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Validation of a human T cell activation assay to identify immunosuppressive compounds

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Samenvatting van de aanvraag

This project proposal aims to validate a human T cell activation assay to identify immunosuppressive compounds. Therefore, we will collect data on concentration-effect relationships of a balanced set of immunosuppressive vs. non-immunosuppressive compounds (including industrial chemicals and (bio)pharmaceuticals) on proliferation and cytokine production of human blood-derived T cells. The T cell activation assay has been developed in two consecutive studies performed with 5 European laboratories in a project initiated by European Centre for Validation of Alternative Methods (ECVAM). Data obtained so far indicate that the assay may be able to distinguish immunosuppressive compounds, against the background of human inter-individual variability. Such an assay will contribute to animal replacement, for instance as screening tool to decide on further investigations in late drug discovery phases, but a predictive human T cell assay may also reduce animal usage in chemical safety studies. The project will be conducted in 3 phases over a period of 15 months. Phase 1 (4 months) will focus on assessing the influence of human inter-individual variability on the test-outcome, by comparing the effects rapamycine (immunosuppressive compound) and d-mannitol (non-immunosuppressive compound) on the CD3/CD28-mediated T cell activation of 10 different donors. Detection of T cell activation comprises of measuring proliferation by incorporation of radioactive DNA-precursors and by detecting cytokine (IFN-g and TNF-α) production by ELISA. In the second phase (8 months), the standardized procedure that will be derived from phase 1, will be used to compare the effects on T cell activation of 20 compounds selected based on immunosuppressive capacity (10 suppressants, 10 non-immunosuppressants). In the third phase (3 months) data will be analysed and reported to an international group of representatives from regulatory agencies, industrial parties and academia. If successful, results will be submitted to ECVAM to consider validation of the human T cell activation assay.

Onderwerpen

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Projectnummer:
114000096
Looptijd: 100%
Looptijd: 100 %
2009
2010
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. M.A.T. Teunis
Verantwoordelijke organisatie:
Hogeschool Utrecht