Cellular Immunology

Eleni Dotsika | Department of Microbiology

Head of the Laboratory of Cellular Immunology

Contact:

+30 210-6478828 | .img@.img">.img@.img |  CV

ABOUT

The Laboratory of Cellular Immunology, founded in 1989, conducts research at the interface of immunology and microbiology of protozoa and bacteria. In preclinical studies based on murine experimental models, we study aspects of innate and adaptive immunity elicited after the accomplishment of preventive or therapeutic protocols of novel vaccines or new drugs. Our aim is a comprehensive immune-profiling approach to determine whether the obtained profile, upon any immune intervention in experimental infection protocols, could be identified as inducer of a preventive and/or therapeutic mechanism that correlates with disease amelioration. This correlation will reveal cellular and molecular targets for further designing successful immune interventions. Specifically, our research activities concern:
• the development of immunotherapeutic interventions against protozoan and bacterial pathogens based on synthetic prophylactic or curative vaccines
• the investigation of natural products as potential anti-protozoan drugs.
In particular, we have employing a new branch of bioinformatics that deals with the rapid design of a candidate vaccine compared with the conventional vaccinology. This reverse vaccinology approach, as part of vaccinomics, is based on T and B immunodominant epitope prediction of surface or cytoplasmic proteins for designing successful candidate vaccines. Also by employing in vitro and in vivo anti-parasitic screening assays of natural products, we search for compounds with dual anti-parasitic and immunomodulatory properties.

RESEARCH PROJECTS

Research activities are focused towards:

A. Innovative immunotherapeutic interventions on infectious disease models.

By “immunotherapeutic interventions” we refer to therapeutic actions that modify the immune system in such a way that, when successful, diseases are controlled by immunological mechanisms. In particular, we are dealing with short interventions (vaccines) that cause constant reprogramming of the immune system, resulting in being able to produce effective protective and/or therapeutic mechanisms against a pathogenic organism. We have focused our studies primarily on the obligatory intracellular protozoan Leishmania spp. that is of great importance for Public Health worldwide including Greece [1], while this experimental model allows a detailed exploration of differentiation, functionality and “cross talk” between innate and acquired immunity [2,3].
For humans, there are 20 pathogenic species of Leishmania that cause a set of diseases known globally as leishmaniases. These diseases are endemic in 98 countries in tropical and subtropical regions and a current estimate shows an annual global incidence of 0.2–0.4 million cases of visceral leishmaniasis (VL) and 0.7–1.2 million cases of cutaneous leishmaniasis (CL). The disease currently affects 12 million people with 350 million people at risk of infection [1]. We have employed various approaches, such as, native antigens in combination with potent adjuvants [4], cellular vaccinations [5], recombinant protein based vaccines, polypeptides and peptide vaccines for developing effective vaccines using experimental mouse models. Our rational for vaccine development is the identification of specific epitopes to enhance the immune response and capacity of specific immune cells to combat experimental infections. Thus, in silico and in vitro approaches to map potential peptides have been used and the identified peptides are tested for their immunogenic capacities in ex vivo and in vivo experimental models.
Macrophages, as the obligatory host cells for Leishmania spp., play a pivotal role in the interplay between innate and adaptive immunity with the T cells recognizing Leishmania antigens to be the protagonists [6, 7, 8]. To this end, our studies directly address the three signals that are required for inducing T cell activation and differentiation, namely: the antigen presentation (Signal 1), the expression of co-stimulatory molecules (Signal 2) and the production of host cell cytokines (Signal 3). Determination of these pathways allow the exploration of the two major issues in combating leishmaniasis: (a) identification of vaccine candidate antigens capable to induce long term prophylaxis and (b) studies of the mode of action of natural products as antileishmanial and immunomodulatory compounds.
In an in vivo situation, the cellular components of the anti-leishmanial immune response is characterized by monocytic cell infiltration at the site of infection which differentiate to dendritic cells (DCs). Some DCs, host parasites without been activated whereas non infected DCs elevate the expression of MHC II antigens. These DCs are associated with parasitic antigens and thus are converted to professional antigen presenting cells capable to induce IFN-γ, IL-12 and TNF-α producing CD4+ TH1 cells [3]. At the same time CD8+ T cells recognizing leishmanial antigens are also activated and produce IFN-γ. Under these conditions, INF-γ activates host cells, macrophages, to destroy intracellular parasites leading to the elimination of the parasitic infection.

A.1 Synthetic Subunit vaccines against experimental models of leishmaniasis.

 

Recently, we have focused to a Leishmania protein similar to the eukaryotic initiation factor eIF4A which shares both antigen and adjuvant properties. It is a prototype of the DEAD box protein family that was originally described as a Th1-type natural adjuvant and thus was tested in vitro and in vivo as prophylactic and immunotherapeutic vaccine candidate [9]. We studied the potentially prophylactic and/or immunotherapeutic effect of LeIF on an in vitro system of L. donovani-infected macrophages. LeIF exhibited potent leishmanicidal effect that was mediated by the production of the antimicrobial molecules NO and ROS and of the Th1-type IL-12 cytokine with a simultaneous moderate reduction of IL-10. Moreover, the protective effect of LeIF was associated with the activation of a TNF-α-dependent pathway while its immunotherapeutic activity was mediated by a TNF-α-independent pathway [10]. By taken advantage of immunoinformatics tools, we used publically available algorithms to screen LieIF antigen for Leishmania-specific epitopes. Five peptides (16-18 amino acids long) belonging to the N-terminal portion of LieIF containing promising MHC class I and II-restricted epitopes were selected and evaluated for their immunogenicity and immunomodulatory properties. Their evaluation in an ex vivo system of BM-DCs revealed that peptide 52-68 aa (LieIF_2) exhibited the most potent immunomodulatory properties. LieIF_2-pulsed BM-DCs up-regulated the expression of the co-stimulatory surface molecules CD80 and CD86, as well as the production of the pro-inflammatory cytokines TNF-α and IFN-γ [11]. Moreover, recombinant LieIF and selected recombinant overlapping polypeptides derived from LieIF induced phenotypic maturation and functional differentiation of murine bone- marrow derived DCs (BM-DCs) that were capable to confer protection in a cutaneous leishmaniasis experimental murine model. These data suggest that selected parts of LieIF could be exploited to develop innovative subunit prophylactic vaccines able to induce effective immunity mediated by MHC class I-restricted as well as class II-restricted T-cell responses.

Current studies on the intrinsic adjuvant properties of LieIF will contribute to the development of synthetic vaccines. Peptide-based vaccines are a very attractive strategy to identify new antigens but few peptide epitopes are so immunogenic to cause efficient T cell responses capable to drive to parasite elimination [12, 13]. However, combining these with appropriate adjuvants is a promising strategy for developing successful prophylactic or even therapeutic vaccine [14].

A.2 Synthetic vaccine development against Streptococcus pneumoniae.

Streptococcus pneumoniae (pneumococcus) is a commensal Gram positive-alpha, hemolytic bacterium, of great importance worldwide, mainly associated with pneumonia and meningitis. It is responsible for about 14.5 million cases of invasive disease and approximately 800,000 deaths of children under 5 years, annually. Currently, two kinds of vaccines are used against pneumococcal disease; the polysaccharide vaccine and the conjugate vaccine [15, 16]. Our study has been focused on four immunocompetent B cell epitopes located on the virulence pneumococcal surface proteins (VPPS) CbpD, PhtD, PhtE and ZmpB [17]. Mice actively immunized with any of the selected epitope analogues or with a mixture of these (G_Mix group) showed enhanced survival against lethal dose of the highly virulent pneumococcal serotype 3. Moreover, the passive transfer of hyperimmune serum obtained from G_Mix group to naive mice also conferred protection to a lethal challenge with serotype 3, demonstrating an antibody-mediating protective mechanism(s). Two peptides, PhD_pep19 and PhtE_pep40, which reside within the zinc binding domains of PhtD and PhtE proteins exhibited superior immunological characteristics [18]. Since zinc uptake is of high importance for the virulence of S. pneumoniae, these studies suggest that these epitopes worth further investigation as novel synthetic compound for the development of a polysaccharide-independent pneumococcal vaccine.

B. Preventive and therapeutic action of natural products

Limited drug options and possibility of resistance development is major and serious hurdle in the elimination of leishmaniasis worldwide. New effective, safe and affordable drugs are of imperative importance. Most chemical drugs that are widely used today were isolated from natural products, and thus natural products will continue to be important raw materials for the development of new drugs [19]. Natural medicinal products derived from olive tree (Olea europaea) are of great importance since its widely recognized that population residing in Mediterranean region experience a low incidence of chronic inflammatory diseases and a higher life expectancy compared to populations of other geographic areas. The basic feature of the Mediterranean diet is the daily consumption of extra virgin olive oil (EVOO) which has been thoroughly investigated for its health beneficial effects. Indeed, although there is a rather small phenolic fraction which exhibits a wide spectrum of biological activities in vitro and in vivo such as anti-inflammatory, antimicrobial and antioxidant [20]. Their action as antimicrobial, antioxidant and anti-inflammatory agents appears to be caused by the reduction of reactive free radicals (ROS) while at the same time regulating inflammatory mediators such as inducible nitric oxide synthase (iNOS) which is a critical factor in the development of chronic inflammatory diseases. Our research interest directed towards the potent pharmacological activity of the phenolic compounds of the olive tree against protozoa infections. More specifically, we tested their effect in in vitro and in vivo experimental models of Leishmania spp. infections. Emphasis were given in searching for phenolic compounds with dual effect against pathogen and in host’s immune system in order to efficient elucidate their mode of action as new lead compounds or drugs [21].

B.1 Evaluation of compounds derived from olive leaves and the olive mill waste water.

We evaluated the anti-promastigote and anti-amastigote activity of various compounds present in olive tree leaves and olive mill wastewater of Olea europaea L. (Oleaceae). The majority of them exhibited antileishmanial activity while Oleuropein exerted the best inhibitory effect in both stationary and middle logarithmic phase promastigotes of L. infantum, L. donovani, and L. major strains. When BALB/c mice were treated with Oleuropein upon their experimental infection with L donovani, developed persisted inhibition of parasite dissemination even 6 weeks after the termination of the treatment, as determined by parasite depletion of > 95% in liver and spleen [22]. It was also found that Oleuropein is able to drive parasite into an apoptotic-like cell death which restrains inflammatory processes that facilitate parasitic dissemination. Parasitic cell death, even though lacks typical metazoan molecular regulators of apoptosis, involves intracellular ROS, Ca+2 homeostasis and mitochondrial ΔΨm, that play pivotal role in this biological procedure. Thus, the absence of inflammatory stimuli, like necrotic parasites, will allow host dynamic immune responses to exterminate invasive parasites [23].

B.2 The evaluation of in vivo leishmanicidal activity of Oleuropein.

Oleuropein-treated mice exhibited extensive oxidative stress that was obviated by the upregulation
of anti-oxidant enzyme of the host (GCLC) whereas the corresponding enzyme of the parasite was highly down-regulated, rendering protozoans more vulnerable. Oleuropein could mount a significant Th1 polarization characterized by the expression of immune genes (IL-12, IL-10, ΤGF-1, IFN-) and transcription factors (Tbx21 and GATA3) in splenocytes and by the production of Leishmania specific IgG1 and IgG2a antibodies. This immunomodulatory effect of Οleuropein was correlated with an inhibitory effect on IL-1β gene expression, rather than with the expression of IL-1a, IL-1rn, and TNF-a. The demonstration that Οleuropein treated BALB/c mice mounted a delayed-type hypersensitivity response suggests the induction of an effective cell mediated immune mechanism capable to eliminate parasite dissemination in infected experimental animals [24].
Promising new drugs against leishmaniasis should be able to kill the parasite and at the same time to elicit desired immune responses. To this end, we investigated purified fractions of crude extracts such as the total phenolic fraction from extra virgin olive oil [25], while current studies concern isolated compounds of extra virgin olive oil, such as oleocanthal. It is noteworthy that the oleocanthal (dialdehydic form of decarboxymethyl ligstroside aglycone) is homologous to nonsteroidal anti-inflammatory drug (NSAID) ibuprofen [26]. In the case of natural infection with the protozoan Leishmania, the anti-inflammatory activity of oleocanthal of the extra virgin olive oil is necessary to regulate the proinflammatory response caused by invasion of the parasite so as to prevent excessive damage to tissues and ultimately to induce an immune responsiveness capable of contributing to the improvement of the disease. Phenols from extra virgin olive oil are key elements of the Mediterranean diet, although they are taken in low but chronic doses as natural NSAIDs, they have drawn great scientific interest in both health and disease. The study of molecular targets and immunological mechanisms that control proinflammatory reactions will lead to the further identification of nutritional components with prominent biological activity to reduce the development of chronic inflammatory diseases.

C. Natural products as husbandry functional nutrients for combating parasitic and viral diseases of teleost fish in intensive aquacultures.

Natural active substances are included in the manufacture of fish feed for the improvement of the feed conversion ratio and/or daily weight gain in fish, for reducing mortality by regulating the micro flora of the gut and/or by protecting the animal against pathogenic microorganisms [27]. Aquaculture is growing more rapidly than all other animal food-producing sectors and Greece, despite the economical crisis, remains a significant world producer with yearly production of 110,000 tons of fish. A major advantage in the use of natural substances is that do not pose any threat to fish, man or environment because of their biodegradability. Due to their beneficiary attributes, we conducted studies using natural products as alternatives to vaccines, antibiotics or chemotherapeutic agents, against parasitic and viral infection, in collaboration with Fish Feed Industries and other Research Centers and Universities [28].
Gilthead sea bream (Sparus aurata) is one of the two main Mediterranean fish species in aquaculture and it is produced mainly in sea cages. The increasing amount of sea cages farms, rise the incidence and dispersal of parasitic diseases. Poor management practices and environmental stress exacerbate this phenomenon in intensive rearing units and limit the production of caged gilthead sea bream. The fatty acid, caprylic acid, present in mammalian milk and in plant oils, is an eight-carbon saturated fatty acid with demonstrated antimicrobial potency in human, veterinary and fish medicine. Our studies concerned the effects of caprylic acid on the fish immune system during natural infection of ectoparasites in gilthead sea bream held in a production unit [29]. We tested the gene expression of IL- 1b, TNF-α, Hepcidin, IgHM and GRP-75 in the head kidney from fish infected with Cryptocaryon spp. and Trichodina spp. Infected fish fed with high dose of caprylic acid exhibited significant up regulated hepcidine gene expression in low temperatures indicating that hepcidine synthesis is increased during parasitic infection as key mediator of anemia and hypoxia.
Conclusively, we demonstrated an interrelationship between dietary caprylic acid, fish immune system and parasitic infection of gilthead sea bream kept in offshore cages. It is of great importance the investigation of caprylic acid and other natural products as feed supplements in other species in aquaculture. Also, studies for the effects of the oregano oil in experimental infection with Noda virus, showed that fish feed supplemented with oregano oil resulted in the effective activation of both innate and adaptive immunity towards the amelioration of the viral infection.

Relevant Bibliography:

1. WHO LEISHMANIASIS: The magnitude of the problem. 2014
Available at: http://www.who.int/leishmaniasis/burden/magnitude/burden_magnitude/en/

2. Kaye P, Scott P. Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol. 2011 Jul 11;9(8):604-15. doi: 10.1038/nrmicro2608. Review. PubMed PMID: 21747391.

3. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-73. Review. PubMed PMID: 2523712.

4. Papadopoulou G, Karagouni E, Dotsika E. ISCOMs vaccine against experimental leishmaniasis. Vaccine. 1998 May-Jun; 16(9-10):885-92. PubMed PMID: 9682333.

5. Tsagozis P, Karagouni E, Dotsika E. Dendritic cells pulsed with peptides of gp63 induce differential protection against experimental cutaneous leishmaniasis. Int J Immunopathol Pharmacol. 2004 Sep-Dec;17(3):343-52. PubMed PMID: 15461868.

6. Tseveleki V, Tsagozis P, Koutsoni O, Dotsika E, Probert L. Cellular FLIP long isoform transgenic mice overcome inherent Th2-biased immune responses to efficiently resolve Leishmania major infection. Int Immunol. 2007, 19(10):1183-9. Epub 2007 Sep 18. PubMed PMID: 17878261.

7. Tsagozis P, Karagouni E, Dotsika E. Function of CD8+ T lymphocytes in a self-curing mouse model of visceral leishmaniasis. Parasitol Int. 2005 Jun;54(2):139-46. PubMed PMID: 15866476.

8. Tsagozis P, Karagouni E, Dotsika E. CD8(+) T cells with parasite-specific cytotoxic activity and a Tc1 profile of cytokine and chemokine secretion develop in experimental visceral leishmaniasis. Parasite Immunol. 2003. Nov-Dec;25(11-12):569-79. PubMed PMID: 15053778.

9. Skeiky, Y.A., et al., A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12. J Exp Med, 1995. 181(4): p. 1527-37.

10. Koutsoni O, Barhoumi M, Guizani I, Dotsika E. Leishmania eukaryotic initiation factor (LeIF) inhibits parasite growth in murine macrophages. PLoS One. 2014 May 15;9(5):e97319. doi: 10.1371/journal.pone.0097319. eCollection 2014. PubMed PMID: 24830439; PubMed Central PMCID: PMC4022710.

11. Koutsoni OS, Routsias JG, Kyriazis ID, Barhoumi M, Guizani I, Tsakris A, Dotsika E. In silico analysis and in vitro evaluation of immunogenic and immunomodulatory properties of promiscuous peptides derived from Leishmania infantum eukaryotic initiation factor. Bioorg Med Chem. 2017 Nov 1;25(21):5904-5916. doi: 10.1016/j.bmc.2017.07.013. Epub 2017 Jul 8. PubMed PMID: 28974324.

12. Agallou M, Athanasiou E, Koutsoni O, Dotsika E, Karagouni E. Experimental Validation of Multi-Epitope Peptides Including Promising MHC Class I- and II-Restricted Epitopes of Four Known Leishmania infantum Proteins. Front Immunol. 2014 Jun 10;5:268. doi: 10.3389/fimmu.2014.00268. eCollection 2014. PubMed PMID: 24959167; PubMed Central PMCID: PMC4051127.

13. De Brito RCF, Cardoso JMO, Reis LES, Vieira JF, Mathias FAS, Roatt BM, Aguiar-Soares RDDO, Ruiz JC, Resende DM, Reis AB. Peptide Vaccines for Leishmaniasis. Front Immunol. 2018 May 11;9:1043. doi: 10.3389/fimmu.2018.01043. eCollection 2018. Review. PubMed PMID: 29868006; PubMed Central PMCID: PMC5958606.

14. Iborra S, Solana JC, Requena JM, Soto M. Vaccine candidates against leishmania under current research. Expert Rev Vaccines. 2018 Apr;17(4):323-334. doi: 10.1080/14760584.2018.1459191. Epub 2018 Apr 10. PubMed PMID: 29589966.

15. Principi N, Esposito S. Development of pneumococcal vaccines over the last 10 years. Expert Opin Biol Ther. 2018 Jan;18(1):7-17. doi: 10.1080/14712598.2018.1384462. Epub 2017 Oct 12. Review. PubMed PMID: 29022363.

16. Brooks WA, Chang LJ, Sheng X, Hopfer R; PPR02 Study Team. Safety and immunogenicity of a trivalent recombinant PcpA, PhtD, and PlyD1 pneumococcal protein vaccine in adults, toddlers, and infants: A phase I randomized controlled study. Vaccine. 2015 Aug 26;33(36):4610-7. doi: 10.1016/j.vaccine.2015.06.078. Epub 2015 Jul 2. PubMed PMID: 26143615.

17. Lagousi T, Routsias J, Piperi C, Tsakris A, Chrousos G, Theodoridou M, Spoulou V. Discovery of Immunodominant B Cell Epitopes within Surface Pneumococca. Virulence Proteins in Pediatric Patients with Invasive Pneumococcal Disease. J. Biol Chem. 2015 Nov 13;290(46):27500-10. doi: 10.1074/jbc.M115.666818. Epub 2015 Sep 22. PubMed PMID: 26396191; PubMed Central PMCID: PMC4646002.

18. Papastamatiou T, Routsias JG, Koutsoni O, Dotsika E, Tsakris A, Spoulou V. Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae. Infect Immun. 2018 Feb 20;86(3). pii: e00673-17. doi: 10.1128/IAI.00673-17. Print 2018 Mar. PubMed PMID: 29263108; PubMed Central PMCID: PMC5820952.

19. Andrade-Neto VV, Cunha-Junior EF, Dos Santos Faioes V, Pereira TM, Silva RL, Leon LL, Torres-Santos EC. Leishmaniasis treatment: update of possibilities for drug repurposing. Front Biosci (Landmark Ed). 2018 Jan 1;23:967-996. Review. PubMed PMID: 28930585.

20. Cicerale S, Lucas LJ, Keast RS. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr Opin Biotechnol. 2012 Apr;23(2):129-35. doi: 10.1016/j.copbio.2011.09.006. Epub 2011 Oct 13. Review. PubMed PMID: 22000808.

21. Rodrigues IA, Mazotto AM, Cardoso V, Alves RL, Amaral AC, Silva JR, Pinheiro AS, Vermelho AB. Natural Products: Insights into Leishmaniasis Inflammatory Response. Mediators Inflamm. 2015;2015:835910. doi: 10.1155/2015/835910. Epub 2015 Oct 11. Review. PubMed PMID: 26538837; PubMed Central PMCID: PMC4619978.

22. Kyriazis JD, Aligiannis N, Polychronopoulos P, Skaltsounis AL, Dotsika E. Leishmanicidal activity assessment of olive tree extracts. Phytomedicine. 2013 Feb 15;20(3-4):275-81. doi: 10.1016/j.phymed.2012.11.013. Epub 2012 Dec 27. PubMed PMID: 23273752.

23. Kyriazis ID, D Smirlis, A Papadaki, O Koutsoni, N Aligiannis, AL Skaltsounis and E. Dotsika. Leishmanicidal Activity of Oleuropein: Leishmania donovani Promastigote Cell Death through a Possibly ROS-Independent Mechanism J Pharmacogn Nat Prod 2017, 3:1 DOI: 10.4172/2472-0992.1000141

24. Kyriazis ID, Koutsoni OS, Aligiannis N, Karampetsou K, Skaltsounis AL, Dotsika E. The leishmanicidal activity of oleuropein is selectively regulated through inflammation- and oxidative stress-related genes. Parasit Vectors. 2016 Aug 9;9(1):441. doi: 10.1186/s13071-016-1701-4. PubMed PMID: 27501956; PubMed Central PMCID: PMC4977900.

25. Koutsoni O, K Karampetsou, ID Kyriazis, P Stathopoulos, N Aligiannis, M. Halabalaki, LA Skaltsounis, E Dotsika. Evaluation of total phenolic fraction derived from extra virgin olive oil for its antileishmanial activity. Phytomedicine 2018, DOI: 10.1016/j.phymed.2018.04.030 (in press)

26. Beauchamp GK, Keast RS, Morel D, Lin J, Pika J, Han Q, Lee CH, Smith AB, Breslin PA. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature. 2005 Sep 1;437(7055):45-6. PubMed PMID: 16136122.

27. Zhu LY, Nie L, Zhu G, Xiang LX, Shao JZ. Advances in research of fish immune-relevant genes: a comparative overview of innate and adaptive immunity in teleosts. Dev Comp Immunol. 2013 Jan-Feb;39(1-2):39-62. doi:10.1016/j.dci.2012.04.001. Epub 2012 Apr 12. Review. PubMed PMID: 22504163.

28. Awad E, Awaad A. Role of medicinal plants on growth performance and immune status in fish. Fish Shellfish Immunol. 2017 Aug;67:40-54. doi:10.1016/j.fsi.2017.05.034. Epub 2017 May 16. Review. PubMed PMID: 28526570.

29. Rigos G, E. Fountoulaki, E. Cottou, E. Dotsika, N. Dourala, I. Karacostas (2013). “Tissue distribution and field evaluation of caprylic acid against natural infections of Sparicotyle chrysophrii in cage-reared gilthead sea bream Sparus aurata.” Aquaculture 408-409:15-19.

FUNDING

PAST MEMBERS

Olga Koutsoni, Biologist (PhD fellow 2005-2009)
Current address: Laboratory of Cellular Immunology, Department of Microbiology, Hellenic Pasteur Institute, Athens, Greece

Ioannis Kyriazis, Biologist (PhD fellow 2005-2009, post-doctoral fellow 2009-2015)
Current address : Center for Translational Medicine and the Center for Metabolic Diseases Research Temple University School of Medicine, Philadelphia, USA.

Panagiotis Tsagozis, Biologist-MD (PhD 2004-2010).
Current address : The Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK; Section of Orthopaedics, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, 17176, Stockholm, Sweden.

Maria Papamattheou, Biologist (PhD 2000-2007)
Current address: Biology Teacher, Secondary Schools, Private Sector.

Evdokia Karagouni, Biologist PhD (post doctoral fellow 1989-1994)
Current address: Head of the Department of Microbiology, Leader of the Group of Immunology of Parasites- Vaccine development, Hellenic Pasteur Institute, Athens, Greece

MSc Students
1. Kalliopi Karampetsou (2014-2016)
2. Panagiotis Hantzovoulos (2007-2009)
3. Irini Kostanda (2008-2010)

REGULATIONS

COURCES

LINKS

PUBLICATIONS

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Koutsoni OS, Karampetsou K., Kyriazis I.D., Stathopoulos P, Aligiannis N., Halabalaki M, Leandros A., Skaltsounis L.A., Dotsika E. 2018. Evaluation of total phenolic fraction derived from extra virgin olive oil for its antileishmanial activity. Phytomedicine (in press).

Papastamatiou T, Routsias JG, Koutsoni O, Dotsika E, Tsakris A, Spoulou V., “Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae”, Infect Immun. 2018 Feb 20;86(3). pii: e00673-17. doi: 10.1128/IAI.00673-17.

2018
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Koutsoni OS, Routsias JG, Kyriazis ID, Barhoumi M, Guizani I, Tsakris A, Dotsika E. 2017. In silico analysis and in vitro evaluation of immunogenic and immunomodulatory properties of promiscuous peptides derived from Leishmania infantum eukaryotic initiation factor. Bioorg Med Chem. Nov 1;25(21):5904-5916.

Boutsini S, Athanasiou LV, Spanakos G, Ntousi D, Dotsika E, Bisia M, Papadopoulos E. 2017. Phlebotomine sandflies and factors associated with their abundance in the leishmaniasis endemic area of Attiki, Greece. Parasitol Res. Nov 10. doi: 10.1007/s00436-017-5675-8

D. Kyriazis, D. Smirlis, A. Papadaki, O. Koutsoni, N. Aligiannis, A. L. Skaltsounis, E. Dotsika. 2017. Leishmanicidal activity of oleuropein: L. donovani promastigote cell death through a possibly ROS-independent mechanism. Journal of Pharmacognosy & Natural Products 3(1):2-7 doi: 10.4172/2472-0992.1000141.

2017
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Kyriazis I.D., O.S. Koutsoni, N. Aligiannis, K. Karampetsou, A.L. Skaltsounis, E. Dotsika (2016). “The leishmanicidal activity of oleuropein is selectively regulated through inflammation and oxidative stress-related genes.” Parasit Vectors. Aug9;9(1):441. doi: 10.1186/s13071-016-1701-4.

2016
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Tseveleki V., T. Tselios, I. Kanistras, O.S. Koutsoni, M. Karamita, S.S. Vamvakas, V. Apostolopoulos, E. Dotsika, J. Matsoukas, H. Lassmann, and L. Probert (2015). “Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis.” Experimental Neurology 267: 254-267.

2015
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Agallou M, E. Athanasiou , O.S. Koutsoni, E. Dotsika, E. Karagouni (2014). “Experimental Validation of Multi- Epitope Peptides Including Promising MHC Class I- and II-Restricted Epitopes of Four Known Leishmania infantum Proteins.” Front Immunol. 10;5:268. doi: 10.3389/fimmu.2014.00268.

Agallou M., E. Dotsika, E. Karagouni (2014). “Low CD40 expression levels in Leishmania infantum-infected bone marrow dendritic cells evokes regulatory responses by down-regulating IL-12 production: Role of ERK1/2.” Eur. J. Inflammation. 12(2): 315-328.

Koutsoni O.S., M. Barhoumi, I. Guizani, E. Dotsika (2014). “Leishmania Eukaryotic Initiation Factor (LeIF) Inhibits Parasite Growth in Murine Macrophages.”PLoS One.15;9(5):e97319doi:10.1371/journal.pone. 0097319.

Agallou M., E. Dotsika, S. Frydas, Karagouni E. (2014). “Toll-like receptor 4 promotes control of Leishmania infantum infection through inducement of leishmanicidal activity in host macrophages: role of mitogen activated kinases.” J Biol Regul Homeost Agents. 28(1):41-52.

2014
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Papagiannopoulos IA, V.I. Sideris, M. Boschmann., O.S. Koutsoni, E. Dotsika (2013). “Anthropometric, hemodynamic, metabolic, and renal responses during 5 days of food and water deprivation.” Forsch Komplementmed. 20(6):427-33. doi: 10.1159/ 000357718.

Rigos G, E. Fountoulaki, E. Cottou, E. Dotsika, N. Dourala, I. Karacostas (2013). “Tissue distribution and field evaluation of caprylic acid against natural infections of Sparicotyle chrysophrii in cage-reared gilthead sea bream Sparus aurata.” Aquaculture 408-409:15-19.

2013
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Kyriazis JD, N. Aligiannis, P. Polychronopoulos, A.L. Skaltsounis, E. Dotsika. (2012). “Leishmanicidal activity assessment of olive tree extracts.” Phytomedicine. 20(3-4):275-81.

2012
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Koutsoni O., M. Barhoumi, I. Guizani and E. Dotsika. (2011). “LiEIF and its recombinant polypeptides enhance the maturation of mouse dendritic cells and the production of the protective IL-12 cytokine.” BMC proceedings 01/2011; 5:1-1. 5:1-1. DOI:10.1186/1753-6561-5-S1.

Barhoumi M., Koutsoni O., Guizani I., Dotsika E., “Characterization of immunomodulatory activity of eIF4A protein” BMC Proceedings 2011, 5 (Suppl 1):O.

2011
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Tsatchev I., I.D. Kyriazis, S. Boutsini, E. Karagouni and E.Ν. Dotsika. (2010).” First Report of canine visceral leishmaniasis in Bulgaria.” Turkish J. Vet. Anim. Science 34(3):1-5.

Chatzovoulos P.S., A.B. Tsoupras, M. Samiotaki, G. Panayotou, C.A. Demopoulos, E.Ν. Dotsika (2010). “PAF-mediated enzymes and PAF-like molecules in L. infantum and L. major promastigotes.” European. Journal of Inflammation 9(3), 231-239.

2010
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Kyriazis I.D., E. Karagouni, K. Soteriadou, A.L. Skaltsounis, E. Dotsika. (2008). “Olive tree extracts with potential leishmanicidal activity.” Planta Med 74 – PA 83, DOI; 10.1055/s-0028-1084081

2008
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Tseveleki V., P. Tsagozis, O.S. Koutsoni, E. Dotsika, L. Probert (2007). “Cellular FLIP long isoform transgenic mice overcome inherent Th2-biased immune responses to efficiently resolve Leishmania major infection.” Int. Immunol 19(10): 1183-1189.

2007
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Karagouni E., F. Athanasopoulou, A. Lytra, C. Komis, E.Ν. Dotsika. (2005). “Antiparasitic and immunomodulatory effect of innovative treatments against Myxobulus sp infection in Diplodus puntazzo.” Veterinary Parasitology. 134(3-4): 215-228.

Τsagozis P., E.E. Karagouni, E.N. Dotsika. (2005). “Function of CD8+ T lymphocytes in a self-curing mouse model of Visceral leishmaniasis.” Parasitology International 54:139-146.

2005
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Karagouni E.E., F. Athanasopoulou, P. Tsagozis, E. Ralli, Th. Moustakareas, K. Lytra and E. Dotsika. (2004).“The impact of a successful anti-myxosporean treatment on the phagocytic functions of juvenile and adult Sparus aurata”. L. Intern. J. Immunol. Pharmac. 18(1): 121-1.

Τsagozis P., V. Tseveleki, , E.N. Dotsika, E.E. Karagouni. (2004). “Vaccination with plasmids encoding the Leishmania major gp63 glycoprotein and CD40L results in a partial suppression of the inflammatory reaction after experimental infection.” Eur. J. Inflamm. 2(2): 91-96.

Athanasopoulou F., E.E Karagouni. E.Ν. Dotsika, V Ragias, J. Tavla, P Christofilloyanis and I.Vatsos. (2004). “Efficacy and toxicity of orally administrated anti-coccidial drugs for innovative treatments of Myxobulus sp. Infection in sharpsnoot seabream Puntazzo puntazzo C.”, Deseases of Aquatic Organisms. 62:217-226.

Athanasopoulou F., E.E Karagouni. E.Ν. Dotsika, V Ragias, J. Tavla, and P Christofilloyanis. (2004). “Efficacy and toxicity of orally administrated anti-coccidial drugs for innovative treatments of Polysporoplasma sparis infection in Sparus aurata L.” Journal of applied Ichthyology. 20: 345-354

Τsagozis P., E.E. Karagouni, E.N. Dotsika. (2004). “Dedritic cells pulsed with peptides of gp63 induced differential protection against experimental cutaneous leishmaniasis.” Internat. J. Immunopathol. Pharmac. 17(3): 343-352.

Papamattheou M., J. Routsias, E.E.Karagouni, C. Sakarellos, M. Sakarellos-Daitsotis, H.M. Moutsopoulos, A.G. Tzioufas, E.N. Dotsika. (2004). “T cell help is required to induce idiotypic-antiidiotypic autoantibody network after immunization with complementary epitope 289-308aa of La/SSB autoantigen in non-autoimmune mice.” Clin. Exp. Imm., 135: 416-426.

2004
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Τsagozis P., E.E. Karagouni, E.N. Dotsika. (2003). “CD8+ T cells with parasite spesific cytotoxic activity and a Tc1 profile of cytokine secretion develop in experimental visceral leishmaniasis.” Parasite Immunol., 23: 569- 579.

Routsias G. J., E.N. Dotsika, Touloupi E., M. Papamattheou, C. Sakarellos, M. Sakarellos-Daitsiotis, H.M. Moutsopoulos, A.G. Tzioufas. (2003). “Idiotypic-antiidiotype circuit in non-autoimmune mice after immunization with the epitope and complementary epitope 289-308aa of La/SSB response.” J. Autoimmun., 21 : 17-26.

2003
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Routsias G. J., E. Touloupi, E.N. Dotsika, V. Tsikaris, C. Sakarellos, M. Sakarellos-Daitsiotis, H.M. Moutsopoulos, A.G. Tzioufas. (2002). “Unmasking the ant-La/SSB response by specific blocking of ant-idiotypic antibodies with sense-complementary peptides to La/SSB major antigenic determinants.” Mol. Med., 8 : 293-305.

2002
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Hemmerlin C., A. Phan Chan Du, Z. Elhilali, A. Moulia, V. Tsikaris, M. Sakarellos-Daitsiotis, C. Sakarellos, E.N. Dotsika, A.G. Tzioufas, H.M. Moutsopoulos, Manh-Thong Cung. (2001). “Conformational study of the complementary peptide to a B-cell epitope of the La/SSB autoantigen.” Chimie/Chemistry, 4 : 729-733.

2001
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Sideris, V., G. Papadopoulou, E.N. Dotsika and E. Karagouni. (1998). “Asymptomatic canine leishmaniasis in the greater Athens area, Greece.” Eur. J. Epidemiol., 15 : 271-276.

Frydas S., M. Reale, R.C. Barbacane, F.C. Placido, E.E. Karagouni, E.N. Dotsika, M. Trakatellis, D. Vacalis, A. Trakatellis, and P. Conti. (1998). “IgG, IgG1 and IgM response in Trichinella spiralis infected mice treated with 4-deoxypyridoxine or fed a vitamine B6 deficient diet.” Molec. Cellul. Biochem., 194(1-2) : 47-52.

Karagouni E.E., A. Chrysicopoulos, Th. Matzavinos, N. Kanakas and E.N. Dotsika. (1998). “Interleukin-1b and interleukin-1a may affect the implantation rate of patients undergoing in vitro fertilization–embryo transfer.” Fertil. Steril., 70 : 553-559.

Doukas V., F. Athanasopoulou, E. Karagouni and E.N Dotsika. (1998). “A case of Aeromonas hydrophyla infection in cultured sea bass (Dicentrarnchus labrax) and Puntazzo puntazzo from the Agean sea.” J. Fish Dis., 21 : 101-104.

Papadopoulou G., E. Karagouni and E.N. Dotsika. (1998). “An iscoms vaccine against experimental leishmaniasis.” Vaccine, 16(9/10) : 885-892.

1998
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Dotsika, E.N., E.E. Karagouni, B. Sundquist, B. Morein A.J. Morgan, and M. Villacres-Eriksson. (1997). “Influence of Quillaja saponaria triterpenoid content on the mmunomodulatory capacity of Epstein-Barr virus(EBV) iscoms.” Scand. J. Immunol., 45 : 261-268.

1997
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Chryssikopoulos A., Th Mantzavinos, N. Kanakas, E.E. Karagouni, E.N. Dotsika, and P.A. Zourlas. (1996). “Correlation of serum and follicular fluid concentrations of placenta protein 14 and CA-125 in in vitro fertilization-embryo transfer patients.” Fertil. Steril., 66(4) : 599-603.

Sideris, V., E.E. Karagouni, G. Papadopoulou, A. Garyfallou and E.N. Dotsika. (1996). “Canine visceral leishmaniasis in the greater Athens area, Greece.” Parasite, 3 : 125-130.

Frydas, S., E.E. Karagouni, E.N. Dotsika, M. Reale, R.C. Barbacane, I. Vlemmas, G. Anogianakis, A. Trakatellis, and P. Conti. (1996). “Generation of TNFá, IFN-γ, IL-6, IL-4 and IL-10 in mouse serum from trichinellosis. Effect of the anti-inflammatory compound 4-deoxypyridoxine (4-DPD).” Immunol. Let., 49 : 179- 184.

1996
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Haralabidis, S., E.E. Karagouni, S. Frydas, and E.N. Dotsika. (1995). “Immunoglobulin and cytokine profile in murine secondary hydatidosis.” Parasite Immunol., 17 : 625-530.

Karagouni, E.E., S. Frydas, E.N. Dotsika, C. Himonas, P.Conti and A. Trakatellis. 1995. “Inhibition of TNF-α and IL-6, but not IFN-γ, by 4-deoxypyridoxine (4-DPD) in Trichinella-infected mouse serum.” Int. J. Immunopath. Pharmacol., 8(1) : 9-14.

1995
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Frydas, S., A. Trakatellis, E.E. Karagouni, E.N. Dotsika, C. Himonas and P. Conti. (1994). deoxypyridoxine inhibits chronic granuloma formation induced by potassium permanganate in vivo.” Molec. Cellul. Biochem., 136 : 59-63.

Karagouni, E.E., E.N. Dotsika and A. Sklavounou. (1994). “Alteration in peripheral blood mononuclear cell function and serum cytokines in oral lichen planus.” J. Oral Pathol. Med., 23 : 28-35.

1994
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Dotsika E.N. “Assays for mediators affecting cellular immune functions.” (1990). Cur. Opin. Immunol., 2 : 932-935.

1990
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Dotsika E.N. and C.J. Sanderson. (1987).“Interleukin 3 production as a sensitive measure of T lymphocyte activation in the mouse.” Immunol., 62 : 665-668.

Dotsika E.N. and C.J. Sanderson. (1987). “A fluorometric assay for determining cell growth in lymphocyte proliferation and lymphokine assays.” J. Immunol. Meth., 105 : 55-62.

1987
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Dotsika E.N. (1984). “Studies on immunological tolerance in mice.” PhD Thesis. The Medical School, University of Bristol, Bristol, UK

1984

MEMBERS

Dr. Eleni Dotsika, DVM

Head of the Laboratory of Cellular Immunology
Research Director
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Olga Koutsoni

Biologist, PhD
Special Technical Scientist
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Kalliopi Karampetsou

Biologist, MSc
PhD student
Tel: +30 210-6478825
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Theodora Papastamatiou

MD, PhD student
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Georgia Gogou

Biologist, MSc
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Όνομα Ερευνητή

Ιδιότητα – Επάγγελμα
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