Dr Magdiel Pérez-Cruz
LE STUDIUM RESEARCH FELLOW / ARD 2020 - BIOPHARMACEUTICALS Programme
Department Medicine, Stanford University - USA
In residence at
Experimental and Molecular Immunology and Neurogenetics (INEM) / CNRS, University of Orléans - FR
Dr Bernhard Ryffel
Therapeutic use of Periostin antibody and CAR Treg in papain and HDM induced severe asthma in mice
Asthma prevalence has significantly increased in the last 30 years, resulting in a severe human health and economic burden for the society affecting 100-150 million people worldwide and results in over 180,000 deaths per year. Risk factors associated with asthma are exposure to allergens during childhood and exposure to environmental factors, such as pollutants.
Several mechanisms are invoked in driving allergic lung inflammation. Recently an increase of the matricellular protein Periostin (PO) was reported in serum of patients, which is now considered as a biomarker of disease severity.
In the last two years, we have been investigating the potential regulatory role of PO in mouse models of human inflammatory lung diseases. We found an upregulation of PO in the lung epithelium and fibroblasts upon endotracheal instillation of endotoxin and the protease allergen papain in BL6 mice. Our preliminary results indicate that blockade of PO by neutralizing antibodies reduces neutrophil recruitment in BALF and lung and attenuates respiratory barrier injury with protein leak, disruption of tight junctions and airway hyperreactivity (unpublished data). Furthermore, the data suggest activation of regulatory T lymphocytes (Treg).
Here I propose to validate the exciting beneficial effect of PO antibody blockade on allergic lung inflammation in mice and test the hypothesis, whether protection may be replicated with CAR-T (chimeric antigen receptor) cells as novel therapeutic approach. Therefore, I propose to develop a new therapeutic platform of CAR Treg cells directed against the Fc portion of previously administered therapeutic monoclonal antibodies, allowing a precise control of Treg immune regulatory activity in papain and HDM induced asthma. The monoclonal antibody directed-CAR Treg 2 (md-CAR Treg) construct design expresses the anti-FITC ScFv and an internal CD28 stimulatory domain. I reported before that md-CAR-conventional T cells can be directed into different tissues after adoptive transfer according to the use of FITC-mAbs that target tissue specific molecules (Pierini et al. 2017). We successfully transduced sorted murine CD25+ Tregs at efficiencies of >90%. Our goal is to test the efficiency of CAR Tregs in pre-clinical models for future translation to the clinic.
In summary, PO antibody blockade inhibits allergic lung inflammation via IL-17 and importantly increased regulator T cell activation, which will be tested by the CAR T cell approach in mice.
Publications in relation with the research project
Periostin (POSTN) is a matricellular protein that plays a key role in development and repair within the biological matrix of the lung. POSTN is highly expressed in several cell types in lung such as epithelial or endothelial cells, fibroblasts, smooth muscle and mast cells, contributing to mucus secretion, alveolar epithelial repair, and lung fibrosis. However, the underlying mechanism how POSTN contributes to the development of lung inflammation remains unclear. In the current study, we attempted to determine whether treatment with a monoclonal anti-POSTN antibody induces a significant inhibition of asthmatic reactions in a mouse asthma model. Mice sensitized and challenged with papain evidenced an increased periostin expression in lung and typical asthmatic reactions, as follows: an increase in the number of eosinophils in bronchoalveolar lavage fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways, and Th2 cytokines including IL-4 and IL-5 and chemokines in the bronchoalveolar lavage (BAL) fluid; emphysema; the detection of thymic stromal lymphopoietin (TSLP) produced by epithelial cells. However, the administration of anti-POSTN prior to the final airway papain challenge resulted in a significant inhibition of all asthmatic reactions. We also demonstrated that anti-POSTN antibody treatment resulted in significant reductions on collagen expression and a reduction in the increased eosinophil. The treatment of animals with anti-POSTN resulted in a significant reduction in the concentrations of the chemokines (CCL-11 and CCL-17) in the airways, without any concomitant increase in the concentration of Th1 cytokines. This study identifies a novel therapeutic strategy for airway hyperresponsiveness, which uses antibodies reactive against POSTN via the inhibition of the Th2 response. It also provides theoretical evidence for the control of allergic asthma and fibrosis by targeting POSTN.