Histology Group

Members:

Dr. med. Juergen Podlech (equivalent to MD)
Phone +49 (0) 6131 39-33134
E-Mail:  podlech@uni-mainz.de

Birgit Kühnapfel (Technician)

Our project

We currently work on the following project:

Dramatic Retardation of B-Cell-Lymphoma Growth by Murine Cytomegalovirus in a Mouse Model of Bone Marrow Transplantation.

Summary

Infection with human cytomegalovirus (hCMV) and tumor relapse are key problems in the therapy of hematopoietic malignancies by bone marrow transplantation (BMT). To date, nothing is known about a possible interplay between CMV infection and tumor relapse. In principle, CMV infection could increase the risk of tumor relapse by its known hematoablative effects which result in a maintenance of immunodeficiency after BMT. Alternatively, virus-induced cytokines or stimulation of an antiviral immune response could suppress tumor growth and prevent tumor relapse.

Here we have established a mouse model of B-cell lymphoma growth after experimental syngeneic BMT in the presence of murine CMV (mCMV) infection. Specifically, BMT was performed with BALB/c mice as donors and recipients, and the recipients were inoculated with a high burden of a lacZ-transfected, highly tumorigenic variant line of the B-cell lymphoma A20, line E12E. This line colonizes preferentially in the liver, expands rapidly to huge colonies, and causes death of all recipients between 4 and 8 weeks. Notably, infection of the recipients with mCMV reduced the number of tumor colonies in the liver, suppressed tumor growth, and prevented tumor-associated mortality.

As documented by two-color immunohistology (black staining of membrane CD45R/B220 on the tumor cells and red staining of viral intranuclear IE1 protein), the tumor-suppressive effect is not caused by infection of the tumor cells. Cross-stimulation of an anti-tumor immune response by mCMV does not offer an explanation either, since retardation of tumor growth became evident before T-cell reconstitution after BMT. We therefore propose a tumor-suppressive effect of a cytokine induced by mCMV. To our knowledge, this is the first observation of an interference of CMV infection with tumor growth. In conclusion, our data indicate that CMV infection may reduce the risk of leukemia/lymphoma relapse after BMT.

Publications

Original papers

1. Metzger, B.; Podlech, J.; Müller, S.; Falke, D.: Supression of humoral immune response against herpes simplex virus induced by defective strains, ts- and TK- mutants. Archives of Virology, 99: 143-152 (1988)
2. Podlech, J.; Weise, K.; Falke, D.: Colonization of adrenal glands and ovaries of mice by HSV-2 variants. I. Virological studies. Archives of Virology, 110: 165-177 (1990)
3. Podlech, J.: Die Besiedlung der Nebennieren und der Ovarien der Maus durch eine pathogene und eine apathogene Variante des Herpes Simplex Virus Typ 2 vom Stamm ER. Medical thesis, University of Mainz (1990)
4. Wiegand, H.; Dienes, H.P.; Schirmacher, P.; Podlech, J.; Bohl, K.; Bohle, M.; Neumann-Haefelin, D.; Falke, D.: Colonization of adrenal glands and ovaries of mice by variants of HSV 1 and 2. II. Histopathological, immunohistochemical and in situ hybridization studies. Archives of Virology, 117: 237-249 (1991)
5. Wollert, K.C.; Fleck, M.; Podlech, J.; Weise, K.; Corell, A.; Falke, D.: Vaginal infection of mice with HSV type 2 variant ER- a new model for human primary genital HSV type 2 infections. Journal of Virological Methods, 36: 265-276 (1992)
6. Fleck, M.; Podlech, J.; Weise, K.; Müntefering, H.; Falke, D.: Pathogenesis of HSV-1/2 induced vaginitis/vulvitis of the mouse: dependence of lesions on genetical properties of the virus and analysis of pathohistology. Archives of Virology, 129: 35-51 (1993)
7. Fleck, M.; Podlech, J.; Weise, K.; Falke, D.: A vaccinia virus - herpes simplex virus (HSV) glycoprotein B1 recombinant or an HSV vaccine overcome the HSV type 2 induced humoral immuno-suppression and protect against vaginal challenge in BALB/c mice. Medical Microbiology and Immunology, 183: 87-94 (1994)
8. Brown, S.M.; Harland, J.; MacLean, A.R.; Podlech, J.; Clements, J.B.: Cell type and cell state determine differential in vitro growth of non-neurovirulent ICP34.5-negative herpes simplex virus types 1 and 2. Journal of General Virology, 75: 2367-2377 (1994)
9. Walev, I.; Podlech, J.; Falke, D.: Enhancement by TNF-a of reactivation and replication of latent herpes simplex virus from trigeminal ganglia of mice. Archives of Virology, 140: 987-992 (1995)
10. Podlech, J.; Richter, J.; Czygan, P.; Klein, P.J.; Müntefering, H.: Bilateral agenesis/aplasia of the lungs: Report of a second case in the offspring of one woman. Pediatric Pathology and Laboratory Medicine, 15: 781-790 (1995)
11. Walev, I.; Dienes, H.P., Bohl, J., Podlech, J.; Falke, D.: Correlation of virus replication, cytokine (TNF-a and Il-1) producing cells, neuronal necrosis and inflammation after intranasal infection of mice with herpes simplex virus strains of different virulence. Archives of Virology, 140: 1957-1967 (1995)
12. Podlech, J.; Hengerer, F.; Fleck, M.; Eray, K.; Falke, D.: Asymptomatic vaginal herpes simplex virus infections in mice: virology and pathohistology. Archives of Virology, 141: 263-274 (1996)
13. Podlech, J.; Hengerer, F.; Fleck, M.; Walev, I.; Falke, D.: Replication of herpes simplex virus type 1 and 2 in the medulla of the adrenal gland after vaginal infection of mice. Archives of Virology 141: 1999-2008 (1996)
14. Podlech, J.; Hengerer, F.; Fleck, M.; Kunkel, J.; Falke, D.: Localization of latency associated transcripts in the uterovaginal plexus of herpes simplex virus type 1 and 2 latently infected mice. Journal of General Virology 78: 1103-1108 (1997)
15. Mayer, A., Podlech, J., Kurz, S., Steffens, H.-P., Maiberger, S., Thalmeier, K., Angele, P., Dreher, L., Reddehase, M.J.: Bone marrow failure by cytomegalovirus is associated with an in vivo deficiency in the expression of essential stromal hemopoietin genes. Journal of Virology 71: 4589-4598 (1997)
16. Dobonici, M., Podlech, J., Steffens, H.-P., Maiberger, S., Reddehase, M.J.: Evidence against a key role for transforming growth factor-ß1 in cytomegalovirus-induced bone marrow aplasia. Journal of General Virology 79: 867-876 (1998)
17. Steffens, H.-P., Podlech, J., Kurz, S., Angele, P., Dreis, D., Reddehase, M.J.: Cytomegalovirus inhibits the engraftment of donor bone marrow cells by downregulation of hemopoietin gene expression in recipient stroma. Journal of Virology 72: 5006-5015 (1998)
18. Podlech, J., Holtappels, R., Wirtz, N., Steffens, H.-P., Reddehase, M.J.: Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation. Journal of General Virology 79: 2099-2104 (1998)
19. Holtappels, R., Podlech, J., Geginat, G., Steffens, H.-P., Thomas, D., Reddehase, M.J.: Control of murine cytomegalovirus in the lungs: relative but not absolute immunodominance of the immediate-early 1 nonapeptide during the antiviral cytolytic-T-lymphocyte response in pulmonary infiltrates. Journal of Virology, 72: 7201-7212 (1998)
20. Alterio de Goss, M., Holtappels, R., Steffens, H.-P., Podlech, J., Angele, P., Dreher, L., Thomas, D., Reddehase, M.J.: Control of cytomegalovirus in bone marrow transplantation chimeras lacking the prevailing antigen-presenting molecule in recipient tissues rests primarily on recipient-derived CD8 T cells. Journal of Virology, 72: 7733-7744 (1998)
21. Bachmann, M., Deister, H., Pautz, A., Laubinger, J., Schmitz, M., Falke, D., Podlech, J., Grölz, D.: The human autoantigen La/SS-B accelerates herpes simplex virus type 1 replication in transfected mouse 3T3 cells. Clinical and Experimental Immunology 112: 482-489 (1998)
22. Fleck, M., Kern, E.R., Zhou, T., Podlech, J., Wintersberger, W., Edwards, C.K., Mountz, J.D.: Apoptosis mediated by fas but not tumor necrosis factor receptor 1 prevents chronic disease in mice infected with murine cytomegalovirus. Journal of Clinical Investigation 102: 1431-1443 (1998)
23. Grzimek, N.K.A., Podlech, J., Steffens, H.-P., Holtappels, R., Schmalz, S., Reddehase, M.J.: In vivo replication of recombinant murine cytomegalovirus driven by the paralogous major immediate-early promoter-enhancer of human cytomegalovirus. Journal of Virology 73: 5043-5055 (1999)
24. Podlech, J., Holtappels, R., Pahl-Seibert, M.-F., Steffens, H.-P., Reddehase, M.J.: Murine model of interstitial cytomegalovirus pneumonia in syngeneic bone marrow transplantation: persistence of protective CD-8-T-cell infiltrates after clearance of acute infection. Journal of Virology 74: 7496-7507 (2000)
25. Holtappels, R., Podlech, J., Grzimek, N.K.A., Thomas, D., Pahl-Seibert, M.-F., Reddehase, M.J.: Experimental preemptive immunotherapy of murine cytomegalovirus disease with CD8 T-cell lines specific for ppM83 and ppM84, the two homologs of human cytomegalovirus tegument protein ppUL83 (pp65). Journal of Virology 75: 6584-6600 (2001)

Abstracts and poster

1. Podlech, J.; Potratz, D.; Preuhs, J.; Müller, S.; Falke, D.: Die Replikation von HSV-2 in der Nebenniere der Maus. Arbeitstagung der Sektion Virologie der deutschen Gesellschaft für Hygiene und Mikrobiologie, Martinsried bei München, Talk and Abstract Nr. 112 (25.-28.3.1987)
2. Podlech, J.; Potratz, D.; Preuhs, J.; Müller, S.; Falke, D.: Replication in and Tropism of HSV-Variants for the Adrenal Glands and the Ovaries of Mice. 12th International Herpesvirus Workshop, Philadelphia, USA, Poster (30.7.-4.8.1987)
3. Wiegand, H.; Dienes, H.P.; Podlech, J.; Schirmacher, P. Neumann-Haefelin, D.; Falke, D.: Replication in and in situ Localization of HSV-DNA and Protein in Liver, Adrenal Glands and Ovaries after Infection with Strains of different Pathogenicity. 13th International Herpesvirus Workshop, Irvine, California, USA, Poster (7.-13.8.1988)
4. Fleck, M.; Podlech, J.; Wollert, K.; Weise, K.; Falke, D.: Vaginal infection of mice with HSV-1 and -2: Antibody formation and pathogenesis. 16th International Herpesvirus Workshop, Asilomar, California, USA, Abstract 8A-39 (7.-12.7.1991)
5. Müntefering, H.; Podlech, J.: Intrauterine und postnatale Virusinfektionen. Verhandlungen der deutschen Gesellschaft für Pathologie, Abstract, Vol. 75: 414 (1991)
6. Fleck, M.; Podlech, J.; Weise, K.; Falke, D.: Die Vaginitis nach HSV-Infektion in der Maus und die Aufhebung der HSV-Immunsuppression durch eine Vaccinia-Virus gB-1-Recombinante. Jahrestagung der Gesellschaft für Virologie, Homburg, Abstract, page 103 (17.-20.3.1993)
7. Podlech, J.; Fleck, M.; Hengerer, F.; Kunkel, J.; Eray, K.; Falke, D.: Die Besiedlung des Nebennierenmarkes nach intravaginaler HSV Infektion der Maus. Frühjahrstagung der Gesellschaft für Virologie e.V., Frankfurt am Main, Abstract, page 284 (23.-26.3.1994)
8. Koch, J.O.; Lingen, M.; Seck, T.; Podlech, J.; Weise, K.; Falke, D.: Ein Glykoprotein-C defizientes Herpes Simplex Virus Typ 1 und seine pathogenen Eigenschaften. Frühjahrstagung der Gesellschaft für Virologie e.V., Frankfurt am Main, Abstract, page 290 (23.-26.3.1994)
9. Holtappels, R.; Polic, B.; Podlech, J.; Reddehase, M.J.: Immune control of pulmonary cytomegalovirus infection after bone marrow transplantation. Mechanisms in Local Immunity; 2. Alps-Adria Immunology and Allergology Meeting, Opatjia, Kroatia (26-28.9.1994)
10. Podlech, J.; Hengerer, F.; Kunkel, J.; Falke, D.: Colonization of the medulla of the adrenal glands after vaginal infection of Balb/c mice by Herpes Simplex Virus Type 1 and 2. 19th International Herpesvirus Workshop, Vancouver, Kanada, Poster (30.7.-4.8.1994)
11. Lingen, M.; Podlech, J.; Weise, K.; Falke D.: In vivo recombination and reappearance of vaginitis. 20th International Herpesvirus Workshop, Groningen, Niederlande, Poster Nr. 222 (29.7.-3.8.1995)
12. Dannigkeit, P.; Pfützner, A.; Ambrosch, A.; Podlech, J.; Forst, T.; Falke, D.; Beyer, J.: Prevalence of CMV- and HSV-DNA in the pancreas and muscle tissue of patients with NIDDM. Abstracts of the 31st Annual Meeting of the European Association for the study of Diabetes, Stockholm, Sweden, 12th–16th September 1995, Abstract No. 305 in Diabetologica, Vol 38, Suppl 1: A79
13. Pfützner, A.; Dannigkeit, P.; Forst, T.; Ambrosch, A.; Podlech, J.; Falke, D.; Beyer, J.: Prävalenz viraler Sequenzen von Zytomegalievirus (CMV) und Herpes simplex Virus (HSV) in Pankreas- und Muskelgewebe von Patienten mit NIDDM. XIII. Internationales Donausymposium über Diabetes mellitus - Moderne Entwicklungen in der Diabetologie, 3.-5. Oktober 1995 in Wien, Abstrakt, in Diabetes und Stoffwechsel, Zeitschrift für angewandte Diabetologie, Verlag Kirchheim Mainz, Sonderheft, Vol. 4, page 23, September 1995
14. Holtappels, R.; Alterio de Goss, M.; Steffens, H.-P.; Podlech, J.; Reddehase, M. J.: Entscheidende Rolle der Rezipientenhämatopoese bei der Kontrolle der Cytomegalovirus-Infektion nach allogener Knochenmarktransplantation. Jahrestagung der Gesellschaft für Virologie, Hamburg, Abstract No. 9 P13 (10.-13.3.1997)
15. Hengerer, F.; Podlech, J.; Falke, D.: Die akute und die latente HSV-Vulvitis/Vaginitis der Maus. Jahrestagung der Gesellschaft für Virologie, Hamburg, Abstract No. 9 P12 (10.-13.3.1997)
16. Mayer, A.; Podlech, J.; Dreis, D.; Reddehase, M. J.: CMV-Infektion in vivo ist assoziiert mit einer Deregulation der Expression essentieller hämatopoetischer Zytokingene im Knochenmarkstroma. Jahrestagung der Gesellschaft für Virologie, Hamburg, Abstract No. 9 P19 (10.-13.3.1997)
17. Podlech, J.; Steffens, H.-P.; Holtappels, R.; Münster, J.; Reddehase, M. J.: Cytomegalievirus-Infektion nach syngener Knochenmarktransplantation im murinen Modellsystem: Letale Multiorgan-Erkrankung nach selektiver Depletion der CD8-T-Zellen. Jahrestagung der Gesellschaft für Virologie, Hamburg, Abstract No. 9 P22 (10.-13.3.1997)
18. Mayer, A.; Dreis, D.; Podlech, J.; Reddehase, M. J.: Lethal cytomegaloviral aplastic anemia (CMV-AA) caused by in vivo downregulation of essential stromal hemopoietin genes. 22th International Herpesvirus Workshop, La Jolla, California, USA, Abstract No. 409 (2.-8.8.1997)
19. Steffens, H.-P.; Podlech, J.; Dobonici, M.; Maiberger, S.; Reddehase, M. J.: Präemptive Therapie mit CD8-T-Zellen verhindert die letale Cytomegalovirus-induzierte Knochenmarksaplasie. Jahrestagung der Gesellschaft für Virologie, Regensburg, Abstract No. 8 V 4 (2.-5.3.1998)
20. Holtappels, R.; Alterio de Goss, M.; Steffens, H.-P.; Podlech, J.; Reddehase, M. J.: Die Rezipientenhämatopoese spielt eine entscheidende Rolle bei der Kontrolle der Cytomegalovirus-Infektion nach Knochenmarktransplantation. Jahrestagung der Gesellschaft für Virologie, Regensburg, Abstract No. 8 P 11 (2.-5.3.1998)
21. Podlech, J.; Holtappels, R.; Wirtz, N.; Steffens, H.-P.; Reddehase, M. J.: Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation. 23th International Herpesvirus Workshop, York, U.K., Abstract No. 356 (1.-7.8.1998)
22. Steffens, H.-P.; Holtappels, R.; Podlech, J.; Alterio de Goss, M.; Reddehase, M. J.: Control of murine cytomegalovirus infection in bone marrow transplantation chimeras. 23th International Herpesvirus Workshop, York, U.K., Abstract No. 341 (1.-7.8.1998)
23. Grzimek, N. K. A.; Podlech, J.; Steffens, H.-P.; Holtappels, R.; Schmalz, S.; Reddehase, M. J.: In situ Analyse der durch den Immediate-Early Promotor-Enhancer des humanen Cytomegalovirus gesteuerten Replikation eines rekombinanten murinen Cytomegalovirus. Jahrestagung der Gesellschaft für Virologie 1999, Bremen, Germany, Abstract No. 1 V 5 (9.-12.3.1999)
24.Holtappels, R.; Steffens, H.-P.; Podlech, J.; Reddehase, M. J.: The NK-cell decoy gene M04-gp34 of murine Cytomegalovirus encodes an antigenic peptide recognized by protective antiviral CD8-T-cells. 24th International Herpesvirus Workshop, Boston/Cambridge, MA, USA, Abstract No. 9.005 (17.-23.7.1999)
25.Erlach, K.C.; Rojan, A.; Podlech, J.; Reddehase, M. J.: Dramatic retardation of B-cell lymphoma growth by murine Cytomegalovirus in a mouse model of bone marrow transplantation. 26th International Herpesvirus Workshop, Regensburg, Abstract No. 7.33 (28.7.-3.8.2001)
26.Holtappels, R.; Podlech, J.; Grzimek, N.K.A.; Thomas, D.; Pahl, M.-F.; Reddehase, M. J.: Experimental immunotherapy of murine Cytomegalovirus disease with CD8-T-cell lines specific for ppM83 and pM84, the two homologs of human Cytomegalovirus ppUL83 (pp65). 26th International Herpesvirus Workshop, Regensburg, Abstract No. 11.04 (28.7.-3.8.2001)

Book articles

1. Podlech, J.; Plachter, B.: Virologie von Rhinitis und Sinusitis: Virale Erreger nicht unterschätzen. HNO Heute 1(1): 44-48 (1996)
2. Müntefering, H.; Podlech, J.: Infektionskrankheiten des Embryo, des Fetus und des Neugeborenen. aus: Remmele, W. (ed.), Pathologie, Vol. 4, Springer-Verlag, page 461-500 (1997)
3. Podlech, J.; Steffens, H.-P.; Holtappels, R.; Mayer, A.; Alterio de Goss, M.; Oettel, O.; Wirtz, N.; Maiberger, S.; Reddehase, M. J.: Cytomegalovirus Pathogenesis after Experimental Bone Marrow Transplantation. aus: Scholz, M.; Rabenau, H. F.; Doerr, H. W.; Cinatl, J. Jr. (Eds.), CMV-Related Immunopathology. Monographs in Virology, Basel, Karger, Vol. 21, page 119-128 (1998)
4. Virologie am Krankenbett; Klinik, Diagnostik, Therapie; D. Falke (ed.) unter Mitarbeit von J. Bohl, R. W. Braun, H. P. Dienes, D. Falke, G. Gerken, B. Jansen, K.-M. Keller, J. Podlech; Springer Verlag, Berlin, Heidelberg, New York (1998)
5. Keller, K.-M.; Podlech, J.; Falke, D.: Erkältungskrankheiten und ihre Komplikationen. aus Pädiatrische Praxis, Vol. 57, page 597-611 (1999/2000)
6. Keller, K.-M.; Podlech, J.; Falke, D.: Erkältungskrankheiten und ihre Komplikationen. aus Internistische Praxis, Vol. 40, page 43-57 (2000) –reprint-
7. Keller, K.-M.; Podlech, J.; Falke, D.: Erkältungskrankheiten und ihre Komplikationen. aus Tägliche Praxis, Vol. 41, page 51-65 (2000) -reprint-