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Volume 2
     

Predicting outcome and developing new therapeutic strategies for haematological stem cell transplant recipients using in vitro techniques (TRANSEUROPE)

   
Project

QLK3-2002-01936

Cell factory area

3.1.3

EU Contribution

2,105,529 Euro

Duration

36 months

Type

RS

Starting date

Foreseen 01 January 2003 (contract not yet signed at date of printing)

Keywords
autoimmune disease
GvHD therapy
skin explant assay
transplant tissue bank
ABSTRACT

Allogeneic stem cell transplantation (SCT) is the only means of cure for haematological malignancies, as well as congenital anaemias and immunodeficiency disorders. The current poor rate of survival (30-50%) is due to post-transplant complications, including infectious episodes, relapse (a lack of a graft versus leukaemia (GvL) effect) and graft versus host disease (GvHD). Tools to predict acute and chronic GvHD and or GvL following different types of allogeneic SCT would enable new clinical protocols and therapeutics strategies to be developed based on individual patient expected risk. By the use of in vitro biotechnology, genetic and clinical risk assessments, we aim to predict outcome following therapy and SCT, develop new European-wide common clinical protocols and improve current therapeutic strategies. The project involves the development of an important European-wide tissue bank for research use within the transplant community.

OBJECTIVES

The ability to translate research from the laboratory to the clinic and predict outcome following SCT or therapy in transplant patients will be a step forward beyond the state of the art in transplantation management. We aim to use in vitro biotechnology (a human skin explant assay) to predict GvHD in haematopoietic allogeneic SCT in particular in patients undergoing reduced intensity conditioning transplant protocols, peripheral blood stem cell transplants and donor lymphocyte infusions. We aim to investigate the efficacy of the use of the therapeutic strategy, extracorporeal photochemotherapy (ECP), for treating GvHD; and predict response to therapy using the skin explant assay. Results will be correlated with genetic and clinical risk assessment and lead to the development of clinical protocols and therapeutic strategies based on individual risk.

DESCRIPTION OF THE WORK

Predicting outcome following SCT and GvHD therapy will be carried out by the aid of an in vitro human skin explant assay, on-going genetic risk analyses, including cytokine gene polymorphism studies and clinical assessments. The skin explant assay can predict the occurrence and severity of acute GvHD in a paediatric and adult patients undergoing SCT. The results are used to modify GvHD prophylaxis on an individual patient basis and aid in the design of therapeutic protocols. The assay will be used to predict GvHD in different cohorts of transplant patients on varying conditioning regimens where increased GvHD is problematic and predicting this effect will be an important step forward in SCT management. The assay can be used to study the immunobiology of GvHD and will be used in a novel way to predict outcome after extracorporeal photochemotherapy (ECP); an important therapy for use in steroid-resistant patients. The molecular mechanisms for the therapeutic efficacy of ECP is thought to involve apoptosis and cytokine release and these mechanisms will be studied within the workpackages. Apoptosis is a mechanism of keratinocyte damage during GvHD and has been visualised in the skin explant assay by the use of the TUNEL (terminal deoxynucleotide nick end labelling) assay. The studies will be extended and the role of Fas - Fas ligand mediated apoptosis in GvHD and role in GvL more fully evaluated. The skin explant assay can detect patient autoimmune response, with keratinocytes being targets for autoimmune T-cells. This aspect will be studied with the potential of the development of new target antigens in autoimmune disease and GvHD. The importance of TRANSEUROPE lies in its innovative strategies for monitoring standard and new transplant therapies, GvHD therapeutic protocols and permitting statistical analysis on large patient groups. It will also develop a European-wide tissue bank for transplant related research.

DELIVERABLES

The deliverables of the project include a patient tissue bank for use within the European community for transplant related research, which will aid the development of standardised diagnostic criteria for GvHD.

Via investigating and predicting the effect of current therapeutic protocols we aim to develop new strategies and concepts for GvHD prevention and therapy. Based on the project results we also aim to develop new therapeutic strategies and European-wide common clinical protocols.

Functional therapeutic risk analysis studies will improve the outlook for SCT patients by ultimately reducing the occurrence of GvHD and complications. Improved therapeutic protocols developed from the knowledge gained in this project will ultimately reduce health care costs and improve the quality of life. Due to the relatively small number of transplants carried out at each SCT centre within Europe a collective network of participants interacting at all levels from the clinic to the laboratory is an indispensable necessity. The project is multidisciplinary, involving molecular biologists, immunologists, transplant clinicians, pathologists and those involved in the treatment and care of autoimmune disease.

CONSORTIUM
COORDINATOR
 
Prof. Anne Dickinson
University of Newcastle upon Tyne
Department of Haematology
Royal Victoria Infirmary
Newcastle upon Tyne
NE1 4LP, United Kingdom
Tel: +44-191-222 6794
Fax: +44-191-222 6794
a.m.dickinson@ncl.ac.uk
 
PARTNERS
 
Dr L. Sviland
Haukeland Sykehus
Aveling for Pathologi
5021 Bergen
Postboks 1, Norway
Tel: +47-5-597 3171
Fax: +47-5-597 3158
lsvi@haukeland.no

Prof. H-J. Kolb
Klinikum Großhadern
Ludwig Maximillian Universität
Medizinische Klinik III
Stammzelltransplantation
Marchioninistraße 15
81377 München, Germany
Tel: +49-89-7095 4241
Fax: +49-89-7095 4242
kolb@med3.med.unimuenchen.de

Prof. H. Greinix
Bone Marrow Transplantation Unit
University Hospital of Vienna, Austria
Tel: +43-1-4040 044 57
Fax: +43-1-4040 022 511

Dr N. Mooney
HLA et Médecine
15 Rue de l'Ecole de Médecine
75006 Paris, France
Tel: +33-1-5310 1500
Fax: +33-1-4329 9644
Nuala.Mooney@bhdc.jussieu.fr

Prof. E. Holler
Dept. Hamatology und Internistiche Onkologie
Klinikum der Universität Regensburg
Franz Josef Strauß Allee 11
93053 Regensburg, Germany
Tel: +49-941-944 5542
Fax: +49-941-944 5543
ernst.holler@Klinik.uni-regensburg.de

Dr M. Lowdell
Royal Free & University College
Medical School
Gower Street, WC1E 6BT London, United Kingdom
Tel: +44- 207-794 0500
Fax: +44- 207-794 0645
m.lowdell@rfc.ucl.ac.uk

Dr L.E. French
Privat-Docent
Department of Dermatology
Geneva University Hospital, Switzerland
Tel: +41-22-372 9455
Fax: +41-22-702 5802
Lars.French@medecine.unige.ch

Dr I. Hromadníková
2nd Medical Faculty
Charles University
V Úvalu 84
15006 Prague, Czech Republic
Tel: +420-2-2443 2258
Fax: +420-2-2443 2220
ilona.hromadnikova@lfmotol.cuni.cz