LE STUDIUM RESEARCH FELLOW / ARD 2020 - Programme Biomédicaments
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and attenuates respiratory barrier injury with protein leak, disruption of tight junctions and airway hyperreactivity (unpublished data).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.