Visual Universitätsmedizin Mainz

Research Team Dr. Jonuleit

Team Jonuleit

Head:

HD Dr. rer. nat. Jonuleit
Helmut Jonuleit, HD Dr. rer. nat.

+49 (0)6131-172957
+49 (0)6131-17473541
helmut.jonuleit@unimedizin-mainz.de

Team:

Dr. Andrea Tüttenberg, wissenschaftliche Assistentin
Dr. Jan Kubach, Postdoc
Anita Correll, Doktorandin
Bettina Trinschek, Doktorandin
Mohamed Hossam El-Din, Doktorand
Mario Hubo, Doktorand
Andreas Sommer, Doktorand
Ayten Balli, MTA
Lydia Paragnik, MTA

Major Research Interests:

The mayor interests of the group are the functional characterization of human dendritic cells and regulatory T cells, development of efficient dendritic cell-based cellular therapies of cancer, T cell modulatory components for treatment of imbalanced immune responses in allergy, autoimmunity and chronic inflammatory diseases and cancer.

Current Funding:

SFB-548: "Analysis and modulation of allergic and autoimmune diseases", Subpoject A8: "Functional characterization of human regulatory T cells"

CD4+CD25+ regulatory T cells (CD25+ Tregs) play a central role in the induction and maintenance of peripheral tolerance. They suppress the activation of autoaggressive CD4+ and CD8+ T cells. In the last years we were able to characterize different human CD25+ Treg subsets. We have shown that naïve CD4+ T cells differentiate after repetitive stimulation with immature dendritic cells (DC) into IL-10-producing Tregs, which suppress the activation of conventional T cells. Furthermore, we identified two functional distinct subsets of human CD25+ Tregs in the peripheral blood characterized by the expression of different surface integrins (α4β7+ and α4β1+ CD25+ Tregs). Both subsets are anergic and inhibit proliferation and cytokine release of conventional T cells in a contact-dependent manner. Additionally, they transfer suppressive activity to co-cultured CD4+ T helper cells by a mechanism called infectious tolerance.
Aim of this project is the identification and functional characterization of Treg-specific proteins, responsible for the functional properties of human Tregs.

SFB-432: "Mechanisms of tumor defense and their therapeutic implications", Subproject B11: "Analysis and modulation of immune suppression by regulatory T cells and dendritic cells in melanoma patients"

Dendritic cells (DC) are specialized for the initiation of T cell immunity, including cytotoxic T cells (CTL), which kill virus infected as well as malignant cells. In mouse models, immunization with antigen pulsed or transfected DC efficiently primes CD4+ and CD8+ T cells, resulting in protective immunity against infectious agents and tumors. Because of their unique properties as professional antigen-presenting cells to induce protective immune responses, several strategies using tumor antigen-loaded DC as “natural adjuvants” for immunotherapy of cancer patients were developed. Numerous preclinical and clinical studies using in vitro-generated monocyte-derived DC in combination with tumor-associated antigens for the treatment of patients with advanced (stage IV) melanoma were implemented. However, in most cases the immune system of advanced stage IV cancer patients allows only a transient anti-tumor response. Moreover, increasing evidence exists that active suppression by anergic conventional T cells, tumorantigen-specific Tregs and tolerogenic DC ultimately prevent "autoaggressive" immune reactions against the tumor.

The abrogation of the suppressive influence of Tregs on anti-tumor immune responses is certainly of vital importance for future anti-cancer vaccine strategies. Aims of this project are the functional characterization of CD25+ Tregs in melanoma patients in different stages of disease and to design protocols for transient manipulation of these suppressors. Additionally, we will develop novel protocols for generation of "conditioned" DC for an efficient DC-based immunotherapy of melanoma patients. Conditioning of mature DC by certain signals, such as TLR ligands, should allow these DC to overcome suppressive Treg-activity for tumor antigens. Thereby, self-tolerance might be broken and effective anti-tumor T cell responses should be induced.
A better understanding of interactions between DC, different members of the Treg family and other cells of the immune system will lead to improved protocols for clinical use of defined DC for the induction of efficient immune responses against cancer.

European Union & NRW: "Applications of proteomics for identification of targets for therapeutic uses by proteomics and biomarker identification for diagnostics by proteomics"

In this project we analyze and compare the proteomes of freshly isolated and activated human CD4+ T cells and CD25+ regulatory T cells (CD25+ Tregs). Goal of this study is the identification and functional characterization of Treg-specific proteins. Therefore, large amounts of different T cell subsets will be isolated from distinct blood products and afterwards proteomes of T cell subsets will be analyzed in cooperation with Protagen AG in Dortmund. The first Treg-specific proteins have been identified and functionally characterized.

Research cooperation with Boehringer-Ingelheim GmbH: "Immunomodulation with regulatory T cells and dendritic cells"

In this project we isolate different T cell populations for generation of monoclonal antibodies specific for human regulatory T cells (Tregs). Goal of this study is the generation and characterization of Treg-specific antibodies for therapeutic uses.

References 2000-2010:

  1. Correll, A., Tuettenberg, A., Becker, C., Jonuleit, H. 2010. Increased regulatory T-cell frequencies in patients with advanced melanoma correlate with a generally impaired T-cell responsiveness and are restored after dendritic cell-based vaccination. Experimental Dermatology in press.
  2. Becker, C., Hoschutzky, H., Rist, W., Lenter, M., Schneider, F. J., Jonuleit, H. 2010. Generation of monoclonal antibodies against human regulatory T cells. J.Immunol.Methods. 353, 62-70.
  3. Tuettenberg, A., Fondel, S., Steinbrink, K., Enk, A. H., Jonuleit, H. 2010. CD40 signalling induces IL-10-producing, tolerogenic dendritic cells. Experimental Dermatology 19, 44-53.
  4. Stahl, H. F., Fauti, T., Ullrich, N., Bopp, T., Kubach, J., Rust, W., Labhart, P., Alexiadis, V., Becker, C., Hafner, M., Weith, A., Lenter, M. C., Jonuleit, H., Schmitt, E., Mennerich, D. 2009. miR-155 Inhibition Sensitizes CD4+Th Cells for TREG Mediated Suppression. Plos One 4:e7158.
  5. Becker, C., Taube, C., Bopp, T., Becker, C., Michel, K., Kubach, J., Reuter, S., Dehzad, N., Neurath, M. F., Reifenberg, K., Schneider, F. J., Schmitt, E., Jonuleit, H. 2009. Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4(+)CD25(+) regulatory T cells. Blood 114, 1263-1269.
  6. Steinbrink, K., Mahnke, K., Grabbe, S., Enk, A. H., Jonuleit, H. 2009. Myeloid dendritic cell: From sentinel of immunity to key player of peripheral tolerance? Human Immunology 70, 289-293.
  7. Tuettenberg, A., Huter, E., Hubo, M., Horn, J., Knop, J., Grimbacher, B., Kroczek, R. A., Stoll, S., Jonuleit, H. 2009. The Role of ICOS in Directing T Cell Responses: ICOS-Dependent Induction of T Cell Anergy by Tolerogenic Dendritic Cells. Journal of Immunology 182, 3349-3356.
  8. Bopp, T., Schmitt, E., Jonuleit, H., Becker, C. 2008. A quest for tolerance: The role of regulatory T cells in allergy. Allergologie 31, 202-+.
  9. Kubach, J., Lutter, P., Bopp, T., Stoll, S., Becker, C., Huter, E., Richter, C., Weingarten, P., Warger, T., Knop, J., Mullner, S., Wijdenes, J., Schild, H., Schmitt, E., Jonuleit, H. 2007. Human CD4(+)CD25(+) regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood 110, 1550-1558.
  10. Bopp, T., Jonuleit, H., Schmitt, E. 2007. Regulatory T cells - The renaissance of the suppressor T cells. Annals of Medicine 39, 322-334.
  11. Jonuleit, H., Schmitt, E. 2007. Control of immune response by regulatory T cells. Allergologie 30, 185-188.
  12. Bopp, T., Becker, C., Klein, M., Klein-Hessling, S., Palmetshofer, A., Serfling, E., Heib, V., Becker, M., Kubach, J., Schmitt, S., Stoll, S., Schild, H., Staege, M. S., Stassen, M., Jonuleit, H., Schmitt, E. 2007. Cyclic adenosine monophosphate is a key component of regulatory T cell mediated suppression. Journal of Experimental Medicine 204, 1303-1310.
  13. Becker, C., Kubach, J., Wijdenes, J., Knop, J., Jonuleit, H. 2007. CD4-mediated functional activation of human CD4(+)CD25(+) regulatory T cells. European Journal of Immunology 37, 1217-1223.
  14. Tuettenberg, A., Koelsch, S., Knop, R., Jonuleit, H. 2007. Oxymetazoline modulates proinflammatory cytokines and the T-cell stimulatory capacity of dendritic cells. Experimental Dermatology 16, 171-178.
  15. Becker, C., Stoll, S., Bopp, T., Schmitt, E., Jonuleit, H. 2006. Regulatory T cells: present facts and future hopes. Medical Microbiology and Immunology 195, 113-124.
  16. Warger, T., Hilf, N., Rechtsteiner, G., Haselmayer, P., Carrick, D. M., Jonuleit, H., von Landenberg, P., Rammensee, H. G., Nicchitta, C. V., Radsak, M. P., Schild, H. 2006. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. Journal of Biological Chemistry 281, 22545-22553.
  17. Tuettenberg, A., Becker, C., Huter, E., Knop, J., Enk, A. H., Jonuleit, H. 2006. Induction of strong and persistent MelanA/MART-1-specific immune responses by adjuvant dendritic cell-based vaccination of stage II melanoma patients. International Journal of Cancer 118, 2617-2627.
  18. Schadendorf, D., Ugurel, S., Schuler-Thurner, B., Nestle, F. O., Enk, A., Brocker, E. B., Grabbe, S., Rittgen, W., Edler, L., Sucker, A., Zimpfer-Rechner, C., Berger, T., Kamarashev, J., Burg, G., Jonuleit, H., Tuttenberg, A., Becker, J. C., Keikavoussi, P., Kampgen, E., Schuler, G. 2006. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Annals of Oncology 17, 563-570.
  19. Kubach, J., Becker, C., Schmitt, E., Steinbrink, K., Huter, E., Tuettenberg, A., Jonuleit, H. 2005. Dendritic cells: Sentinels of immunity and tolerance. International Journal of Hematology 81, 197-203.
  20. Stassen, M., Jonuleit, H., Muller, C., Klein, M., Richter, C., Bopp, T., Schmitt, S., Schmitt, E. 2004. Differential regulatory capacity of CD25(+) T regulatory cells and preactivated CD25(+) T regulatory cells on development, functional activation, and proliferation of Th2 cells. Journal of Immunology 173, 267-274.
  21. Stassen, M., Fondel, S., Bopp, T., Richter, C., Muller, C., Kubach, J., Becker, C., Knop, J., Enk, A. H., Schmitt, S., Schmitt, E., Jonuleit, H. 2004. Human CD25(+) regulatory T cells: two subsets defined by the integrins alpha(4)beta(7) or alpha(4)beta(1) confer distinct suppressive properties upon CD4(+) T helper cells. European Journal of Immunology 34, 1303-1311.
  22. Tuettenberg, A., Jonuleit, H., Tuting, T., Bruck, J., Biermann, V., Kochanek, S., Knop, J., Enk, A. H. 2004. Early adenoviral gene expression mediates immunosuppression by transduced dendritic cell (DC): Implications for immunotherapy using genetically modified DC. Journal of Immunology 172, 1524-1530.
  23. Jonuleit, H., Schmitt, E. 2003. The regulatory T cell family: Distinct subsets and their interrelations. Journal of Immunology 171, 6323-6327.
  24. Jonuleit, H., Adema, G., Schmitt, E. 2003. Immune regulation by regulatory T cells: implications for transplantation. Transplant Immunology 11, 267-276.
  25. Tuettenberg, A., Jonuleit, H., Tuting, T., Bruck, J., Knop, J., Enk, A. H. 2003. Priming of T cells with ad-transduced DC followed by expansion with peptide-pulsed DC significantly enhances the induction, of tumor-specific CD8(+) T cells: implications for an efficient vaccination strategy. Gene Therapy 10, 243-250.
  26. Bethke, K., Staib, F., Distler, M., Schmitt, U., Jonuleit, H., Enk, A. H., Galle, P. R., Heike, M. 2002. Different efficiency of heat shock proteins (HSP) to activate human monocytes and dendritic cells: Superiority of HSP60. Journal of Immunology 169, 6141-6148.
  27. Witsch, E. J., Peiser, M., Hutloff, A., Buchner, K., Dorner, B. G., Jonuleit, H., Mages, H. W., Kroczek, R. A. 2002. ICOS and CD28 reversely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells. European Journal of Immunology 32, 2680-2686.
  28. Mahnke, K., Schmitt, E., Bonifaz, L., Enk, A. H., Jonuleit, H. 2002. Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunology and Cell Biology 80, 477-483.
  29. Jonuleit, H., Schmitt, E., Kakirman, H., Stassen, M., Knop, J., Enk, A. H. 2002. Infectious tolerance: Human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. Journal of Experimental Medicine 196, 255-260.
  30. Enk, A. H., Jonuleit, H. 2001. How do dendritic cells prevent autoimmunity: what is a mature dendritic cell in the mouse? Response. Trends in Immunology 22, 547.
  31. Jonuleit, H., Schmitt, E., Steinbrink, K., Enk, A. H. 2001. Dendritic cells as a tool to induce anergic and regulatory T cells. Trends in Immunology 22, 394-400.
  32. Jonuleit, H., Giesecke-Tuettenberg, A., Tuting, T., Thurner-Schuler, B., Stuge, T. B., Paragnik, L., Kandemir, A., Lee, P. P., Schuler, G., Knop, J., Enk, A. H. 2001. A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. International Journal of Cancer 93, 243-251.
  33. Jonuleit, H., Schmitt, E., Stassen, M., Tuettenberg, A., Knop, J., Enk, A. H. 2001. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. Journal of Experimental Medicine 193, 1285-1294.
  34. Schuler-Thurner, B., Dieckmann, D., Keikavoussi, P., Bender, A., Maczek, C., Jonuleit, H., Roder, C., Haendle, I., Leisgang, W., Dunbar, R., Cerundolo, V., von den Driesch, P., Knop, J., Brocker, E. B., Enk, A., Kampgen, E., Schuler, G. 2000. Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1(+) melanoma patients by mature monocyte-derived dendritic cells. Journal of Immunology 165, 3492-3496.
  35. Jonuleit, H., Schmitt, E., Schuler, G., Knop, J., Enk, A. H. 2000. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. Journal of Experimental Medicine 192, 1213-1222.
  36. Ross, R., Jonuleit, H., Bros, M., Ross, X. L., Yamashiro, S., Matsumura, F., Enk, A. H., Knop, J., Reske-Kunz, A. B. 2000. Expression of the actin-bundling protein fascin in cultured human dendritic cells correlates with dendritic morphology and cell differentiation. Journal of Investigative Dermatology 115, 658-663.
  37. Steinbrink, K., Paragnik, L., Jonuleit, H., Tuting, T., Knop, J., Enk, A. H. 2000. Induction of dendritic cell maturation and modulation of dendritic cell-induced immune responses by prostaglandins. Archives of Dermatological Research 292, 437-445.
  38. Jenne, L., Arrighi, J. F., Jonuleit, H., Saurat, J. H., Hauser, C. 2000. Dendritic cells containing apoptotic melanoma cells prime human CD8(+) T cells for efficient tumor cell lysis. Cancer Research 60, 4446-4452.
  39. Jonuleit, H., Giesecke, A., Kandemir, A., Paragnik, L., Knop, J., Enk, A. H. 2000. Induction of tumor peptide-specific cytotoxic T cells under serum-free conditions by mature human dendritic cells. Archives of Dermatological Research 292, 325-332.
  40. Jonuleit, H., Tuting, T., Steitz, J., Bruck, J., Giesecke, A., Steinbrink, K., Knop, J., Enk, A. H. 2000. Efficient transduction of mature CD83(+) dendritic cells using recombinant adenovirus suppressed T cell stimulatory capacity. Gene Therapy 7, 249-254.
  41. Muller, G., Muller, A., Jonuleit, H., Steinbrink, K., Szalma, C., Paragnik, L., Lingnau, K., Schmidt, E., Knop, J., Enk, A. H. 2000. Fetal calf serum-free generation of functionally active murine dendritic cells suitable for in vivo therapeutic approaches. Journal of Investigative Dermatology 114, 142-148.
  42. Thurner, B., Haendle, I., Roder, C., Dieckmann, D., Keikavoussi, P., Jonuleit, H., Bender, A., Maczek, C., Schreiner, D., von den Driesch, P., Brocker, E. B., Steinman, R. M., Enk, A., Kampgen, E., Schuler, G. 1999. Vaccination with Mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. Journal of Experimental Medicine 190, 1669-1678.
  43. Brand, U., Bellinghausen, I., Enk, A. H., Jonuleit, H., Becker, D., Knop, J., Saloga, J. 1999. Allergen-specific immune deviation from a T(H)2 to a T(H)1 response induced by dendritic cells and collagen type I. Journal of Allergy and Clinical Immunology 104, 1052-1059.
  44. Steinbrink, K., Jonuleit, H., Muller, G., Schuler, G., Knop, J., Enk, A. H. 1999. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 93, 1634-1642.
  45. Stoll, S., Jonuleit, H., Schmitt, E., Muller, G., Yamauchi, H., Kurimoto, M., Knop, J., Enk, A. H. 1998. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development. European Journal of Immunology 28, 3231-3239.
  46. Brand, U., Bellinghausen, I., Enk, A. H., Jonuleit, H., Becker, D., Knop, J., Saloga, J. 1998. Influence of extracellular matrix proteins on the development of cultured human dendritic cells. European Journal of Immunology 28, 1673-1680.
  47. Steinbrink, K., Wolfl, M., Jonuleit, H., Knop, J., Enk, A. H. 1997. Induction of tolerance by IL-10-treated dendritic cells. Journal of Immunology 159, 4772-4780.
  48. Kuhn, U., Brand, P., Willemsen, J., Jonuleit, H., Enk, A. H., van Brandwijk-Petershans, R., Saloga, J., Knop, J., Becker, D. 1998. Induction of tyrosine phosphorylation in human MHC class II-positive antigen-presenting cells by stimulation with contact sensitizers. Journal of Immunology 160, 667-673.
  49. Jonuleit, H., Kuhn, U., Muller, G., Steinbrink, K., Paragnik, L., Schmitt, E., Knop, J., Enk, A. H. 1997. Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. European Journal of Immunology 27, 3135-3142.
  50. Enk, A. H., Jonuleit, H., Saloga, J., Knop, J. 1997. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. International Journal of Cancer 73, 309-316.
  51. Jonuleit, H., Wiedemann, K., Muller, G., Degwert, J., Hoppe, U., Knop, J., Enk, A. H. 1997. Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells - A role for IL-15 in attraction of T cells. Journal of Immunology 158, 2610-2615.
  52. Jonuleit, H., Knop, J., Enk, A. H. 1996. Cytokines and their effects on maturation, differentiation and migration of dendritic cells. Archives of Dermatological Research 289, 1-8.
  53. Jonuleit, H., Lohmann, S., Muller, G., Lempertz, U., Enk, A., Knop, J. 1996. Specific stabilization of the 4F7 molecule on dendritic cells by contact allergens. Archives of Dermatological Research 288, 745-752.
  54. Mohamadzadeh, M., Jonuleit, H., Kolde, G., Pavlidou, A., Schmitt, E., Knop, J. 1993. Functional and Morphological Characterization of 4F7+ Spleen Accessory Dendritic Cells. International Immunology 5, 615-624.
  55. Jonuleit, H., Schmitt, E. 2005. Regulatory T-cells in antitumor therapy: isolation and functional testing of CD4+CD25+ regulatory T-cells. Methods Mol.Med. 109:285-96., 285-296.