Wed, 2013-04-17 12:09 | 
Summary of thesis:
T regulatory cells (Treg) play a central role in the network of central and peripheral mechanisms of tolerance participating in the maintainance of the homeostasis of the organism [1]. Several subsets of Treg have been described with at least two major subsets: naturally occurring Tregs (nTreg), characterized by the constitutive expression of the transcription factor FOXP3, and exerting their action via cell contact, and inducible Tregs (iTreg) acting through the release of cytokines, such as IL-10 (TR1 ) and TGF-b1 (Th3) [2,3]. It has been suggested that their accumulation is responsible for the inability to eliminate pathogens and the subsequent chronicity of infections [4]. However, animal studies have shown that the absence of these populations may be the cause uncontrolled immune responses and autoimmune destructive inflammation of the tissues [5]. Recently, in our laboratory by studying a human model of chronic inflammation, specifically, chronic viral hepatitis / cirrhosis (B and C), we observed mobilization of nTregs in the liver (characterized by a dramatic increase of FOXP3 expression), which follows a certain pattern, depending upon the inflammatory stage and the expression of apoptosis mediators (Fas, FasL, TRAIL, and caspases) [6]. These data could be integrated into a single operating model of nTregs, relative to the tissue damage due to inflammation caused by excessive apoptosis. According to this model, acute or chronic tissue damage, regardless of etiology, causes increased apoptosis of the tissue, which leads to increased phagocytosis and antigen presentation of autoantigens. Consequent accumulation nTreg aims to prevent possible catastrophic autoimmunity in affected tissue from autoreactive T cell-clones.
The aim of this thesis will be to prove the correctness of the above model. Specifically,
1. Will study the molecules and intracellular pathways of apoptosis and autophagy which become activated during the inflammation, relative to the possible accumulation of regulatory cells, defining their type (nTregs, iTregs/Tr1, Th3).
2. Will seek for possible variations in the expression of these molecules, depending on the cause of tissue damage
3. Will study the effect of treatment (antiviral therapy in patients with chronic viral, immunosuppressive therapy in patients with autoimmune hepatitis) in the inflammatory process in the liver and thus in the model described above. Especially in patients with chronic viral hepatitis/ cirrhosis has been suggested that the increased presence of nTreg probably justifies the chronicity of infection through repression of specific (against pathogens) immune responses [4]. This study will investigate the role of natural and inducible Treg before and after treatment
4. Will be studied pathways of cytokines that are associated with severe inflammation and fibrosis, as the superfamily of TGF-b (b1,-b2,-b3), activin, epidermal growth factor (EGF), growth factor of connective tissue ( CTGF), the platelet derived growth factor (PDGF) and vascular endothelial growth factor (VEGF)
5. Finally, completing this study, we will try to confirm the correctness of the above hypothesis in other models of human inflammation, such as ulcerative colitis and inflammatory arthritis of the hip due to usage of implants.
References
1. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;2:816-22.
2. Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression, Trends Mol Med 2007;13:108-116.
3. Jonuleir H, Schmitt E. The regulatory T cell family: Distinct subsets and their interrelations. J Immunol 2003;6322-7.
4. Manigold T, Racanelli V. T-cell regulation by CD4 regulatory T cells during hepatitis B and C virus infections: facts and controversies, Lancet Infect Dis 2007:7:804- 813.
5. Kim JM, et al. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007;8:191-7.
