Projects / Programmes
Development and optimization of clinical potential of tolerogenic dendritic cells and the immunomodulatory role of lectin receptor DC-SIGN
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 1.07 |
Natural Sciences |
Other natural sciences |
New generation tolerogenic dendritic cells, migration, CCR7, cellular therapies, DC-SIGN
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
26198 |
PhD Urban Švajger |
Microbiology and immunology |
Head |
2011 - 2013 |
0 |
Organisations (1)
Abstract
Dendritic cells (DCs) represent a heterogeneous population of most important antigen (Ag)-presenting cells (APCs), with a central role in modulation of immune responses of both innate and adaptive immunity. DCs are unique in their ability to present Ags and possess extensive functional plasticity. In this manner, DCs can elicit both effector as well as regulatory immune responses (1, 2).
Under specific conditions, the DCs can obtain tolerogenic properties. Such DCs induce T-cell anergy or even regulatory T cells, instead of various subtypes of effector T cells (2). Fully activated, mature DCs achieve increased probability to encounter potential Ag-specific T cells through expression of the chemokine receptor CCR7, which guides DCs towards increasing concentrations of chemokines CCL19 and CCL21 into T-cell areas of lymph nodes (3). Tolerogenic DCs (TDCs) generated by numerous recently discovered protocols (4-12), in contrast to mature DCs, do not express CCR7, due to dominating immature characteristics (low co-stimulatory molecules). This fact alone, in spite of extensive tolerogenic characteristics of various TDCs (expression of inhibitory molecules and immunosuppressive cytokines), limits their very promising role in therapy of immune-mediated diseases in humans (13). Work in this project will encompass studies related to immunological mechanisms and generation of new protocols enabling the generation of new generation of TDCs, with high CCR7 expression and the ability to migrate in response to CCL19 and CCL21.
DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a lectin receptor, selectively expressed by DCs. It is involved in Ag-recognition, cellular adhesion and modulation of DC functions (14). DC-SIGN recognizes several viral (Ebola, HIV-1, etc.) and non-viral (M. tuberculosis, H. pylori, etc.) pathogens (15). Numerous pathogens exploit DC-SIGN ligation to increase their infectivity and to avoid classical Ag-presentation pathways and DC activation, thereby increasing their chances of survival in the host (16-19). Due to recently discovered immunological role of DC-SIGN, many questions still exist regarding its influence on DC development and function. Additionally, DC-SIGN is becoming an important therapeutical target in search for novel anti-microbial drugs. Related work will include research of yet unidentified aspects of immumodulatory role of DC-SIGN, detailed understanding of DC-SIGN-mediated signaling, as well as evaluation of potential agonism/antagonism of novel synthetic DC-SIGN inhibitors.
References
1. Banchereau J, et al. (2000) Annu Rev Immunol 18:767-811.
2. Steinman RM, Hawiger D, & Nussenzweig MC (2003) Annu Rev Immunol 21:685-711.
3. Forster R, Davalos-Misslitz AC, & Rot A (2008) Nat Rev Immunol 8(5):362-371.
4. Hackstein H & Thomson AW (2004) Nat Rev Immunol 4(1):24-34.
5. Steinbrink K, Wolfl M, Jonuleit H, Knop J, & Enk AH (1997) J Immunol 159(10):4772-4780.
6. Chorny A, et al. (2005) Proc Natl Acad Sci U S A 102(38):13562-13567.
7. Butts CL, et al. (2007) Horm Metab Res 39(6):404-412.
8. Xia CQ, Peng R, Beato F, & Clare-Salzler MJ (2005) Scand J Immunol 62(1):45-54.
9. Hackstein H, et al. (2003) Blood 101(11):4457-4463.
10. Turnquist HR, et al. (2007) J Immunol 178(11):7018-7031.
11. Svajger U, Obermajer N, & Jeras M (2010) Immunology 129(4):525-535.
12. Svajger U, Vidmar A, & Jeras M (2008) Int Immunopharmacol 8(7):997-1005.
13. Anderson AE, et al. (2009) J Leukoc Biol 85(2):243-250.
14. Svajger U, Anderluh M, Jeras M, & Obermajer N (2010) Cell Signal 22(10):1397-1405.
15. van Kooyk Y & Geijtenbeek TB (2003) Nat Rev Immunol 3(9):697-709.
16. Gringhuis SI, et al. (2010) Nat Immunol 11(5):419-426.
17. Tremblay MJ (2010) Nat Immunol 11(5):363-365.
18. Gringhuis SI, den Dunnen J, Litjens M, van
Significance for science
Within the immunological sciences, the discoveries in immune tolerance always somewhat lagged behind those dealing with immune activation. In the field of dendritic cells (DCs), the mechanisms that enable their activation or tolerance, can be subsequently applied in the clinical context of using either positive or negative vaccines based on DCs. While there are already several hundred clinical studies using DCs as cancer vaccines registered within NIH (National Institute of Health), there are only a few using tolerogenic DCs as negative vaccines. This fact does not highlight minor significance of tolerogenic DCs, but is only a reflection of a slower development in the field of evoking immune tolerance using cellular vaccines. This fact highlights the importance of intensive research in this field. Work in the project Z1-4302 led to discovery of new ways to manipulate human DCs in vitro/ex vivo in terms of augmenting these cells with superior tolerogenic characteristics. We discovered an important negative-feedback mechanism involving interferon-gama (IFN-g), which, when present at high concentrations like those characteristic for strong Th1-directed T cell responses, induces extensive tolerogenic characteristics in DCs. Such DCs can subsequently silence the responses of cytotoxic CD8+ T cells. The study was further developed which led to discovery of, previously unknown, synergistic tolerogenic effects between IFN-g and specific immunosupressive molecules such as IL-10, the active form of vitamin D3 and corticosteroids. Combinations of IFN-g with above mentioned immunosuppressive factors induces superior immunosupressive characteristics in DC, which significantly exceed the tolerogenic effects of these agents by themselves. Additionally, we have discovered that the combined effect of IFN-g and vitamin D3 greatly induces the expression of the chemokine receptor CCR7, which directs DCs to secondary lymphoid tissues. this is of vital importance for DCs to come into contact with responding T cells and to initiate suppressive immunity. The discovery of mechanisms and protocols that enable appropriate ex-vivo manipulation of human DCs towards immune tolerance is currently a hot topic. Results in this field will bring novel approaches to fight immune-mediated diseases characterized by excessive activity of the immune system. the second part of the project was based on research associated with recently discovered receptor DC-SIGN, selectively expressed by DCs. DC-SIGN represents an important surface marker since it possess many functions including those associated with Ag-presentation, signaling. It is also a pattern recognition receptor and an entry point for various pathogens. We have discovered novel synthetic inhibitors of DC-SIGN based on the mannose structure. Potential use of such DC-SIGN antagonists lies in the inhibition of DC infection from these pathogens, which use the receptor to infect cells. these DC-SIGN inhibitors were also biologically evaluated and published with IC50 values in the lower micromolar range.
Significance for the country
In Slovenia, the field of advanced therapies, more specifically cellular therapies and immunotherapies have made a notable advancements in the last decade. Under the auspices of Blood Transfusion Centre of Slovenia, where project Z1-4302 took place, the development of advanced therapies is a central priority, being an important part of long-term strategy of the institution with emphasis on clinical translation. Dendritic cell-associated immunotherapies represent an important future tool to treat various immune-mediated diseases including various types of cancer, complications associated with allogeneic transplantations, as well as autoimmune and chronic inflammatory diseases. Regarding negative immune cell therapies (intended to silence excessive immune responses) in Slovenia, we already perform s.c. extracorporeal photopheresis (ECP), whose mechanisms are directly associated with immunosuppression mediated by dendritic cells. the discoveries gained during the project Z1-4302 offer novel tools, which could be potentially used to optimize such methods as ECP and increase tolerogenicity of the cellular product. They can also be used to introduce novel cellular therapies based on DCs that can be quickly translated into the clinic. The discoveries made in the field of DC-SIGN receptor are particularly important for understanding of mechanisms of immunomodulation that occur after receptor activation, as well as for development of novel synthetic inhibitors, which represent potential future anti-microbial drugs. Understanding of the precise role of DC-SIGN in immunity is crucial to fight numerous pathogens, which use the receptor to infect cells of the immune system. The importance of such discoveries in Slovenia is undoubtedly in applications for internatinal patents, as well as in potential establishment of a "spin-off" company, that would pursue the devlopment of novel anti-microbial drugs.
Most important scientific results
Annual report
2011,
2012,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
final report,
complete report on dLib.si
