Giovazzino, Angela (2018) A study of immune tolerance control in physiological models and in immune-mediated diseases. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: A study of immune tolerance control in physiological models and in immune-mediated diseases
Date: 10 December 2018
Number of Pages: 42
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Mediche Traslazionali
Dottorato: Medicina clinica e sperimentale
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
Beguinot, FrancescoUNSPECIFIED
Ruggiero, GiuseppinaUNSPECIFIED
Date: 10 December 2018
Number of Pages: 42
Keywords: Immune tolerance; T-reg, T-cells
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited: 07 Jan 2019 08:05
Last Modified: 23 Jun 2020 14:16

Collection description

Immune response is based on a complex molecular and cellular network able to ensure protection against pathogens and simultaneously maintain tissue homeostasis. Multiple immunoregulatory processes are physiologically involved in preventing potentially deleterious immune reactions against self tissues. The key role of regulatory immune cell populations, as represented by CD4+CD25+Foxp3+ Treg cells, in induction and maintenance of immunological tolerance has been largely demonstrated. Aim of this study is to investigate on cell-dependent control of immune response in physiological conditions as well as in the context of immune-mediated diseases, also addressing the possibility to modulate deranged immune effectors. With this purpose we focused: i. a human model of autoimmunity, as represented by a subgroup of patients affected by Myelodysplastic Syndrome (MDS), a hematological disorder characterized by immune-mediated selection and expansion of pathological stem precursors; ii. human and animal models of pharmacological and metabolic immune-modulation; iii. the functional analysis of a T cell population, characterized by the co-expression of CD3 and CD56 molecules, whose quantitative defect has been observed in autoimmune diabetes. Immune-response has been largely recognised as a finely tuned micro-site process. Thus, the possibility to focus cell-mediated immune tolerance control in Bone Marrow (BM), the microenvironment in which immune-mediated selection of pathological stem precursor takes place, represent a powerful analysis tool to investigate on MDS pathogenesis. Our study of BM T cell repertoire revealed an inverse correlation between BM Treg levels, activation status and BM clonal expansion of CD8+ T lymphocytes in MDS patients. Thus, BM Treg were proposed to represent a key element for the control of the deranged immune effectors in an inflammatory microenvironment. Cross talk between immune response and metabolism is still largely undefined. Particularly, Treg availability has been observed in vitro to specifically depend on the oscillatory activity of the mammalian Target Of Rapamycin (mTOR), a Serine/Threonine kinase playing a key role in regulating cell growth and metabolism in response to nutritional cues. The employment of mTOR pharmacological inhibition for the control of tumour cell growth has been largely described. We found that dosage and administration schedule of the mTOR inhibitor Everolimus, able to ensure mTOR oscillatory activity, is relevant to induce immune-tolerance rather than inhibition of cell growth in a model of tolerance induction, as represented by allogeneic kidney transplant. Our study also addressed the possibility to use nutraceutical compounds, by us selected for their immune-modulating effects in a veterinary model of chronic infection, to control immune effector activity in vitro. Our data are conceivable with the possibility to employ these substances as pharmacological co-adjuvants to modulate pro-inflammatory activity in contexts of altered immune homeostasis. Co-expression of CD3 and CD56 molecules identifies a lymphocyte population whose functional activity is largely undefined. A severe reduction of this cells has been associated with the extent of β-cell loss in patients affected by type 1 diabetes. We found that CD3+CD56+ lymphocytes, by us named TR3-56, represent a distinct subgroup of T lymphocytes, able to preferentially modulate effector function of cytotoxic T cells. Indeed, the co-culture of TR3-56 with CD8+ effector cells mediates significant inhibition of their cytotoxic activity and IFN- γ production. No effects were observed when cytotoxic T cells were cultured with NK, CD4 or CD8 T lymphocytes. A contact-dependent mechanism has been observed to underlie immune-modulating activity of TR3-56 cells. A better knowledge of cell mediated processes involved in immune-tolerance control is expected to significantly improve the availability of innovative immune-modulating strategies, thus ameliorating clinical management of immune-mediated disorders.


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