The role of lymphocytes in Alopecia Areata
Research type
Research Study
Full title
The role of lymphocytes in Alopecia Areata
IRAS ID
168614
Contact name
Andrew McDonagh
Contact email
Sponsor organisation
Sheffield Teaching Hospitals NHS Foundation Trust
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Alopecia areata (AA) is an autoimmune disease caused by collapse of the immune privilege (IP) of the hair follicle (HF) in its anagen (growing) phase. The IP is normally maintained by local production of potent immunosuppressive molecules such as α-melanocyte stimulating hormone (a-MSH), transforming growth factor β1 (TGF-β1), insulin-like growth factor 1 (IGF-1) and interleukin 10 (IL-10). All these molecules are known to effectively down-regulate MHC class I and class II expression by inhibiting the production and action of interferon-γ (IFN-γ). IFN-γ is a potent cytokine stimulus for the expression of MHC class I in both organ-cultured human scalp HF and murine pelage HF as the addition of IFN-γ in cultured HF increase the ectopic MHC class I expression in the proximal hair bulb, thus expressing self-epitopes to cytotoxic CD8+ T-cells (CTLs). IFN-γ is also a potent activator of Th1 chemokines such as CXCL9 and CXCL10, where genetic and biochemical analyses have revealed that the protein tyrosine kinases JAK1 and JAK2 (proteins associated with the IFN-γ receptor) and the transcription factor STAT1 play a central role. Phosphorylated STAT1 dimerises and translocates to the nucleus where it binds to the gamma-activated sequence (GAS), found in the upstream region of STAT1 regulated genes, which leads to an altered T-cell balance and expression of MHC class I and II.
Recent data has also been published on the JAK inhibitors Tofacitinib (JAK1/JAK2/JAK3 pan inhibitor) and Ruxolitinib (JAK1/JAK2 dual inhibitor) to have a 100% restoration of hair growth in the mouse model of alopecia areata (C3H/HeJ). Furthermore, Ruxolitinib (20 mg, po bid) is currently run in a clinical study in 10 alopecia areata patients (NCT01950780) with an expected read out in August 2015.
Besides the INF-γ-induced MHC class I expression in anagen HF of AA, the physiological balance of CD4+ T lymphocytes has been shown to be altered where Treg activity is attenuated and Th17 and Th1 dominate the scene. The inductor of this imbalance is most likely also IFN-g that recruits inflammatory and antigen presenting cells (eg neutrophils, dendritic cells and macrophages) to which CD4+ T-cells and CD8+ CTLs respond. The regulatory T-cells are important for immunesuppression and prevention of autoimmune diseases and the reduction of Tregs in the skin of AA patients are likely to play a major role. There is recent evidence of at least two kinds of Th17 cells are present in AA –one that is essential in host defence and for pathogen clearance through the production of IL-17 (good Th17) and one (Th17/Th1 or Th17.1 cells) that induces pro-inflammatory actions expressing both the IL-23 receptor (IL-23R) and producing IL-17 as well as IFN-g, but not IL-10, or other anti-inflammatory molecules. The cytokine environment in AA drives the induction of Th1 and Th17.1 from naïve Th0 whereas Tregs, Th2 and Th17 are attenuated. It is therefore important to stimulate Treg differentiation and function (eg by IL-2, TGF-β, activation/stabilisation of foxp3) as well as inhibiting the expression of Th17.1 specific molecules (eg IL-6, IL-17, STAT3, RORC, IRF4) by blocking the binding of IL-23 to its receptor IL-23R.
An obvious target would thus be the IFN-γ-STAT1 signalling pathway which has potential to both balance the T-helper subtypes and cytokine secretion as well as the MHC class I & II expression. We would therefore like to test the hypothesis that suppressing the production of pro-inflammatory cytokines via selective inhibition in the JAK1/JAK2-STAT1 signalling pathway is sufficient to enhance the production of HF immunosuppressive agents such as TGF-β1, IGF-1, α-MSH, IL-10 which will lead to restoration of the HF immune privilege by balancing the CD4+ T-cell population and diminishing the call for CD8+ T-cells in alopecia areata.
Our strategy is to use selected natural products which are known to have an inhibitory effect on JAK/STAT pathway. These include Epigallocatechin gallate (EGCG) extracted from green tea as well as brevelin A which are known to inhibit STAT1. We will also be using selected panel of JAK1 & JAK2 inhibitors targeting specifically the JAK/STAT pathway. This molecules will be provided by Astra Zeneca in the context of the current collaboration between University of Sheffield and AstraZeneca, R&D Mölndal. The aim is to test the inhibitory effect of these molecules on the release of proinfammatory cytokines such as INF-γ will be evaluated on in vitro system using cultured lymphocytes isolated from alopecia areata and control individuals. Subsequently, we will attempt to identify defective Treg subsets in both controls and patients by characterising Treg Foxp3+CD4+ isolated from blood and comparing the distribution of resting Treg cells (rTreg), activated Treg cells (aTreg) and memory Treg cells in AA patients and controls.REC name
South Central - Hampshire A Research Ethics Committee
REC reference
15/SC/0481
Date of REC Opinion
26 Sep 2015
REC opinion
Further Information Favourable Opinion