From the bench to the pipeline: testing the immunosuppressive potential of novel therapy targeting Annexin A1

Abstract

Autoimmune diseases and mood-related disorders are among the major plagues of our modern society, as they impair the normal daily life of patients at both social and physical levels. Autoimmunity is caused by the loss of immunological tolerance i.e. the inability of immune cells to make a distinction between self and non-self antigens. Intriguingly, patients suffering from autoimmune diseases also show higher rate of “unjustified” mood disorders, such as depression and anxiety. Recent evidence indicates mood disorders as biomarkers for autoimmunity rather than co-morbidities since their occurrence is unrelated to the time of diagnosis of the autoimmune disease or to the degree of disability. In this thesis I investigated the phenotype of T cell-specific transgenic mice overexpressing Annexin-A1 (AnxA1tg): homeostatic immunomodulatory protein with dual opposite functions in the innate and adaptive immune system. Consistent with the previously observed pro-inflammatory role in T cells, AnxA1tg mice showed higher susceptibility to develop autoimmune diseases like multiple sclerosis and systemic lupus erythematosus. Most interestingly, using a battery of behavioural tests, we showed an increased anxious-like behaviour in AnxA1tg mice compared to wild type. This phenotype was associated with a specific gene pattern in the brain and in T cells as shown by microarray analyses. Adoptive transfer of AnxA1tg-CD4+ T cells into wild-type mice caused an increased anxiety-like behaviour in the recipient animals thus providing first experimental evidence for emotional dysfunction in autoimmunity-prone animals. In conclusion, the results of this study provide novel evidences for the strong link between immune system and CNS. More specifically, our findings highlight a novel function of CD4+ T cells as the drivers of mental and physical wellbeing. Future studies will assess the potential of strategies targeting AnxA1 in T cells as new therapeutic tools for the combined treatment for autoimmunity and associated mental disorders.