The immune system reacts against parasitic infection and environmental substances like allergens with a type-2 response. While per se a beneficial and protective mechanism, millions of individuals are compromised by a dysregulation of type-2 immunity, suffering from chronic inflammatory conditions like asthma.
Traditionally, type-2 pathology was thought to be in particular an exaggerated response of the adaptive immune system characterized by Th2 cells, IgE production and an activation of eosinophils and mast cells. Typical inflammatory mediators of such a response include Interleukins 4, 5, 9 and 13. However, it has been increasingly accepted that type-2 inflammation is initiated and maintained by both, the adaptive and innate immune system with epithelial cells and innate lymphoid cells 2 (ILC2) both playing an important role.
All of the afore mentioned cellular players of dysregulated type-2 immunity have one feature in common: they demonstrate expression and up-regulation of GATA-binding factor 3 (GATA-3), a so-called master transcription factor.
Master transcription factors are key molecules in the regulation of intracellular signalling processes. They are responsible for an integrated cellular response to multiple signals and exert their activity by binding to promoter sites of genes thereby enabling their transcription.
In type-2 inflammatory diseases GATA-3 orchestrates inflammation e.g. by the production of key pro-inflammatory cytokines. Reducing GATA-3 activity leads to a downregulation of inflammation and normalization of the dysregulated type-2 immunity (immunomodulation), ultimately providing a therapeutic effect
sterna biologicals is the first company which has been able to pharmacologically tackle GATA-3 dysregulation in type-2 inflammation with a novel, first-in-class, special antisense
It directly promotes the expression of the Th2 cytokines IL-4, IL-5, and IL-13 and suppresses the expression of counter-acting Th1 cytokines at the same time. Thus, GATA-3 is necessary and sufficient for Th2 cytokine expression in CD4-positive T cells. Very recently, it has been demonstrated that GATA-3 is also expressed in mast cells and eosinophils, i.e. effector cells of allergic immune responses.
In contrast, Tbet is the characteristic transcription factor of Th1 cells. It is expressed after appropriate stimulation of these cells and is responsible for the induction of Th1 cytokines, mainly of interferon-γ. In parallel, Tbet suppresses Th2-cytokine expression. Thus, Tbet is indispensable for the induction of Th1 cell activities.