'Universidad de Sevilla - Secretariado de Recursos Audiovisuales y Nuevas Tecnologias'
Abstract
Trabajo presentado para optar al grado de Doctor por la Universidad de Sevilla, Departamento de Fisiología médica y biofísica.--Calificación: Sobresaliente Cum LAUDEType 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of islet β
cells. Current treatments are based on replacement therapy using insulin analogs but,
due to the impossibility to simulate physiological glucose control, it leads to diabetes
complications. Thus, novel treatments are required. As a difference of what happens
with the immunosuppressor therapy, which have limited clinical efficacy, the induction
of antigen specific tolerance (AST) can specifically block the activation of autoreactive
T cells, preserving the survival and function of the pancreatic β cells and preventing the
development of T1DM. Here, two different strategies are followed, in order to induce a
tolerogenic environment. The expression of the self-antigen insulin under noninflammatory conditions, using the SV40 background allows the restoration of the
antigen specific tolerance in the RIPB7.1 mouse model. Also, the protective role in
pancreatic islets of the liver receptor homologue 1 (LRH1) against apoptosis was
considered, as well as the prevention of hyperglycemia in T1DM mouse models by the
induction of an anti-inflammatory environment promoted by the LRH1 agonist BL001.
However, the limitations of BL001 as potential medication prompted us to develop an in
vitro drug-screening platform that allowed the identification of two novel LRH1 agonists,
BL002 and BL003. These non-toxic agonists protect mouse islets from cytokinesinduced apoptosis, improving their survival. Thus, the AST induced by SV40 vector as
well as the new generation of LRH1 agonists BL002 and BL003 must be considered as
two promising therapies for the treatment of T1DM