Zurich initiative on novel cytokine-directed treatments for immune dysregulation
Cytokines that share the common γ chain receptor (γc), particularly, interleukin (IL)-2, IL-7 and IL-15, play crucial roles in the homeostasis, activation and control of immune responses. However, in immune-mediated disorders, such as autoimmune diseases and inflammatory pathologies, these homeostatic processes and cytokines are dysregulated. This, in turn, affects the activation and regulation of the tripartite interactions of phagocytes / antigen-presenting cells (APC), effector lymphocytes, and regulatory-type immune cells. Within this research program, we propose to study the homeostatic mechanisms and cytokines in three diseases, in which dysregulation of the IL-2, IL-7, and/or IL-15 system(s) is very likely or has been suggested to play an important role in the pathogenesis, including hemophagocytic lymphohistiocytosis (HLH) and systemic lupus erythematosus (SLE).
These disorders are particularly interesting to study and compare, with HLH representing a dysregulation of phagocyte activity and SLE a prototypic B cell-mediated systemic autoimmune disease associated with functional impairment of regulatory T (Treg) cells, with interactions of these immune cell subsets being implicated in both of them. We hypothesize that treatments modulating these homeostatic cytokines can be harnessed to restore a balanced immune homeostasis within phagocytes / APCs, effector lymphocytes, and regulatory-type immune cells, which has several advantages over the currently used immunosuppressive treatments in these disorders.
We plan to tackle this overarching hypothesis in a stepwise, translational manner by studying preclinical animal models, patient samples, and patients with HLH and SLE undergoing targeted immunotherapies.