THE FIFTH FRAMEWORK PROGRAMME
1998-2002
Quality of Life and Management of Living Resources

Predicting outcome and developing new therapeutic strategies for haematological stem cell transplant recipients using in vitro techniques including biotechnology and genomics.
Translational research from the laboratory to the clinic.

Acronym: TRANSEUROPE QLRT-2001-01936
RTD project
Therapeutic strategies QOL-2001-3.1.3

OBJECTIVES AND EXPECTED ACHIEVEMENTS.
To date, stem cell transplantation (SCT) remains the only means of cure for haematological malignancies (leukaemia and lymphoma) as well as congenital anaemias and immunodeficiency disorders. It is also rapidly being initiated for use in some autoimmune disorders and solid tumours. Within Europe over 4,000 allogeneic transplants are performed a year; a number which is rising annually. The success rate as measured by survival at 5 years has remained at the 30-50% level for over a decade. This poor rate of survival post transplant is due to post transplant complications, which include infectious episodes, relapse and graft versus host disease (GvHD). The project aims to improve transplant outcome by the use of novel assays for predicting response to new approaches to therapy and predicting transplant outcome.

The project will involve biotechnology (a human skin explant assay) and genomics, cytokine and related gene polymorphisms as well as HLA major and minor typing, and other known clinical parameters, in assessing transplant outcome.

· To translate research from the laboratory to the clinic.
· To develop a European-wide data and tissue bank for correlation of results with EUROBANK and for research across European transplant centres.
· Research into the immunopathology, including apoptosis, of graft versus host reactions as assessed in vitro using immunocytochemistry and confocal microscopy .
· To use the skin explant assay for predicting GvHD in haematopoietic allogeneic stem cell transplants in particular in patients undergoing "mini or maxi" or reduced intensity conditioning transplant protocols, peripheral blood stem cell transplants and donor lymphocyte infusions .
· To assess the use of a skin explant assay for the safe and adequate removal of alloreactive T cells prior to individual immunotherapy .
· To correlate results with donor/recipient chimerism, clinical outcome and individual risk assessment.
· Research into the efficacy of the use of the therapeutic strategy, extracorporeal photochemotherapy (ECP), for down regulating alloreactivity and treating GvHD - response to therapy being predicted by the skin explant assay .
· To study the mechanism of action of ECP, especially with regard to apoptotic mechanisms, cytokine production and signal transduction.
· Research into the potential role of heat shock proteins (HSP) in both GvHD, as a quantitative read-out for skin explant assay GvHR using confocal microscopy and as potential targets for anti-leukaemic therapy and role in autoimmunity This will include in vitro assessments and monitoring of GvL and GvHD responses pre- and post- transplant and pre and post ECP.
· Results from the project will be collected on a central database correlated with clinical outcomes and genotyping including minor histocompatibility testing and cytokine gene polymorphism analysis for individual patient risk assessments. This information will be used to develop new therapeutic strategies for testing in the future Phase I clinical trials.

· The development of protocols for the functional assessment and prediction of transplant patients' response to therapy (donor lymphocyte infusions, extracorporeal photochemotherapy, specific immunotherapy) and to predict transplant outcome.
· Correlation of results with patient and donor genotype analysis including cytokine gene polymorphism genotype for assessment of therapeutic risk on an individual patient basis.
· To develop new therapeutic strategies based on individual risk assessment.
· In depth assessment of apoptotic mechanisms and HSP distribution including via the use of participants Patented peptides, the potential of the development of new therapeutics and or therapeutic strategies .

· A patient tissue bank for use within the European community for transplant related research
· Via investigating and predicting the effect of current therapeutic protocols, develop new strategies and concepts for GvHD prevention and therapy.
Based on the project results develop new therapeutic strategies and European-wide common clinical protocols.