The Regulatory Importance of SOCS molecules in Th2 Immune Responses and Disease

Atopic dermatitis, asthma, hay fever and food allergy can adversely affect the quality of life for many people and while current treatments for allergic disease treat the symptoms there are no cures. White blood cells called a Th2 lymphocyte are thought to be the ultimate cause of allergic disease and the work outlined in this proposal aims to understand some of the key mechanisms that determine how Th2 lymphocytes develop and predispose to allergic disease. We have found that two suppressor proteins called SOCS2 and SOCS3 appear to counteract each other in the development of these allergic Th2 cells. We have obtained genetically engineered mice that lack SOCS2 and will use this model to determine whether these mice develop asthma infections and other allergic disease. We will also address whether they can clear worm infections more efficiently, another key feature of these Th2 lymphocytes. These mice and other key models outlined in the proposal will also allow us to determine whether drugs that target these SOCS in Th2 cells will have the potential to cure allergic diseases

Allergies are systemic disorders that manifest as atopic dermatitis (AD), food allergy and allergic rhinitis (AR), all characterised by elevated IgE levels and peripheral eosinophilia. The aetiology of allergy involves complex interactions between local and systemic immune responses, but Th2-cell differentiation and expression of Th2-type cytokines are important in disease development. Significantly higher levels of IL-4 and IL-13 lead to isotype switching to IgE synthesis. Polarisation of different CD4+ T-helper cell subsets is driven by cytokines. The suppressors of cytokine signalling (SOCS) family control cytokine signalling and the contribution of SOCS (1, 2 and 3) to the development of T helper 2 (Th2) allergic disease is the focus of this proposal. We have found that SOCS2-/- CD4+ T cells have markedly enhanced Th2 differentiation and that SOCS2-/- mice have elevated type 2 cytokine production after helminth antigen challenge. Moreover, in in vivo models, of atopic dermatitis SOCS2-/- mice had significantly elevated specific IgE, eosinophilia, type 2 responses and inflammatory pathology relative to WT mice. This preliminary work supports the hypothesis that SOCS2 null CD4+ T cells are prone to develop into Th2 thus these mice are prone to allergy. Are key goals are to
1) Examine T-helper polarization & signalling in SOCS2-/- T cells
2) Explore if Th2 responses directly linked to SOCS dysregulation in CD4+ T cells?
3) Measure SOCS expression seen in T-cells from patients with allergy to determine if this is also true in patients.
This work will have important implications in the understanding of molecular mechanisms involved in the predisposition to atopic disease