Objective
The development of recombinant human proteins including monoclonal antibodies, cytokines and growth factors by the Biotechnology Industry is restricted because of the unsuitability of animal-based in-vitro and in-vivo test systems due to cross-species problems in detecting immuno-pharmaco-toxicology of these products.
The primary objective of this proposal is to develop in-vitro tests with human cells to evaluate the immuno-pharmacotoxicological properties of biotechnology-derived cytokines. Specifically, the aims include development of human kidney and liver in-vitro models that will more closely mimic the in-vivo situation. For liver and kidney advanced cell culture methodology is available and both organs have been shown to be prominent targets of toxic biotechnology derived products. There is a need to have models with similar tissue level of cellular organization allowing cell-cell networking and communication. This will be achieved by having cell co-culture systems maintained on microporous substrates under perifusion conditions which allows constant nutrient supply. Recent studies from our laboratories and other groups indicate that primary cells maintained under these conditions have significantly improved maintenance of differentiated functions. In addition, we will exploit our recent findings that renal structural cells (epithelial, endothelial and mesangial) are immunologically active cells. The novel aspects of this proposal include: 1. the exclusive use of human renal and liver cells in a perifusion co-culture system.
2. the development of molecular markers of renal and hepatic cellular response to cytokines leading to novel in-vitro tests.
3. the eventual replacement of primary human cells with human cell lines for in-vitro test systems more adaptable for use by the biotechnology/pharmaceutical industry.
Specific Measurable Objectives are:
1. co-culture of human glomerular mesangial cells and glomerular endothelial cells under perifusion conditions as a model of the renal glomerulus. 2. co-culture of human renal proximal tubular cells and renal microvascular endothelial cells under perifusion conditions as a model of the renal proximal tubule.
3. co-culture of human hepatocytes and Kupffer cells under perifusion conditions as a model of the liver.
4. establishing the effects of therapeutic cytokines on these primary human cell models using ECVAM recommended end-points and novel molecular markers. 5. simplification of the test systems, for example, through the use of selected cell lines, to make it suitable for use by the pharmaceutical industry.
These relate directly to the priorities addressed under area 7.1 of the Bioteclmology 1994-1998 Workprogramme; specifically they comply with 7.1.3. In vitro tests for immuno-pharmaco-toxicology - especially in-vitro tests to evaluate the pharmaco/toxicological properties of biotechnology-derived substances; and 7.1.4 cell cultures for the development of in-vitro tests. To achieve the objectives a trans-European multi-disciplinary collaboration involving academic (Innsbruck, Dublin, Bath, Rouen and Konstanz) and industrial partners (Janssen Pharmaceuticals, Belgium; SME-Biotrin - diagnostics, Ireland and SME-Tyrol Tools, Austria - plastic mouldings) with proven expertise in EU projects and in developing and marketing products is required. Each partner brings special expertise to the project. The partners are involved in ECVAM (European Centre for Validation of Alternative Methods) and IVTIP (In Vitro Testing Industrial Platform) and will use their communal expertise in the exploitation of results.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugs
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
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Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
6020 INNSBRUCK
Austria