, Reisbach G, Hammerschmidt W, and Zeidler R

Subjects
Animals, Antibodies, Viral blood, Antigen Presentation, B-Lymphocytes immunology, Cell Line, Enzyme-Linked Immunosorbent Assay, Enzyme-Linked Immunospot Assay, Herpesvirus 4, Human genetics, Humans, Mice, Mice, Inbred BALB C, T-Lymphocytes immunology, Vaccines, Virosome administration & dosage, Vaccines, Virosome genetics, Vaccines, Virosome immunology, Viral Vaccines administration & dosage, Viral Vaccines genetics, Virion genetics, Virion metabolism, Virion ultrastructure, Herpesvirus 4, Human immunology, Viral Vaccines immunology
Abstract

Epstein-Barr Virus (EBV) is an ubiquitous human herpesvirus which can lead to infectious mononucleosis and different cancers. In immunocompromised individuals, this virus is a major cause for morbidity and mortality. Transplant patients who did not encounter EBV prior to immunosuppression frequently develop EBV-associated malignancies, but a prophylactic EBV vaccination might reduce this risk considerably. Virus-like particles (VLPs) mimic the structure of the parental virus but lack the viral genome. Therefore, VLPs are considered safe and efficient vaccine candidates. We engineered a dedicated producer cell line for EBV-derived VLPs. This cell line contains a genetically modified EBV genome which is devoid of all potential viral oncogenes but provides viral proteins essential for the assembly and release of VLPs via the endosomal sorting complex required for transport (ESCRT). Human B cells readily take up EBV-based VLPs and present viral epitopes in association with HLA molecules to T cells. Consequently, EBV-based VLPs are highly immunogenic and elicit humoral and strong CD8+ and CD4+ T cell responses in vitro and in a preclinical murine model in vivo. Our findings suggest that VLP formulations might be attractive candidates to develop a safe and effective polyvalent vaccine against EBV.

Published
2011
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29. The c-Jun N-terminal kinase pathway is critical for cell transformation by the latent membrane protein 1 of Epstein-Barr virus.

Author

Kutz H, Reisbach G, Schultheiss U, and Kieser A

Subjects
Animals, Anthracenes pharmacology, B-Lymphocytes virology, Cell Line, Cell Line, Transformed, Epstein-Barr Virus Infections pathology, Fibroblasts virology, Herpesvirus 4, Human metabolism, Humans, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Lymphoproliferative Disorders pathology, Mice, Mice, SCID, Mitogen-Activated Protein Kinase 8 antagonists & inhibitors, Mitogen-Activated Protein Kinase 8 metabolism, Rats, Signal Transduction, Cell Transformation, Viral, Herpesvirus 4, Human pathogenicity, JNK Mitogen-Activated Protein Kinases metabolism, Viral Matrix Proteins metabolism
Abstract

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) transforms cells activating signal transduction pathways such as NF-kappaB, PI3-kinase, or c-Jun N-terminal kinase (JNK). Here, we investigated the functional role of the LMP1-induced JNK pathway in cell transformation. Expression of a novel dominant-negative JNK1 allele caused a block of proliferation in LMP1-transformed Rat1 fibroblasts. The JNK-specific inhibitor SP600125 reproduced this effect in Rat1-LMP1 cells and efficiently interfered with proliferation of EBV-transformed lymphoblastoid cells (LCLs). Inhibition of the LMP1-induced JNK pathway in LCLs caused the downregulation of c-Jun and Cdc2, the essential G2/M cell cycle kinase, which was accompanied by a cell cycle arrest of LCLs at G2/M phase transition. Moreover, SP600125 retarded tumor growth of LCLs in a xenograft model in SCID mice. Our data support a critical role of the LMP1-induced JNK pathway for proliferation of LMP1-transformed cells and characterize JNK as a potential target for intervention against EBV-induced malignancies.

Published
2008
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30. The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold.

Author

Humme S, Reisbach G, Feederle R, Delecluse HJ, Bousset K, Hammerschmidt W, and Schepers A

Subjects
Blotting, Southern, Blotting, Western, Cell Line, DNA, Viral analysis, Herpesvirus 4, Human genetics, Herpesvirus 4, Human physiology, Humans, In Situ Hybridization, Fluorescence, Plasmids, B-Lymphocytes cytology, Cell Transformation, Viral physiology, Epstein-Barr Virus Nuclear Antigens physiology
Abstract

The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the earliest viral proteins expressed after infection and is the only latent protein consistently expressed in viral-associated tumors. EBNA1's crucial role in viral DNA replication, episomal maintenance, and partitioning is well examined whereas its importance for the immortalization process and the tumorgenicity of EBV is unclear. To address these open questions, we generated, based on the maxi-EBV system, an EBNA1-deficient EBV mutant and used this strain to infect primary human B cells. Surprisingly, lymphoblastoid cell lines (LCL) emerged from these experiments, although with very low frequency. These cell lines were indistinguishable from normal LCLs with respect to proliferation and growth conditions. A detailed analysis indicated that the entire viral DNA was integrated into the cellular genome. At least 5 of the 11 latent EBV proteins were expressed, indicating the integrity of the EBV genome. EBNA1-positive and DeltaEBNA1-EBV-LCLs were injected into severe combined immunodeficient (SCID) mice to examine their tumorgenicity in comparison. Both groups supported tumor growth, indicating that EBNA1 is not mandatory for EBV's oncogenic potential. The results shown provide genetic evidence that EBNA1 is not essential to establish LCLs but promotes the efficiency of this process significantly.

Published
2003
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31. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing.

Author

Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubal S, Schmitt B, and Lindhofer H

Subjects
Animals, Antibodies, Bispecific chemistry, Antibodies, Bispecific genetics, Antigen-Presenting Cells metabolism, Antigens, Neoplasm immunology, Antigens, Neoplasm physiology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Adhesion Molecules immunology, Cell Adhesion Molecules physiology, Cells, Cultured, Coculture Techniques, Cytokines biosynthesis, Dendritic Cells immunology, Epithelial Cell Adhesion Molecule, Humans, Interleukin-2 biosynthesis, Mice, Rats, Recombinant Fusion Proteins chemical synthesis, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins pharmacology, T-Lymphocytes metabolism, Tumor Cells, Cultured, Antibodies, Bispecific pharmacology, Antibody-Dependent Cell Cytotoxicity immunology, Antigen-Presenting Cells immunology, Antineoplastic Agents immunology, Lymphocyte Activation immunology, T-Lymphocytes immunology
Abstract

Bispecific Abs (bsAb) are promising immunological tools for the elimination of tumor cells in minimal residual disease situations. In principle, they target an Ag on tumor cells and recruit one class of effector cell. Because immune reactions in vivo are more complex and are mediated by different classes of effector cell, we argue that conventional bsAb might not yield optimal immune responses at the tumor site. We therefore constructed a bsAb that combines the two potent effector subclasses mouse IgG2a and rat IgG2b. This bispecific molecule not only recruits T cells via its one binding arm, but simultaneously activates FcgammaR+ accessory cells via its Fc region. We demonstrate here that the activation of both T lymphocytes and accessory cells leads to production of immunomodulating cytokines like IL-1beta, IL-2, IL-6, IL-12, and DC-CK1. Thus this new class of bsAb elicits excellent antitumor activity in vitro even without the addition of exogenous IL-2, and therefore represents a totally self-supporting system.

Published
1999

32. G-CSF, GM-CSF and IL-6 levels in cord blood: diminished increase of G-CSF and IL-6 in preterms with perinatal infection compared to term neonates.

Author

Weimann E, Rutkowski S, and Reisbach G

Subjects
Chorioamnionitis blood, Enterocolitis, Necrotizing blood, Female, Gestational Age, Humans, Linear Models, Perinatal Care, Pregnancy, Risk Factors, Sepsis blood, Fetal Blood metabolism, Granulocyte Colony-Stimulating Factor blood, Granulocyte-Macrophage Colony-Stimulating Factor blood, Infant, Newborn blood, Infant, Premature, Diseases blood, Interleukin-6 blood
Abstract

Aim: The objectives of this study were 1) to clarify the physiologic regulation of cytokines such as IL-6, G-CSF and GM-CSF in preterm and term neonates and 2) to evaluate the influence of perinatal stress and infection on endogenous cytokine levels., Method: We examined cord blood levels of G-CSF, GM-CSF and IL-6 using a bioassay in 43 term and 44 preterm neonates., Results: Compared to normal neonates (G-CSF: mean (m) = 97.6 +/- 16.3 pg/ml; IL-6: m = 20.2 +/- 4.6 pg/ml), we found elevated G-CSF levels in newborns with perinatal stress (m = 247.1 +/- 72.1 pg/ml; p = 0.003) and increased levels for G-CSF (m = 8980.9 +/- 4388 pg/ml; p = 0.0003) and IL-6 (m = 705 +/- 322.3 pg/ml; p = 0.025) in neonates with infection. Term newborns with infection had higher G-CSF levels than preterms (m = 15575 +/- 9374 pg/ml versus m = 5384.1 +/- 4470.9 pg/ml; p = 0.024). G-CSF levels of newborns with infection were correlated with birth weight (r = 0.50; p = 0.024) but not with gestational age (r = 0.40; p = 0.057). GM-CSF was only detectable in cord blood in 4 cases of normal healthy neonates., Conclusions: The response of G-CSF levels in preterms to infection is diminished. Body cell mass is more important than gestational age to provide high G-CSF levels during states of infection.

Published
1998
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33. Differential modulation of IL-1-induced endothelial adhesion molecules and transendothelial migration of granulocytes by G-CSF.

Author

Eissner G, Lindner H, Reisbach G, Klauke I, and Holler E

Subjects
Cell Adhesion physiology, Cell Movement, Cells, Cultured, Down-Regulation, E-Selectin metabolism, Flow Cytometry, Granulocyte Colony-Stimulating Factor metabolism, Humans, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Endothelium, Vascular metabolism, Granulocyte Colony-Stimulating Factor pharmacology, Granulocytes physiology, Intercellular Adhesion Molecule-1 metabolism, Interleukin-1 pharmacology, Vascular Cell Adhesion Molecule-1 metabolism
Abstract

Granulocyte colony stimulating factor (G-CSF) is widely used for mobilization of haemopoietic stem cells into the peripheral blood. However, little is known about the mechanisms involved in mobilization and the immune modulatory effects of this growth factor. In this report we show that G-CSF down-regulated intercellular adhesion molecule 1 (ICAM-1) induced by Interleukin-1 (IL-1) on human endothelial cells. Interestingly, the G-CSF-mediated down-modulation of IL-1-induced ICAM-1 appeared to be biphasic. In pharmacological concentrations (> 300 ng/ml), and in dose ranges of plasma G-CSF levels above that of nonfebrile healthy individuals (30 pg/ml), a significant decrease in surface ICAM-1 could be observed. This could be explained, at least in part, by an increased autocrine G-CSF production by endothelial cells in response to IL-1 and exogenous G-CSF. In contrast to ICAM-1, IL-1-triggered VCAM-1 expression was superinduced by G-CSF with the optimal concentration of 30 pg/ml. To evaluate the functional significance of these findings, 51Cr adhesion assays with peripheral blood mononuclear cells (PBMC) or granulocytes known to lack the VCAM-1 counter-receptor very late antigen 4 (VLA-4) and IL-1-stimulated endothelial cells, in the presence or absence of G-CSF, were performed. G-CSF could not inhibit the IL-1-induced adhesion of PBMC to endothelial cells, which may be due to the differential adhesion molecule modulation. In contrast, granulocyte adhesion induced by IL-1 could effectively be blocked by co-incubation with G-CSF. Finally, G-CSF also inhibited transendothelial migration of granulocytes through IL-1-activated endothelial cells in a concentration-dependent manner.

Published
1997
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34. Antibodies to the beta 1-integrin chain, CD44, or ICAM-3 stimulate adhesion of blast colony-forming cells and may inhibit their growth.

Author

Oostendorp RA, Spitzer E, Reisbach G, and Dörmer P

Subjects
Antibodies, Monoclonal immunology, Cell Adhesion drug effects, Cell Differentiation drug effects, Cell Division drug effects, Cells, Cultured, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells immunology, Humans, Stromal Cells cytology, Antibodies, Monoclonal pharmacology, Antigens, CD, Antigens, Differentiation, Cell Adhesion Molecules immunology, Hematopoietic Stem Cells cytology, Hyaluronan Receptors immunology, Integrin beta1 immunology
Abstract

Early hematopoietic progenitor cells adhere to bone marrow stromal cells (BMSCs) mainly through VLA-4/VCAM-1 interactions. However, many adhesion molecules are expressed by these cell types. Cell adhesion molecules not only mediate adhesion; some are also capable of triggering cellular signaling events. These signals can be induced by several anti-adhesion molecule antibodies. In this study, we investigated the effects of several of such stimulatory antibodies against alpha L (CD11a), alpha 4 (CD49d), and beta 1 (CD29) integrin chains, ICAM-3 (CD50), CD34, CD44, and CD45. All antibodies reacted strongly with CD34-positive bone marrow (BM) cells, but only those against beta 1 integrin (TS2/16, Lia1/2) or CD44 (NKI-P2) reacted with BMSCs. To test the ability of these antibodies to stimulate adhesive interactions, we analyzed their effect on stroma-adherent blast colony-forming cells (Bl-CFCs). We found that TS2/16 (anti-beta 1 integrin), NKI-P2 (anti-CD44), and 152-2D11 (anti-ICAM-3) enhanced adhesion of BM mononuclear cells to stroma (TS2/16:3.4-fold, NKI-P2: 3.8-fold, 152-2D11: 2.6-fold) when compared with isotype-control-treated cells. The increase in stroma-adherent cells was accompanied by an increase in Day 5-7 blast colonies of 3.8-, 2.6-, and 1.9-fold, respectively. One antibody against CD29:Lia1/2 strongly inhibited the formation of blast colonies, an effect that was at least partially caused by its growth-inhibitory activity. Of the other antibodies tested, none displayed growth-modulatory activity. We have found previously that Bl-CFCs depend strongly on VLA-4 and VCAM-1. However, in TS2/16- or 152-2D11-treated cultures, we observed not only these, but also VLA-5-dependent adhesive interactions. In contrast, VLA-5 did not appear to be involved in NKI-P2-treated cultures. Our data indicate that interactions mediated by beta 1-integrins are involved in the growth of Bl-CFCs. Furthermore, interactions mediated by beta 1-integrins, CD44, and ICAM-3 differentially modulate VLA-4- and VLA-5-dependent progenitor/BMSC interactions.

Published
1997

35. Regulated plasma levels of colony-stimulating factors, interleukin-6 and interleukin-10 in patients with acute leukaemia and non-hodgkin's lymphoma undergoing cytoreductive chemotherapy.

Author

Reisbach G, Kamp T, Welzl G, Geiz C, Abedinpour Fariborz, Lodri A, Kaboth W, Dörmer P, and Nerl C

Subjects
Acute Disease, Adult, Aged, Aged, 80 and over, Female, Fever, Humans, Leukemia, Myeloid drug therapy, Lymphoma, Non-Hodgkin blood, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Thrombocytopenia blood, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Granulocyte Colony-Stimulating Factor blood, Granulocyte-Macrophage Colony-Stimulating Factor blood, Interleukin-10 blood, Interleukin-6 blood, Leukemia, Myeloid blood, Lymphoma, Non-Hodgkin drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Abstract

Endogenous plasma levels of granulocyte colony stimulating factor (G- CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF),IL-6 and IL-10 were measured in a total of 70 patients undergoing cytoreductive chemotherapy for treatment of acute leukaemia or non-Hodgkin's lymphomas. the diagnoses were acute myeloid leukaemia (AML; n = 30), acute lymphoblastic leukaemia (ALL;n=6), non-Hodgkin's lymphomas (NHL; n=11) and other malignant haematological disorders including myelodysplastic syndromes (n=23). After chemotherapy, plasma G-CSF was elevated (mean 5.6 ng/ml; range 1.2-10 ng/ml), and was inversely correlated with white blood cell counts (WBC) (r=-0.7, p<0.001). Occurrence of fever (T>38.0 degrees C) during severe myelosuppression (WBC<1x10(9)/1) was associated with an additional increase of G-CSF levels (P<0. (P<0.001). Plasma IL-6 correlated significantly with fever (range <1 to 1100 pg/ml, mean 130 pg/ml; r=0.5, P<0.001) but revealed only a weak association with WBC or platelet counts. In patients treated with recombinant G-CSF (n = 9), an association between IL-6 and fever was still observed after chemotherapy. During the nonfebrile status (total n = 242; AML n = 124), IL-6 levels remained <9 pg/ml in 90% of cases, whereas G-CSF increased with leucopenia (r = -0.72;P<0.001). In contrast, endogenous GM-CSF remained normal and IL-10 showed only a slight increase (21% of samples; maximum 22 pg/ml) in severe leucopenia. In particular, IL-10 levels did not correlate with G-CSF or IL-6 levels. We conclude that systemic release of G-CSF and IL-6 is obviously nit abrogated by cytoreductive chemotherapy in acute leukaemia and NHL may add to the therapeutic efficacy of recombinant cytokines. Also, plasma levels of G-, GM-CSF or IL-6 appear to be regulated by separate mechanisms.

Published
1996
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36. Constitutive and modulated cytokine expression in two permanent human bone marrow stromal cell lines.

Author

Thalmeier K, Meissner P, Reisbach G, Hültner L, Mortensen BT, Brechtel A, Oostendorp RA, and Dörmer P

Subjects
Base Sequence, Blotting, Northern, Bone Marrow radiation effects, Bone Marrow Cells, Cell Line, Dexamethasone pharmacology, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Growth Inhibitors genetics, Humans, Interleukin-1 genetics, Interleukin-1 pharmacology, Interleukin-11 genetics, Interleukin-6 genetics, Leukemia Inhibitory Factor, Lymphokines genetics, Molecular Sequence Data, Polymerase Chain Reaction, RNA, Messenger metabolism, RNA-Directed DNA Polymerase, Stromal Cells radiation effects, Bone Marrow metabolism, Cytokines genetics, Gene Expression drug effects, Gene Expression radiation effects, Stromal Cells metabolism
Abstract

We present a detailed analysis of cytokine expression patterns of the two permanent human bone marrow stromal cell lines, L87/4 and L88/5. These cell lines, previously established in our laboratory, are highly radiotolerant without cell detachment and support long-term cultures of CD(34+)-enriched human cord blood cells. RT-PCR analysis of 22 different cytokines or cytokine receptor mRNAs showed an almost identical expression pattern in the two stromal cell lines compared to primary human Dexter-type stroma. Since stromal feeder lines employed in long-term cultures usually are irradiated and grown in media containing corticosteroids, we analyzed the impact of irradiation and dexamethasone on cytokine production in the two cell lines by RT-PCR, Northern blot analysis, bioassays, and RIAs. By RT-PCR analysis, constitutive mRNA expression of c-kit, G-CSF, GM-CSF, IL-1 beta, IL-6, IL-7, IL-8, IL-11, Kit ligand (KL), LIF, M-CSF, MIP-1 alpha, TGF-beta, and TNF-alpha was demonstrated in both cell lines, with L87/4 a more potent cytokine producer than L88/5. Northern blot data showed an increase in mRNA levels for GM-CSF, IL-1 beta, and LIF by irradiation and IL-1 alpha treatment in both cell lines. IL-1 alpha-induced GM-CSF, IL-1 beta, IL-6, IL-11, and LIF mRNA levels were reduced by the addition of dexamethasone, whereas dexamethasone had no influence on the amounts of IL-1 alpha-induced G-CSF mRNA. L87/4 and, to a lower extent, L88/5 cells showed dexamethasone-dependent increases in KL mRNA, while KL mRNA levels were not stimulated by IL-1 alpha.

Published
1996

37. VLA-4 and VCAM-1 are the principal adhesion molecules involved in the interaction between blast colony-forming cells and bone marrow stromal cells.

Author

Oostendorp RA, Reisbach G, Spitzer E, Thalmeier K, Dienemann H, Mergenthaler HG, and Dörmer P

Subjects
Antibodies, Monoclonal physiology, Bone Marrow Cells, Cells, Cultured, Humans, Integrin alpha4beta1, Stromal Cells physiology, Bone Marrow physiology, Hematopoietic Stem Cells physiology, Integrins physiology, Receptors, Lymphocyte Homing physiology, Vascular Cell Adhesion Molecule-1 physiology
Abstract

The molecular basis and functional significance of interactions between haemopoietic progenitor cells and the stromal microenvironment is still poorly understood. Here we investigated a broad panel of surface adhesion molecules for their involvement. For this purpose, the colony-forming capacity of stroma-adherent Bl-CEC, BFU-E and GM-CFC was studied. Both mononuclear bone marrow cells (BMC) and bone marrow-derived stromal cells (BMSC) express a wide variety of adhesion molecules. However, only antibodies against beta 1-, alpha 4-integrin (both chains of the very late activation antigen-4 (VLA-4)) and vascular cell adhesion molecule (VCAM-1) inhibited colony formation from stroma-adherent Bl-CFC by 50% or more. Antibodies against a panel of other adhesion molecules, including the alpha 5-integrin chain, were without effect. Subsequent pretreatment experiments revealed that VLA-4 on progenitors interacted with stromal VCAM-1. The inhibitory antibodies did not interfere with the clonogenic capacity of but with adhesion of BFU-E and GM-CFC. Whether the inhibitory antibodies act similarly on progenitors which depend on BMSC for growth and/or differentiation, such as BI-CFC, remains to be determined.

Published
1995
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38. [54-year-old patient with anemia, jaundice, hepatosplenomegaly and paravertebral space-occupying lesions].

Author

Denzlinger C, Humann M, Steiner W, Bader J, Greither L, Günther W, Reisbach G, Munker R, Baumgart R, and Leeping M

Subjects
Anemia, Dyserythropoietic, Congenital complications, Anemia, Dyserythropoietic, Congenital genetics, Diagnosis, Differential, Diagnostic Imaging, Erythrocytes pathology, Female, Humans, Middle Aged, Anemia, Dyserythropoietic, Congenital diagnosis, Cholestasis, Extrahepatic etiology, Hematopoiesis, Extramedullary, Hepatomegaly etiology, Splenomegaly etiology
Published
1995

39. Mitogenicity of anti-Thy-1 monoclonal antibodies attributable to an Fc-dependent mechanism.

Author

Kummer U, Haunschild J, Reisbach G, Delecluse HJ, and Thierfelder S

Subjects
Animals, Cell Line, Cell Membrane immunology, Hybridomas immunology, Immunoglobulin Fc Fragments, Immunoglobulin G, Immunoglobulin Isotypes, Lymphocyte Activation, Mice, Mitogens, Rats, Thy-1 Antigens, Antibodies, Monoclonal, Antigens, Surface, Membrane Glycoproteins, T-Lymphocytes immunology
Abstract

We analyzed the mechanism by which certain anti-Thy-1 monoclonal antibodies (mAb) activate T cells directly without additional stimuli. Using a panel of rat anti-Thy-1 antibodies which included more than 30 IgG2c mAb, we found that only the IgG2c isotype was able to induce a strong proliferative response in both resting T cells and a T cell lymphoma, suggesting that this form of T cell activation is isotype restricted and might be a consequence of a unique physico-chemical property of the IgG2c heavy chain. Results from surface distribution studies of Thy-1 molecules, following specific interactions with anti-Thy-1 antibodies of different isotypes, again showed that only IgG2c mAb formed Thy-1 aggregates of high valence on the surface of a T cell lymphoma, and such clustering always evoked a biological response. This led us to propose that IgG2c mAb have the inherent tendency to self-associate, probably through homophilic Fc-Fc contacts, and that this feature renders anti-Thy-1 mAb mitogenic. To prove this, we set up cross-inhibition studies with randomly selected mitogenic (IgG2c) and nonmitogenic (IgG2b) anti-Thy-1 mAb. The results clearly demonstrated that IgG2c antibodies enhance their own binding, analogous to the new form of antibody binding that was recently demonstrated between murine IgG3 mAb and a multivalent antigen. Confirmation of this was also provided by IgG2c-derived F(ab')2 fragments, which were unable to cause proliferation. Furthermore, masking the Fc part of cell-bound IgG2c mAb with a monomeric and thus non-aggregating IgG-binding protein A-derived fragment cancelled their mitogenic ability. Finally, induction of T cell proliferation appeared to be independent of cross-linking via Fc gamma R. The results support a model in which noncovalent intermolecular homophilic contacts of the Fc regions of the IgG2c isotype bring about effective aggregation of Thy-1 molecules, thereby stimulating the mitotic apparatus of the cell.

Published
1993
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40. Characterization of hemopoietic cell populations from human cord blood expressing c-kit.

Author

Reisbach G, Bartke I, Kempkes B, Kostka G, Ellwart J, Birner A, Thalmeier K, Mailhammer R, Bornkamm GW, and Ullrich A

Subjects
ADP-ribosyl Cyclase, ADP-ribosyl Cyclase 1, Antibodies, Monoclonal, Antigens, CD34, Antigens, Differentiation analysis, Antigens, Differentiation, Myelomonocytic analysis, B-Lymphocytes metabolism, Bone Marrow Cells, Cell Separation, Cells, Cultured, Flow Cytometry, Fluorescent Antibody Technique, Granulocytes cytology, Hematopoietic Stem Cells immunology, Humans, Macrophages cytology, Membrane Glycoproteins, Proto-Oncogene Proteins immunology, Proto-Oncogene Proteins c-kit, Sialic Acid Binding Ig-like Lectin 3, T-Lymphocytes metabolism, Antigens, CD analysis, Fetal Blood cytology, Hematopoietic Stem Cells metabolism, Proto-Oncogene Proteins analysis
Abstract

Human cord blood or bone marrow cells expressing the CD34 surface antigen include a population of pluripotent progenitors. We identified and isolated a subpopulation of cells coexpressing CD34 and c-kit, a transmembrane receptor with tyrosine kinase activity. Novel monoclonal antibodies (16A6, 14A3, 3D6) directed against the extracellular domain of c-kit were used for immunofluorescence labeling and sorting of low-density mononuclear cells (MNCs) from umbilical cord blood and bone marrow. The frequency of c-kit-labeled MNCs from cord blood (mean 5.0% +/- 2.1%, n = 16) was similar to that from adult bone marrow (mean 3.7% +/- 1.3%, n = 4). On average, 1.4% of CD34-positive cells were recorded in cord blood and 2.1% in bone marrow MNCs. Roughly 60% of CD34-positive cells coexpressed c-kit. The ability of CD34+/c-kit+ cells to form multilineage colonies (CFU-GEMM) was assayed after sorting with an antibody that did not show any significant effect on c-kit ligand (RL) or granulocyte/macrophage colony-stimulating factor (GM-CSF)-induced colony formation. For CD34+/c-kit+ cells, we found a 20- to 50-fold enrichment as against total MNCs, and a 2-fold enrichment if compared with the CD34+/c-kit-population. To study expression of c-kit in lymphocytic precursors, monoclonal anti-CD7 or anti-CD10 antibodies were used simultaneously. In contrast to CD34-expressing cells, however, no consistent double-labeled subpopulation of lymphocytic cells was detected. Furthermore, coexpression of CD38 (73% +/- 14%, n = 4) or CD33 (29% +/- 12%, n = 5) on a majority of c-kit-positive cells showed their lineage commitment to erythropoiesis and granulocytopoiesis.

Published
1993

41. B-cell chronic lymphocytic leukaemia cells express and release transforming growth factor-beta.

Author

Kremer JP, Reisbach G, Nerl C, and Dörmer P

Subjects
Aged, Aged, 80 and over, Biological Assay, Blotting, Northern, Female, Gene Expression physiology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, RNA, Messenger analysis, RNA, Neoplasm analysis, Transforming Growth Factor beta genetics, Leukemia, Lymphocytic, Chronic, B-Cell blood, Transforming Growth Factor beta blood
Abstract

Transforming growth factor-beta (TGF-beta) has been described as a potent inhibitor of various cell types, among others of primitive haematopoietic progenitors in vitro, and as a negative autocrine regulator of normal B lymphocyte growth and differentiation. In the present study we investigated TGF-beta gene expression in peripheral blood mononuclear cells (PBMC) and in B cells from patients with B-cell chronic lymphocytic leukaemia (B-CLL) and from normal controls. Monocyte depleted B-CLL cells expressed constitutively mRNA for TGF-beta 1 and secreted low amounts of TGF-beta activity into the culture medium. Stimulation of cells by phorbol ester noticeably enhanced mRNA levels as well as protein secretion in most cases. TGF-beta activity was of the same magnitude as in normal controls. We next analysed TGF-beta in highly enriched B lymphocytes from B-CLL (95-100% CD19+), and found that TGF-beta secretion was up to 3 times higher than in the original PBMC population. It is discussed that B-CLL cells might escape from negative regulation by TGF-beta and, on the other hand, inhibit normal haematopoietic cell proliferation and thereby achieve a growth advantage in the haematopoietic tissues.

Published
1992
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42. Sister chromatid exchanges and proliferation kinetics of human metastatic breast tumor cells lines.

Author

Reisbach G, Gebhart E, and Cailleau R

Subjects
Breast Neoplasms pathology, Cell Line, Female, Humans, Kinetics, Neoplasm Metastasis, Breast Neoplasms genetics, Crossing Over, Genetic, Sister Chromatid Exchange
Abstract

The rate of sister chromatid exchanges (SCEs) and the profiles of proliferation (= number of first, second, and third cycle metaphases distinguishable by their staining patterns after BrDU substitution for one, two, or three rounds of DNA replication) have been estimated in three (resp. five) metastatic human breast tumor cell lines. Line MDA MB 231 exhibited SCE rates equalling the level of normal cells, while line MDA MB 435 exhibited a slight increase, and line MDA MB 468 a more distinct increase of the SCE rate over the baseline frequency of normal cells. By the BRDU labelling technique the lines 231 and 435 were shown to be rather fast proliferating in culture, while the line 468, and even more the lines 330 and 361 showed a much slower proliferation pattern. From these results it was concluded that increased SCE rates are rather a facultative than an obligatory feature of malignant cells, and that the Br-DU-labelling technique might be suitable for gaining additional information on proliferation characteristics of tumor cells lines.

Published
1982

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