ROLE OF IGE IN IMMUNOSURVEILLANCE: MECHANISM AND POTENTIAL THERAPEUTIC APPLICATIONS
Tesi di Dottorato
Data di Pubblicazione:
2017
Citazione:
ROLE OF IGE IN IMMUNOSURVEILLANCE: MECHANISM AND POTENTIAL THERAPEUTIC APPLICATIONS / L.m.j. Ferreira Espinoza ; tutor: D. M. Fornasari ; supervisor: A. T. Brini ; head of phd programm: M. Locati. DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE, 2017 Apr 04. 29. ciclo, Anno Accademico 2016. [10.13130/ferreira-espinoza-lorena-maria-jose_phd2017-04-04].
Abstract:
IgE is the class of immunoglobulins responsible for the protection against intestinal parasites and exerts a key role in the pathophysiology of allergic reactions. In addition, it has been demonstrated its involvement in the immune response against tumors in various animal models. According to our model, the function of IgE in the anti-tumor response is mediated by the binding of IgE with its high affinity receptor FcεRI expressed, in mice, on the surface of mast cells and basophils. Activation of FcεRI receptor leads to cell degranulation with release of preformed and newly synthesized mediators able to recruit effector cells that induce the establishment of a powerful inflammation at the tumor site. This inflammation, leading to cell death, could determine the processing of tumor antigens and the resulting immune response against tumor.
Based on promising data obtained previously in our laboratories, regarding the adjuvant effect of exogenous IgE in the anti-tumor vaccination and on the many controversial epidemiological studies about a possible link between allergies and cancer protection, we decided to investigate the possible role of endogenous IgE in the immunosurveillance of tumor. The use of two transgenic mouse models, one knock-out for the production of IgE (IgE-KO mice) and the other high IgE producer (KN1 mice), allowed us to investigate the possible involvement of host endogenous IgE in the immunity against cancer. Either in the absence or with a normal amount of IgE, tumor growth, preceded by vaccination with irradiated TS/A tumor cells (mammary adenocarcinoma), is not hindered and is comparable to not immunized mice. Differently, in high IgE producer mice, a single immunization was sufficient to obtain a complete anti-tumor protection. Moreover, challenging mice with a different tumor cell line, N2C tumor cells (less aggressive than TS/A tumor cells), the anti-tumor protection is observed even without immunization in 100% of KN1 mice compared to IgE-KO and wild type control mice.
To demonstrate that the protection observed in KN1 mice is due to the interaction of IgE with its high affinity FcRI receptor, we decided to delete the FcRI alpha gene in KN1 mice to remove their receptor. For this purpose we crossed KN1 mice with FcRI-KO mice, in order to obtain a double-mutant mouse model (DM), characterized by elevated levels of IgE but lacking in the expression of the high affinity receptor for IgE. The inoculation of N2C tumor cells in DM mice showed that the previously anti-tumor protection, observed in KN1 mice, has been widely lost and this is the fundamental point of this study because demonstrates that IgE-FcRI axis is the basis of the role of IgE in anti-tumor immune response.
We also demonstrated, through an in vitro test of mediators release, the existence of tumor-specific IgE in the serum of KN1 and DM mice that were challenged in vivo with N2C tumor cells; moreover, the depletion of IgE from sera of KN1 and DM mice validate the specific contribution played by IgE in the mediators release.
Another point of this study was to understand how IgE acts in the observed anti-tumor effect. KN1 mice depleted of CD8+ T cells prior to tumor cells inoculation lost the anti-tumor protection. This result allowed us to point out that the anti-tumor immunosurveillance, driven by IgE, is largely mediated by an immune response dependent on CD8+ T cells. Next, we decided to isolate tumor-specific IgE through hybridoma technology, starting from spleen or bone marrow of KN1 mice that previously rejected the tumor in vivo. We tried to isolate tumor-specific IgE to employ them either in preventive vaccination or in therapeutic treatment protocols, in mice with already developed tumors, but unfortunately we were abl
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
L.M.J. FERREIRA ESPINOZA
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