Head

University Medical Center Ulm
Department of Pediatrics and Adolescent Medicine
Research Lab, House 16
Eythstr. 24
89075 Ulm
Germany

Tel.: +49-731-500-57292

e-mail 1: dorit.fabricius@uniklinik-ulm.de
e-mail 2: dorit.fabricius@uni-ulm.de

Research Profile

Plasmacytoid dendritic cells (pDC) are crucial mediators of innate and adaptive immune responses. A better understanding of pDC regulation may improve immunotherapeutic approaches to cancer, infectious diseases and autoimmunity. Apart from production of IFN-alpha and TNF-alpha we showed that pDC can secrete large amounts of the serine protease granzyme B (GrB), but no perforin. In the last years we investigated the regulation of GrB in pDC based on our finding that pDC-GrB effectively suppresses T cell proliferation. While the cytokines IL-3 and IL-10 played a key role for GrB induction, toll-like-receptor agonists and CD40 ligand inhibit GrB secretion. To characterize the physiological function of pDC-GrB, we explored the effect of commonly used antiviral vaccines on pDC and found that particularly TBEV vaccine was able not only to induce marked IFN-alpha secretion, but also to efficiently suppress pDC-derived GrB, which allowed for an efficient T cell response. PDC of healthy individuals after TBEV vaccination produced less GrB than before vaccination, a mechanism possibly contributing to a successful cellular immune response to the vaccine. Our data point to a potential involvement of GrB-secreting pDC in suppression of tumor-specific T cells and suggest that pDC can have a regulatory role, mediated by GrB in the absence of perforin; a mechanism that has also been described for regulatory T cells. Since IL-3 and IL-10 can also be found in the environment of malignant tissues, pDC-GrB may be involved in suppression of tumor-specific T cells. Interestingly TBEV was used in a tumor vaccination study as natural agonist and we assume that suppression of GrB contributed to the observed anti-tumor-effect. We intend to continue elucidating in more detail the role of pDC-derived GrB and intend to utilize an in-vitro culture model of immune responses against B cell leukemias. By including pDC from healthy subjects and from patients with B cell leukemias, we hope to achieve a better understanding of the role pDC play in health and disease and how this potent immunomodulating cell population may be manipulated therapeutically.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the vast majority of patients initially respond to chemotherapy, relapses occur in approximately 20% of cases and have a poor prognosis. Thus, novel therapeutic strategies are required to treat minimal residual disease and improve long-term survival. B cell precursor (BCP)-ALL cells express low levels of costimulatory and antigen-presenting molecules and therefore are poorly recognized by the immune system. Previous reports show that CpG oligodeoxynucleotides (CpG) can induce immunogenicity of non-Hodgkin’s lymphomas including B-CLL and in certain B cell leukemias. In our study on the effect of various combinations of known potent B cell stimulators including CpG, interleukin (IL)-2 family cytokines and CD40 ligand (CD40L) on the immunogenicity of BCP-ALL cells we could show that the combination of CpG, IL-4 and CD40L was not only able to enhance expression of costimulatory and antigen-presenting molecules on BCP-ALL cells, but also enabled BCP-ALL cells to induce proliferative T cell responses and to generate cytotoxic T cells (CTLs). Of note, these CTLs exhibited significantly enhanced anti-leukemic cytotoxicity not only towards treated but also towards untreated BCP-ALL cells. Untreated control BCP-ALL cells induced only minimal T cell proliferation and cytotoxicity even in an allogeneic setting. Our results demonstrate that combined treatment with CpG, IL-2 family cytokines and CD40L is more efficient than CpG alone in inducing an immunogenic phenotype in BCP-ALL cells. In vitro CTL generation shall now be further optimized by additional stimulation of tumor-lysate-loaded activated pDC and the role of pDC in anti-leukemic immunity shall be further characterized. Apart from in vitro studies we will utilize a humanized leukemia mouse model that will be transplanted with BCP-ALL. In this xenotransplantation model we will test the anti-leukemic immune response of beforehand in vitro generated specific CTL. The planned in vivo study may provide novel insights in mechanisms of immunogenization and contribute to the development of immunotherapeutic vaccination approaches in the management of therapy-resistant BCP-ALL.

Funding

  • German Research Foundation (DFG)
  • State of Baden-Wuerttemberg (Schlieben-Lange-Program)

Recent Publications (selection)

  1. Fabricius D., Neubauer M., Mandel B., Schütz C., Viardot A., Vollmer A., Jahrsdörfer B. Debatin K.M. Prostaglandin E2 Inhibits Interferon-a Secretion and Th1 Costimulation by Human Plasmacytoid Dendritic Cells via EP2 and EP4 Receptor Engagement.The Journal of Immunology (2010), 184: 677-684
  2. Jahrsdörfer B., Vollmer A., Blackwell S., Maier J., Sontheimer K., Beyer T., Mandel B., Lunov O., Tron, K., Nienhaus G.U., Simmet T., Debatin KM., Weiner GJ., Fabricius D. Granzyme B produced by human plasmacytoid dendritic cells suppresses T cell expansion.Blood (2010), 115: 1156-1165
  3. Hagn M., Ebel V., Sontheimer K., Schwesinger E., Beyer T., Fabricius D., Barth T.F.E., Viardot A., Hepp J., Scharffetter-Kochanek K., Simmet T., and Jahrsdörfer B. CD5+ B cells from individuals with systemic lupus erythematosus express granzyme B in an interleukin 21-dependent manner.The European Journal of Immunology (2010), 40(7): 2060-2069
  4. Hagn M., Schwesinger E., Ebel V., Sontheimer K., Maier J., Beyer T., Syrovets T., Laumonnier Y., Fabricius D., Simmet T., Jahrsdörfer B. Human B cells Secrete Granzyme B when Recognizing Viral Antigens in the Context of Acute Phase Cytokine IL-21.The Journal of Immunology (2009), 183: 1838-1845
  5. Fabricius D., Blackwell S.E., O'Dorisio M. S. and Jahrsdörfer B. Human Plasmacytoid Dendritic Cell Function: Inhibition of IFN-alpha Secretion and Modulation of Immune Phenotype by Vasoactive Intestinal Peptide. The Journal of Immunology (2006), 177(9): 5920-5927
  6. Fabricius D., Bonde S., Zavazava N. Induction of Stable Mixed Chimerism by Embryonic Stem Cells Requires functional Fas/FasL Engagement. Transplantation (2005), 79(9): 1040-1044
  7. Fabricius D., Zavazava N. Embryonic stem cells: technical aspects and hurdles in organ transplantation.Current Opinion in organ transplantation (2004), 9: 289-293