|
|
|
Proyectos
europeos
CORDIS
RTD-PROJECTS / © European Communities.
Title: Predicting outcome and developing new therapeutic strategies
for haematological stem cell transplant recipients using in vitro
techniques
Objective: 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 Europe-wide
common clinical protocols and improve current therapeutic strategies.
The project involves the development of an important Europe-wide tissue
bank for research use within the transplant community.
Start Date: 2003-01-01
End Date: 2005-12-31
Project Reference: QLK3-CT-2002-01936
Title: The occurrence, detection and treatment of adenovirus
infection in patients undergoing Allogeneic stem cell transplantation
Objective: Future progress in hemopoietic stem cell transplantation
is hampered by disseminated adenoviral (AdV) infection, which is estimated
to kill 175 transplant patients in EU yearly. Current virological
tests are poor either for predicting those patients who will develop
life threatening AdV disease or evaluating the efficacy of antiviral
drugs. We therefore propose to perform rapid, sensitive quantitation
of plasma adenoviral DNA load in a multi-centre prospective study
using Real -Time Quantitative PCR (RQ-PCR) for disease monitoring,
prognostication and monitoring of responses to antiviral drugs, in
conjunction with pharmacokinetic/dynamic studies and in vitro AdV
sensitivity. AdV-specific T-cell reactivity and neutralizing antibodies
will be measured in all patients to explore the feasibility of immuno-therapy.
Based on the data a protocol for the management of AdV infections
in immuno-compromised hosts will be delivered to the community.
Start Date: 2002-09-01
End Date: 2005-08-31
Project Reference: QLK2-CT-2002-01432
Title: Development and clinical study of a bioartificial liver
based on reversibly immortalised human hepatocytes
Objective: Mortality of acute liver failure is high, an alternative
to transplantation is needed and hepatic assist systems taking over
the complex liver function, are still in the experimental phase. Two
promising European bioartificial liver (BAL)systems have been tested
with porcine cells. Large clinical use of BALs (like renal dialysis
for renal patients) becomes possible when safe, functional cell scan
be cultivated in large numbers. We aim to develop an effective safe
BAL with reversibly immortalised human hepatocytes.
This will be achieved by development of reversibly immortalised cell
lines, in vitro safety and functionality tests of the cell lines and
1 existing cell line, testing favourable cell lines in the BALs, cell
preservation studies, bioreactor improve, in vivo studies of one or
both BALs or a hybrid BAL with the most favourable cell line, phase
I clinical trials, founding an SME to cultivate the cells and to load
BALs with them.
Start Date: 2001-08-01
End Date: 2005-07-31
Project Reference: QLK3-CT-2001-01889
Title: Suicide Gene Therapy in Stem Cell Transplantation
Objective: The outcome of allogeneic stem cell transplantation
(allo-SCT), the treatment for haematological malignancies, is significantly
limited by a severe and potentially life-threatening complication
induced by donor lymphocytes, i.e. graft-vs-host disease (GvHD). The
aim of this 3 year pre-competitive project is the development, pre-clinical
evaluation and exploitation in the clinical setting of an innovative
therapeutic strategy for the transfer into donor lymphocytes of a
suicide gene-conferring sensitivity to a pro-drug thus allowing their
subsequent selective in-vivo elimination and cure of GvHD.
New suicide and marker genes, viral vectors and protocols for cell
manipulation will be developed and rapidly transferred to industrial
partners to prepare the exploitation in the clinical setting. Finally,
clinical protocols using this strategy will be developed with the
final goal of offering safer and more effective allo-SCT to a larger
number of patients.
Start Date: 2001-08-01
End Date: 2004-07-31
Project Reference: QLK3-CT-2001-01265
Title: Diagnostic approaches to Chimerism testing after Allogenic
stem cell transplantation for early detection of graft rejection and
relapse: technical development, standardization, and European coordinated
clinical implementation
Objective: Transplantation of hematopoietic stem cells from related
or unrelated donors is becoming an increasingly important approach
to treatment of different malignant and non-malignant disorders. There
is thus growing demand for clinical diagnostic methodologies permitting
the surveillance of donor- and recipient-derived hemopoiesis (=chimerism)
during the post transplant period. The techniques currently used are
very heterogeneous, rendering uniform evaluation and comparison of
diagnostic results between centers difficult. International efforts
aimed at the development of standardized methods are therefore urgently
needed. We intend to establish a diagnostic standard for the monitoring
of chimerism after all ogeneic stem cell transplantation (SCT). Leading
laboratories in this field from 10 European countries will collaborate
to develop and standardize a molecular diagnostic assay meeting stringent
quality criteria that could be adopted at all diagnostic centers involved.
Implementation of international consensus criteria for appropriate
investigation of chimerism after all ogeneic SCT will provide a basis
for optimum diagnostic support for clinical decision making.
The aim of this Concerted Action is the development of a standardized
diagnostic methodology for the detection and monitoring of chimerism
(i.e. patient/donor origin of hemopoiesis) in patients undergoing
all ogeneic stem cell transplantation (SCT).The methodology has to
meet stringent quality criteria regarding reproducibility, sensitivity,
and ability to quantify patient- and donor-derived hematopoietic cells
after all ogeneic SCT. Once established and validated, the standardized
and quality-assured consensus protocol will be made available to the
scientific community by publication in a leading international journal.
The standardized technique will be profitable to many diagnostic centers
in the field, and will provide a basis for optimal diagnostic support
for therapy decisions.
Start Date: 2002-09-01
End Date: 2004-08-31
Project Reference: QLG1-CT-2002-01485
Title: Establishment of novel targets for risk assessment and
monitoring of Xenogeneic infections in the course of animal to human
transplantation
Start Date: 2002-09-01
End Date: 2004-08-31
Project Reference: QLK2-CT-2002-70785
Title: European network for fetal transplantation
Objective: In uterus stem cell transplantation is a novel therapy
targeted at the fetus, within the uterus early in a pregnancy. This
therapy is intended to treat a genetic disorder, diagnosed within
the first 12 weeks of gestation, before the pathological effects become
manifested. Currently, there are some successful cases reported and
European centres are in a leading position in the field. However,
there is a pressing need for consensus in many aspects of this therapy
and a consortium of European centres with expertise in many areas
of stem cells and transplantation will be uniquely placed to ensure
that the in utero procedure can be used to maximum benefit.
The successful transplantation of stem cells into a recipient fetus
wile in utero, in order to prevent the serous pathological effects
of a genetic disorder, diagnosed in prenatal life. The establishment
of audited protocols, which ensure the safety and the efficacy of
the procedure. The establishment of cell banks, in centre throughout
Europe, which are specifically intended to furnish cells appropriate
for the in utero-transplant procedure. Publication of recommendations
and guidelines to assist those intending to use the procedure. This
aspect of the programme will encompass gene-therapy protocols.
Start Date: 2000-12-01
End Date: 2004-11-30
Project Reference: QLG1-CT-2000-01475
Title: Establishment of a cell line and DNA bank for genetic
risk assessment and post transplant monitoring of complications following
Stem Cell Transplantation
Objective: Allogeneic stem cell transplantation(SCT) remains
the ultimate treatment for patients with lympho-proliferative and
haematological disorders. Genetic differences, including transplantation
antigens and cytokine gene polymorphisms, between patient and donor
constitute genetic risk in SCT. Success of SCT relies on an accurate
assessment of genetic risk factors in order to improve outcome. Genetic
risk factors will be assessed by the use of an immortalised cell and
DNA bank where outcome of the transplant is known. We aim to pool
resources and establish a biological collection of fully geno-typically
characterised patient and donor immortalised cells for both in vitro
patient monitoring post transplant and as a constant supply of DNA
for genetic risk assessment; thus creating a unique and important
European collection for use within the transplant community.
Start Date: 2001-03-01
End Date: 2004-02-29
Project Reference: QLRI-CT-2000-00010
Title: Hypoxic renal injury
Objective: Ischemia/reperfusion injury is a well known feature
of acute/chronic renal dysfunction, known as acute renal failure(ARF),
with 1-5% of hospitalised patients being affected. This is a major
social economic problem of the ageing population and patients receiving
kidney transplantation (cold ischemia), a demand increasing with age.
ARF is associated with cell death by apoptosis or necrosis. Currently
we do not know the impact of initiating and/or inter related events
during the onset and progression of ARF. It is imperative to characterize
a sequence of events that links primary damaging components such as
an unbalanced NO/O>2 - and/or xanthine/adenosine ratio to an end
stage injury. Experiments will be carried out in-vivo and in-vitro
using rodent material by 4 groups that are recognized for cutting
edge science. The outcome of the project will be the establishment
of an early index of cell death with the opportunity to intervene
pharmacologically, thereby preventing progression of cell injury once
initiated. The application of such newly established prognostic parameters
to human subjects would serve to predict the severity of renal injury
in humans and open avenues for novel therapeutic interventions.
Start Date: 2001-01-01
End Date: 2003-12-31
Project Reference: QLK6-CT-2000-00064
Title: Information Technology For Stem Cell Registries Network
Objective: Bone Marrow Transplantation of hematopoietic stem
cells is used for therapy of malignant diseases and for atomic power
accident victims. Registries of volunteer bone marrow donors and banks
of stem cells (cord blood units) are organised. The number of donors
and conserves (at the stem cell banks) must be very high, and various
ethnic groups must be included to achieve a genetic match between
donor and recipient. Thus, it is of common interest to have a network
of donor registries and stem cell banks in Central European Countries.
Start Date: 2001-05-01
End Date: 2003-04-30
Project Reference: IST-2000-26117
Title: Optimisation of typing policies for European marrow donors
registries: socio-economic evaluation of molecular techniques and
recruitment strategies
Objective: Although 6 million potential donors are registered
worldwide, finding a donor compatible for allogeneic stern cell graft
is hard because of HLA polymorphism. MADO (Marrow Donors) aims at
evaluating optimisation of Registries in Europe by increasing the
proportion of donors with rare HLA types to reduce inequality of patients
in a cost/effective way. The main concept is an evolving filter to
screen potential donors at low cost before full HLA typing for the
likely presence of frequent types, using new markers and techniques.
Organisational scenarios will then be designed. MADO involves 9 WP
over 2 years and 12 partners in EU countries: 4 European Registries,
sociologists, economists, public health unit,
immuno-genetics/molecular laboratories, bio informatics, industry.
The overall expected achievement is a number of well-documented possible
scenarios to help decision for organisation of coherent strategies
of Registry management
Start Date: 2001-12-01
End Date: 2003-11-30
Project Reference: QLG7-CT-2001-00065
Title: Implementation of a Cord Blood Allocation Network
Objective: Residual blood from the umbilical cord of neonates
(cord blood, CB) has become an important alternative to bone marrow
as source of transplantable hematopoietic stem cells in the treatment
of leukaemia and other diseases. To support the CB specific advantages
over other stem cell sources an adequate allocation mechanism must
be implemented. It is
imperative to minimise the duration of the allocation procedure. This
will have direct positive impact to the transplantation outcome and
therapy costs. The implementation of a cord blood allocation network
by using modern work flow management tools will ensure an equal chance
for each patient to get the best transplant available and, thus, solve
possible allocation conflicts. By constantly analysing the systems
operation a cyclical mechanism is fed to
improve the allocation process and the quality of service. The deployment
of such a quality chain is also part of the objectives of the study.
Start Date: 2000-10-01
End Date: 2003-09-30
Project Reference: QLRI-CT-2000-00887
End Date: 2002-04-26
Project Reference: QLK3-CT-2001-42378
Title: Microprobe multi-sensor for graft viability monitoring
during organ preservation and transplantation
Objective: This proposal seeks to provide the medical community
with an innovative way for reliable monitoring of organs during transplantation.
The monitoring, done using a purposely developed microsystem, would
provide means for continuous evaluation of organ feasibility both
during transport and postoperative initial evolution. To-date, the
need for a perfect temperature and pathogen isolation of the organ
during transport has been a major barrier in evaluating the needs
and results of a constant monitoring. The recent development of silicon
micro-biosensors opens a way in which to attain this objective without
resigning to the mentioned organ isolation. Any action taken to increase
the number of organs viable and improve their postoperative function
shall be welcome by the European Society.
Objectives:
The proposed project intends to assist (1) the viability assessment
of organs due for transplantation, expanding thus the number of available
grafts and their possible destinies, and (2) the monitoring of organ
behaviour during the initial postoperative period. The technological
goal of this project is to raise awareness in the microsystems field
through their use in a biomedical application that also requires a
high level expertise on microelectronics design. Development of applications
displaying these sort of needs and requiring these kind of solutions
will contribute to enhance the European industry competitiveness broadening
the market for both the silicon industries and the biomedical industries
themselves
Start Date: 2000-01-01
End Date: 2002-12-31
Project Reference: IST-1999-13047
Title: Cord blood as an allogeneic source of stem cell for clinical
use
Objective: Cord blood cells, collected at birth, have new
interesting properties which can be used for treatment of leukemias
and other malignant diseases and also for the treatment of genetic
or acquired hematological disorders. Cord blood banks have been established
worldwide, and thanks to international collaboration, results of allogeneic
unrelated cord blood transplants have been analysed. From these studies,
it can be concluded that this new source of hematopoietic stem cells
is a life-saving therapy used in a large variety of potentially fatal
diseases mostly in children. The objectives of this proposal are to
better characterise hematopoietic stem cells present in cord blood
and take advantage of the immaturity and proliferative characteristics
of the cells to treat a large variety of malignant, immunological,
genetic and infectious diseases. The proposal will be divided in 4
components: hematopoiesis, immunology, clinical applications of cord
blood cells and interface between transplant centres and cord blood
banks.
Start Date: 2000-01-01
End Date: 2002-12-31
Project Reference: QLK3-CT-1999-00380
Title: Implanted liver assist system
Objective: The prime objective of this proposal is the completion
of a process of research and development into the feasibility of an
implantable pump, a liver assist device (ILIAS). ILIAS is designed
to be positioned in the human hepatic portal system and to be capable
of improving liver function and reducing portal hypertension arising
subsequent to cirrhosis of the liver.
Start Date: 1997-08-01
End Date: 2001-12-31
Project Reference: BMH4972600
Title: The safety and feasibility of retroviral mediated gene
transfer in autologous stem cell transplantation for haematological
malignancies
General Information: The haematological malignancies comprise
the acute and chronic leukaemias, Hodgkin's disease and non-Hodgkin's
lymphomas, and multiple myeloma. Many patients are curable with combination
chemotherapy, but for those whose disease proves resistant to conventional
approaches, the options are few and the outcome is poor. Novel treatment
strategies such as gene therapy may improve disease free survival
in the long-term but have yet to be proved both safe and effective.
In the meantime, autologous stem cell transplantation [ASCT] has been
widely used in an attempt to improve outcome. This approach permits
the administration of high doses of therapy, as the patient can be
rescued from the inevitable bone marrow failure by the reinfusion
of cryopreserved autologous stem cells. However the use of ASCT has
yet to be optimised. First, stem cells can be derived from the blood
or bone marrow but there are qualitative differences between the two
sources and the cells may therefore differ in their kinetics of recovery
and their durability. Second, despite high dose therapy and stem cell
rescue, many patients experience disease recurrence. The relapse may
originate from contaminating tumour cells within the cryopreserved
stem cells, or from tumour cells within the patients which survived
the high dose therapy, or from both sources. This issue is of more
than theoretical importance. If tumour cells persist in the transplant
products then strenuous efforts should be made to remove them prior
to infusion. If the relapse originates from residual tumour cells
within the patient, then the emphasis must be on improved methods
of tumour eradication. Studies in which unique genetic sequences are
introduced into the tumour cells, so as to facilitate their detection
later, are currently the only means of resolving this question. If
transplantation of genetically manipulated material in this way can
be shown to be safe, then the ultimate goal will be to introduce genes
whose protein products have a therapeutic role. For this to be successful
the transgene must be expressed at a level sufficient to confer a
therapeutic benefit, for a sustained period of time. To date clinical
progress with therapeutic gene transfer strategies has been disappointing.
Furthermore, it has been virtually impossible to perform such studies
in Europe. Regulations correctly require that all vectors used for
in vivo gene delivery be produced to standards of good manufacturing
practice (GMP) and that patients are monitored for prolonged periods
of time to exclude potential adverse effects. Although commercial
companies are now beginning to offer viral vector production facilities,
this is usually at costs prohibitive to academic clinical institutions.
Without the availability of vector production at reasonable cost,
the progress of gene therapy in Europe has fallen far behind that
in the U.S.A. The aim of this proposal is to demonstrate the safety
and feasibility of retroviral mediated gene transfer [RMGT] in the
management of patients with haematological malignancies. Five teams
with extensive expertise in autologous stem cell transplantation [ASCT]
will utilise the resources of a recently established academic retroviral
vector production facility. Retroviral vectors carrying 'marker genes'
will be constructed and validated in vitro in each centre before being
produced to standards of good manufacturing practice [GMP] at the
production facility. Clinical grade vector will then be used in studies
designed to demonstrate; (i) the safety of RMGT in clinical practice,
(ii) the origin of relapse after ASCT, (iii) the kinetics of reconstitution
of stem cells derived from blood and bone marrow, (iv) the durability
of engraftment and the duration of expression of the transgene, and
thereby evaluate the ability of transduced stem cells to sustain the
delivery of therapeutically useful products, (v) the role of drug
resistance genes in the management of haematological malignancies,and
(vi) to determine the ability of transduced genes to elicit an immune
mediated response.
Start Date: 1998-12-01
End Date: 2001-11-30
Project Reference: BIO4980208
Title: Convergence of european renal transplant pathology assessment
procedures
Start Date: 1998-10-01
End Date: 2001-09-30
Project Reference: IC20980011
Title: Immunotherapy of leukaemia using suicide gene transduced
donor lymphocytes in the context of allogeneic bone marrow transplantation
Objective:
- To demonstrate
1.1. the ability to transduce and select donor Iymphocytes in conditions
required for a clinical study;
1.2. the safety of genetically modified donor lymphocytes in the context
of allo-BMT;
1.3. the survival and immunocompetence of transduced donor lymphocytes
in vivo;
1.4. the in vivo selective elimination of transduced cells by ganciclovir
treatment;
1.5. the in vivo safety and efficacy of secondary infusions of transduced
donor Iymphocytes after selective elimination of previously infused
cells
- To verify
2.1 the effects of transduced cells on the incidence and severity
of GvHD;
2.2. ganciclovir response of GvHD secondary to the infusion of transduced
donor cells;
2.3. the impact of this strategy on leukemic relapse and overall disease-free
survival
Start Date: 1997-12-01
End Date: 2001-11-30
Project Reference: BMH4972760
Title: Establishment of novel targets for risk assessment and
monitoring of xenogeneic infections in the course of animal to human
transplantation
Objective: This proposal is aiming at a certain number of issues
including European Public Health, ethics and economy. Particularly,
specifically designed strategies for patient surveillance in order
to detect and control putative xenozonotic infections shall be developed.
Those include PRC based techniques (ultra-sensitive real-time PRC)
and specific antibody detection tools (natural virus proteins and
recombinant proteins and peptides for ELISA and Western blot assays)
for patient surveillance in order to detect and to control putative
xenozonotic infections shall be developed. At current, established
regulatory guidance on animal production for xeno-transplantation
and the validation of European standards of animal health and welfare
and risk assessment of possible transmission of diseases from pig
to man in the course of transplantation of porcine tissues and whole
organs is missing. Novel detection essays will be a prerequisite for
defining such guidelines on a European level.
Start Date: 1999-12-15
End Date: 2000-09-14
Project Reference: QLK2-CT-1999-40210
Title: Organ transplant tolerance by infusion of large numbers of
donor hemopoietic stem cells
Start Date: 1999-01-01
End Date: 2000-12-31
Project Reference: BIO4980525
Title: Ethical guidance on the use of human embryonic and fetal
tissue transplantation
Objective:
- To ethically evaluate the practice of embryonic and fetal tissue
transplantation as well as the existing guidelines and regulations
of embryonic and fetal tissue tranplantation.
- To make an inventory and ethical analysis of the moral issues involved.
- To make a comparative analysis of existing guidelines, regulations
and debates in a number of European countries.
- To study empirical questions concerning the practice of fetal tissue
transplantation, more in particular on:
- the uses and distribution of abortuses and human fetal tissue;
- attitudes and experiences of professionals involved in the handling
of fetal tissue for transplantation purposes;
- attitudes and experiences of women who where requested to donate
fetal tissue for transplantation purposes.
- To formulate recommendations, given the importance of refining and
supplementing the current guidelines and regulations.
Start Date: 1998-05-01
End Date: 2000-10-31
Project Reference: BMH4983928
Title: Gene therapy of muscular distrophy by transplantation
of genetically-modified bone marrow
General Information: Muscular dystrophies (MD) are a heterogeneous
group of severe muscle-wasting disorders caused by mutations in the
genes coding for the membrane-associated protein dystrophin or for
other members of the dystrophin-associated protein complex linking
the muscle fiber cytoskeleton to the extracellular matrix. No therapy
is available for these severe syndromes, which have a long, progressive
and devastating course, and are associated to high social and health
care costs. Gene therapy of MD, i.e., delivery of a functional copy
of the mutated gene to a significant fraction of the skeletal and
heart muscle tissue, represents a formidable scientific and medical
task. This, however, would be a definitive therapy, and even if only
partially successful, would result in significant medical and economic
benefits. At present, clinical application of gene therapy of MD is
limited by a number of technical limitations, from immunogenicity
of viral vectors to low recovery, survival and differentiation capacity
of transplanted myoblasts. The difficulty in establishing an efficient
delivery route for either vectors or genetically-modified cells is
the most significant problem facing both in-vivo and ex vivo approaches.
We have recently obtained evidence for the existence of a bone marrow
(BM)-derived, circulating myogenic progenitor, which can migrate into
areas of muscle degeneration, undergo myogenic differentiation, and
participate to regeneration of the damaged fibers. The availability
of a cell population which could be engineered, transplanted, and
then systemically delivered to a large number of muscles could theoretically
represent a substantial step forward in the design of a cell-mediated
replacement therapy. It would now be necessary to establish whether
the chronic regeneratory stimulus that characterizes both human and
mouse MD is sufficient to recruit the BM-derived progenitors, and
whether this cell population is quantitatively sufficient to progressively
replace a significant fraction of the skeletal muscle. The aim of
this demonstration project is to provide evidence that transplantation
of normal, or genetically engineered, BM can revert the phenotypic
consequence of MD in suitable animal models and in real-life conditions.
Three mouse mutants, mdx, ADR, and dy/dy, respectively models for
Duchenne, myotonic, and congenital MD, will be transplanted with genetically-marked
BM from a transgenic, co-isogeneic donor, or with genetically-corrected
autologous BM. Contribution of BM-derived myogenic progenitors to
muscle regeneration, and the effect of this treatment in reversing
the dystrophic phenotypes, will be quantitatively analyzed at morphological
and functional level by a combined effort of four highly-qualified
groups working in three different European countries. The rationale
of this project includes the possibility of testing whether transplantation
of a complete hematopoietic system is sufficient to tolerize an immunocompetent
animal towards the expression of a foreign protein (i.e., the one
missing in each specific mutant) expressed by the muscle tissue. At
the end of this two-year demonstration project, we will be able to
evaluate the therapeutic potential of a muscle cell replacement strategy
based on BM transplantation, and formulate a possible strategy for
further clinical application (allogeneic, or genetically-modified
autologous, BM transplantation).
Start Date: 1998-10-01
End Date: 2000-09-30
Project Reference: BIO4980547
Title: Predicting graft versus host disease in bone marrow transplantation
using in vitro techniques
General Information:
Graft versus host disease (GVHD) is the most serious complication
following bone marrow transplantation(BMT)-incidence 40-60% and can
be fatal in 50% of cases. Two BMT centres in Europe have unique assays
for predicting acute GVHD, a human skin explant model (Partner 1)
and minor histocompatibility antigen (Hag) typing for HAl (Partner
2). Both centres have established these techniques by former research
and publication. The aim now is to demonstrate the ability to predict
GVHD in different cohorts of patients across Europe in large BMT centres
. To date predicting GVHD and then modifymg therapy has not yet been
achieved. An important step forward would be to demonstrate an accurate
prediction of GVHD so that future studies could prevent and regulate
GVHD more effectively. This cannot be achieved at a single centre
level and requires this type of demonstration project across BMT Centres.
Measurable objectives (every 6 months) would include co-ordination
of clinical results (transplant outcome) with the results of both
predictive models for GVHD. Specific objectives will include:
1. Partner 1 to aid other BMT Centres (Partners 3 and 5) in the use
of the skin explant assay for predicting GVHD in adult and paediatric
transplant recipients 2. To use the mHAl typing (HLA-identical sibling
transplants only) results to further substantiate and strengthen the
results obtained from the skin explant model and 3. To assess and
evaluate the model in several BMT centres (Partners 1,2 and 5) to
predict which patients will develop GVHD. This will influence the
selection of donors and in the future enable therapy to be modified
on an individual patient basis. Partner 1 is the only centre in Europe
which has established this model as a useful and important predictive
test for GVHD. This novel method has been used in a single BMT centre
(Partner 1) for 9-10 years and has been demonstrated to be better
than other cellular tests for predicting GVHD, especially in HLA-identical
sibling transplants. The major aim will be to reduce mortality and
morbidity of BMT recipients by more careful selection of donors and
ultimately reduce in-patient hospital stay and cost of treatment.
Whilst improving results another significant outcome of the demonstration
project may be an additional reduction m treatment cost if prolonged
chronic GVHD is also reduced.
Results from this demonstration project will contribute a significant
step forward beyond the state of the art .This is due to the novel
techniques used which when demonstrated within the larger European
Bone Marrow Transplant ( BMT) community will significantly influence
treatment modalities and modes of graft versus host disease ( GVHD)
prevention.
The importance of demonstrating these techniques within the European
BMT community lies with the potential benefit to larger numbers of
transplant cases. In 1995, a total of 3287 allogenic bone marrow transplants
were perforrned in Europe by 343 teams from 31 countries and data
were reported to the European group for Blood and Marrow Transplantation
(EBMT). The main indications being leukaemias, lymphomas and certam
inherited haematological disorders. The EBMT and the International
Bone Marrow Transplant Registry (IBMTR) document annual transplant
activity and have bi-annual and annual meetings respectively. The
numbers of transplants occurring in Europe and Worldwide is rising
expotentially with still the main cause of mortality being GVHD.
Results demonstrated would be quickly and easily disseminated to BMT
groups within the European community with the aim of influencing EBMT
workshops for further participation, multilateral co-operation and
involvement in potential new clinical trials for modifying GVHD therapy
and prophylaxis based on results obtained from our multi-centre study.
Start Date: 1998-12-01
End Date: 2000-11-30
Project Reference: BIO4980236
Title: Predicting graft versus host disease in bone marrow transplantation
using in vitro techniques
Start Date: 1998-11-01
End Date: 2000-10-31
Project Reference: IC20980218
Title: Active peripheral tolerance applied to transplantation
autoimmunity: revisiting an ancient concept with strategies and biotechnologies
General Information: This project is intended to develop and
co-ordinate a European network of 7 partner laboratories to produce
and develop novel therapeutic strategies for the prevention and the
treatment of autoimmune diseases and avoidance of transplant rejection.
Autoimmunity constitutes the third major pathogenetic process in developed
countries after cancer and atherosclerosis. Organ and bone marrow
transplantation represent the only therapeutic possibility for a variety
of life threatening conditions. In both of these situations similar
immune mechanisms are involved and current therapeutic approaches
are essentially based on non-antigen specific immunosuppression. This
strategy is insufficiently efficacious and exposes to severe side
effects linked to long term over-immunosuppression and direct drug
toxicity.
The aim of this collaborative project is to establish ways in which
the immune response to the target antigens of the pathogenic process
can be selectively inhibited, thus avoiding the hazards of long term
non-specific immunosuppression. This may be achieved through peripheral
tolerance defined as durable antigen specific unresponsiveness in
the absence of generalized immunosuppression.
Observations made by the partner laboratories have indicated that
peripheral tolerance is not only explained by deletional mechanisms.
Various strategies, mainly using biological agents, will be developed
to promote such peripheral tolerance and to dissect the underlying
active mechanisms.
Some of these strategies will target specific mechanisms of T cell
activation, others will interfere at the level of cell-cell interactions
for antigen presentation or target recognition. Particular attention
will be devoted to the five following steps: a) antigenic presentation,
b) the delivery of activation and co-stimulatory signals to T cell
precursors, c) T cell polarization towards regulatory T-cell functions
including the generation of distinct cytokine-producing phenotypes,
d) effector/target contact and, e) apoptosis. Taking advantage of
the complementarity of technologies, animals models and biological
reagents used in each laboratory, collaboration will be set up with
the parallel aim of better understanding the basic mechanisms and
potential clinical applications to the treatment of human autoimmune
diseases and prevention of organ rejection.
Start Date: 1997-10-01
End Date: 2000-09-30
Project Reference: BIO4972151
Title: Xenotransplantation - strategies for the prevention of
carbohydrate related (hyperacute) rejection
General Information: The overall aim of the project is to make
clinical xenotransplantations possible. We shall concentrate on pigs
as organ donors, although we will screen for possible other species
as well. The project shall focus on carbohydrate related phenomena
in xenotransplantation. In pig to man transplantation, hyperacute
rejection occurs mainly as the result of reaction between carbohydrate
antigens expressed on endothelial cells of the pig organ, and preformed
anticarbohydrate antibodies of the recipient. A major target of these
human natural antibodies is the nonreducing terminal disaccharide
Gal alpha,3Ga We shall focus on strategies to inhibit/interfere with
carbohydrate dependent rejections in xenotransplantation. The studies
proposed will partly take place in close collaboration with industry.
Part of the technology for the production of final products (Columns,
etc) is known from other areas, indicating a possible market within
3-5 years. Additional basic knowledge will be produced that will contribute
to the production of a new generation of anti-inflammatory/anti-rejection
drugs. The market for carbohydrate products in relation to xenotransplantation
was recently, perhaps optimistically, estimated to I billion dollars
in a "full scale" scenario.
Our present view is that the disarming of only one of the several
pathogenic routes will be insufficient to ensure success. The binding
of anticarbohydrate antibodies is followed by complement activation
and cell mediated events at later stages. All these different rejection
events require specific approaches for their prevention. In that perspective
we will also combine a number of different strategies for prevention
of xenograft rejection. We envisage to use pig organs that are transgenic
for human complement regulatory proteins or apply other methods to
block complement activation. In addition, we think of strategies to
block leucocyte influx into the tissue.
Transplantation as a medical treatment that has been extremely successful
during recent years. 5 year graft survival for kidney allografts is
about 80% using nonrelated human donors and about 90 % using related
donors. Transplantation of an organ to a seriously ill patient in
most cases results in a full quality life. At present, the shortage
of donor organs, is the only hindrance for curing thousands of patients
in Europe. Compared to conventional therapy, if existing, transplantation
is a relatively non-expensive treatment. The economic benefit for
the national health care budgets is substantial taking into account
the decreased need for continuous treatment, and treatment of related
complications and also the fact the many/most transplanted patients
regain an active professional life.
The project proposed is transdiciplinary, ranging from basic molecular
biology/cell biology/structural biology over clinical trials to ethical
and cultural aspects. It is problem-oriented from its start, it contains
important basic research as well as more applied research and still
the participant researchers are all well founded in their own disciplines.
Such a project will speed up the solution to an important medical
problem with impact on health care and society and it will also promote
cross fertilization and the development of novel concepts worthy of
further basic diciplinary research.
More specifically we will:
- develop, produce and test carbohydrate based inhibitors/immunoadsorbents
for clinical use.
- test and evaluate the use of glycosylhydrolases and blocking antibodies
to abolish or cover antigen expression.
- develop animal and human models to test the different therapeutic
concepts. - try to understand the regulation of "terminal"
glycosyltransferases with the purpose of creating low expressors of
Galal ,3Gal.
- screen for additional carbohydrate related rejection phenomena -
produce a documentary TV-film on xenotransplantation from a cultural,
historical and ethical perspective and a scientific report on ethical
attitudes in relation to ethical structures and norms.
Start Date: 1997-11-01
End Date: 2000-12-31
Project Reference: BIO4972242
Title: Characterization of porcine complement regulatory molecules.
Application to xenotransplantation
General Information: Research objectives and content
Little is known about the regulation of complement in pigs and the
current enthusiasm for using the pig as an organ donor for humans
increases the need for an understanding of pig complement. Pigs are
currently being engineered to express human complement regulators
in the expectation that organs from these pigs will be less susceptible
to damage by human complement and will escape hyperacute rejection.
However, these experiments have been conducted in relative ignorance
of pig complement and of its own regulatory molecules. This project
is intended to accomplish a deep characterization of the pig complement
regulatory molecules, mainly in the context of the pig to human xenotransplantation.
Thus, it is focused in the three cell membrane-bound molecules: MCP
(or CD46), CD59 and DAF {or CD55). We will characterise fully the
tissue expression of these three molecule and to analyse their roles
in vivo. We will address the species selectivity of pig complement
regulators. This is, if porcine regulators inhibits the activation
of the human complement and the relative efficiency of both systems.
These latter questions have obvious relevance to pig-human transplantation.
Finally, is intended to carry out several functional analysis of the
regulatory capacity of these three molecules. We will assess the relative
importance of the proteins in defence against homologous and heterologous
complement.
Training content (objective, benefit and expected impact)
This project will provide new data which will be of value to those
engaged in the design of animal organs for transplantation into humans.
It will also provide novel information on the regulatory molecules
of porcine complement and the possible role of complement regulators
in homeostasis, fertility and infection in the pig by virus and parasite.
On the other hand, it will contribute to comparative immunology, since
it will introduce novel concepts in the evolution of the cornplement
system Links with industry / industrial relevance (22)
The Spanish industry BioVet-UCO, where the applicant comes from, has
expressed a great interest in this project, since it will support
partialy this fellowship. The company concentrates on research, development
and manufacturing, manufacturing with a technological focus on monoclonal
antibodies. BioVet-UCO will pay special attention to swine immunology
taking into account the emerging relevance of pigs as organ donors
for xenotransplantation. Thus, BioVet-UCO is also interested in the
study of the porcine complement regulatory molecules and in the development
and characterisation of monoclonal antibodies to these molecules.
Transgenic swine would need a special immunological care and BioVet-UCO
will offer reagents for immunological control. These reagents could
also be applied to the study of xenotransplantation and xenograft
rejection.
Start Date: 1998-03-02
End Date: 2000-03-01
Project Reference: FMBI972590
Title: Induction of specific and indefinite tolerance to alloantigens
and/or primarily vascularized allografts by DNA-mediated gene transfer
General Information: The main objective of this experimental project
is to induce and maintain specific and indefinite tolerance to alloantigens
and/or primarily vascularized allografts by DNA mediated gene transfer.
In order to induce allotolerance, genes encoding cytokines or second-signal
blockers and/or MHC molecules will be transfected either in the organ
itself prior to grafting or in recipient bone marrow and stem cells
by using and comparing the efficiency of three gene vectors i.e. adenovirus,
retrovirus and liposomes. The ultimate goal of the project is to develop
innovative therapies for inducing tolerance in human allograft transplantation.
The importance of these intercellular mediators (cytokines such as
TGF-Beta, IL-4 and IL-10), co-stimulatory (CD28/B7-1.2), apoptotic
(Fas/Fas-L) or MHC molecules in the T cell response suggests that
the expression of these proteins which regulate the immune response,
at a high level locally in the allograft itself or in recipient bone
marrow and stem cells prior to grafting might prolong the graft survival
and/or induce specific tolerance to allograft.
The following complementary experiments based on the latest developments
in Transplantation Immunology are proposed:
I) Transfection of the graft itself by viral or non viral vectors
expressing genes encoding
(1) down-regulating cytokines such as IL-4, IL-10, TGF-beta; (2) blockers
of co-stimulatory molecules such as CTLA-4Ig or (3) Apoptotic molecules
such as FAS/FAS-L.
A) viral vector
Transfection of genes encoding (1) cytokines and/or (2) down-regulating
factors such as CTLA_4Ig by adenoviral vector in rats (M.Dallman,
London)
B)NON-VIRAL VECTOR
Transfection of genes encoding cytokines such as TGF-beta, IL-4 and
IL-10 in miniatures swine by LIPOSOMAL VECTOR (M.Baru and P.Gianello,
Brussels)
II)production of transgenic mice expressing TH2 cytokines (IL-10 and
IL-4) under the control of inducible promoter (P.Vieira, Oieras)
III) transfection of recipient bone marrow and stem cells by retroviral
vectors expressing genes encoding mhc molecules.
retroviral vector
A) Induction of tolerance to vascularized allografts by inoculation
of transfected recipient bone marrow or stem cells expressing various
MHC molecules. (K.J. Wood, Oxford)
B) Tolerance to human CD34+ cells in SCID mice after gene transfection
by retroviral vectors (JL. Touraine, Lyon)
IV) tolerance induction to alloantigens and/or primarily vascularized
allografts by using gene delivery in both the graft itself and recipient
bone marrow or stem cells (M. Baru, M. Dallman, P. Gianello, JL Touraine,
P. Vieira, K. Wood).
The most efficient vectors for gene transfection into the graft itself
(transgene, Lip, adenovirus) and most appropriate retroviral vectors
for expressing genes into the recipient bone marrow or stem cells
will be selected. Protocols combining both approaches will be investigated
in vivo by using the most relevant models of cells or primarily vascularized
allograft.
Start Date: 1997-08-01
End Date: 2000-07-31
Project Reference: BIO4972262
Title: Concertation of the european strategies for intervention
in Parkinson's disease with special emphasis on functional neurosurgery
Objective: To intensify and coordinate efforts in the field
of neurosurgical interventions for Parkinson's disease (NIPD) in Europe.
Start Date: 1997-10-01
End Date: 2000-09-30
Project Reference: BMH4972397
Title: Re-building muscle from cultured satellite cells: Novel
Approaches to improve myoblast transplantation
Objective: On the short term: optimisation of myoblast transplantation
techniques by enhancing their proliferative and migratory potential.
On the long term: a) reconstruction or replacement by myoblast transplantation
of damaged or missing muscle following accident, surgery and ageing
and b) cure of muscle and non-muscle diseases through myoblast-mediated
gene transfer.
Start Date: 1997-05-01
End Date: 2000-04-30
Project Reference: BMH4972767
Title: European Union Network for investigation of dendritic
cell immunotherapy for induction of anti-viral and anti-tumor immunity
and transplantation tolerance
General Information: The proposed Research Network comprises
ten Partners who will collaborate in the seven defined Tasks over
three years (six periods) for training of long-term goal is to use
DC for immunotherapy of human diseases. The eleven postdoctoral Researchers.
Ten Researchers will work for three research objectives of this joint
research project address the main issues periods with the principal
host Partner, and for the remainder with up to that need to be resolved
before this goal can be implemented at the three different Partners
engaged in similar Tasks. The eleventh Researcher Community level.
Seven, interrelated Tasks have been identified. Molecular and cellular
techniques will be used to define, for murine and human DC: will be
engaged in Network Tasks, working between Partners and liaising lineage
and stage-specific genes and proteins (Task 1); conditions for with
the Network Coordinator.
growth and purification of subsets with specific properties (Task
2); antigen receptors and processing compartments (Task 3); and costimulatory
molecules for regulation of T cell activation (Task 4). This knowledge
will then be applied in vivo, in both experimental and/or clinical
settings, for induction of anti-viral immunity (Task 5), anti-tumor
immunity (Task 6) and transplantation tolerance (Task 7).
Start Date: 1996-10-01
End Date: 2000-09-30
Project Reference: FMRX960053
Title: Treatment of diabetes by islet cell transplantation
Objective: - To conduct a clinical trial on beta cell transplantation
in diabetic patients with the purpose of identifying graft and recipient
conditions which favour survival of beta cell allograft prepared from
donor pancreata.
- To develop alternative sources for beta cell grafts with the purpose
of increasing the availability of donor tissue for transplantation
in diabetic patients.
Start Date: 1996-01-01
End Date: 1998-12-31
Project Reference: BMH4951561
Title: Novel possibilities for manipulating subsets of lymphocytes
in transplantation and autoimmunity
Objectives: An organ transplantation outcomes have improved the demand
for this treatment is steadily increasing. If we are to continue this
progress, two crucial issues must be solved: how can the supply of
donor organ be improved and how can we induce specific and long lasting
tolerance to replace non specific suppression. Induction of specific
tolerance in xenotransplantation can potentially solve these issues.
The major axis of this project is to try to induce specific tolerance
in xenotransplantation by exploiting the fact that B Lymphocytes can
now be subdivided into subsets performing different functions.
The major barrier to xenotransplantation is the presence of preformed
antibodies, mostly of the IgM type, which recognise glycoproteins
or glycolipids from the xenograft. These preformed antibodies in the
rat-guinea-pig model seem to be synthesised by the B-l subset. Using
treatments by monoclonal anti-mu or anti-delta antibodies, we can
manipulate, eliminate or enhance B cell subsets. Therefore we shall
attempt to delete the mature B cell subset. We shall then expose the
reconstituting immune system to xenoantigens. Immature B Lymphocytes
are specially sensitive to tolerance induction. The state of the immune
system will then be checked by injecting xenoantigens mixed with adjuvant
and xenografts will be performed. All these studies will need the
measure of the life span and apoptotic mechanisms of the different
B cell subsets. We shall also make use of the finding that thymic
epithelium grafts in able to induce transplantation tolerance.
We propose also to apply the concepts and the tools described above
to analyze the autoimmune diabetes of NOD mice which are a model for
human insulin dependent diabetes mellitus (IDDM). While it is clear
that the destruction of beta cells in pancreas is mediated by T Lymphocytes,
it has been observed recently that treatment of neonatal NOD mice
with anti-mu antibodies prevents the occurrence of diabetes. This
suggest that B cells can somehow participate in the initiation of
the disease. We shall try to identify the nature of the guilty subset
and to understand the role of this subset in diabetes. Several companies
are interested by this programme but they think that more basic research
is needed before they bring supply to this project. All the teams
involved in this project have been cooperating for a long time, mainly
through bilateral interactions. They want now to establish a solid
European network exploiting some of the most recent findings and concepts
of fundamental immunology in order to manipulate specifically the
immune response directed against xenografts and autoantigens.
Start Date: 1995-12-01
End Date: 1998-11-30
Project Reference: BIO4950055
Title: Neuroepithelial cell lines for repair of cognitive function
General Information: Transplantation of neural tissues in
the central nervous system is widely used to pursue neurobiological
issues concerning the normal and pathological brain. Recent developments
have opened up the possibilities of grafting primary precursor cells
cultured in vitro instead of fetal brain tissues. In that way E10
neural tube of transgenic mice bearing thermolabile TAg of SV40 virus
will be dissected in order to isolate new multipotential immortalised
neuroepithelial cell lines. These cell lines will be characterised
at non permissive temperature using immunocytochemical and nucleic
markers for neurons and glia. Selected lines will be transfected with
Lac Z reporter gene and microtransplanted into various brain regions.
Then the survival, the fate of grafted cells and their capability
to restore cognitive function of ischaernied rat will be studied.
In addition to provide cell lines of readily expandable cells optimal
for recovery of cognitive function, these transplantable cells would
be excellent tools to study differentiation, cell plasticity and to
introduce in brain exogenous gene.
Project Reference: FMBI960870
Title: The development of a DNA fungal probe assay for the diagnosis
of opportunistic fungal infections in AIDS/Transplant patients
General Information: This proposal aims to develop and test
a user friendly kit for the diagnosis and identification of opportunistic
fungal pathogens. These are a frequent, and often life-threatening
complication in immunocompromised patients e.g. AIDS. Studies show
that at least 58-81% of all AIDS patients contract a fungal infection
at some stage during their illness, with a mortality rate of 10-20%,
and similar incidences and indeed consequences in Transplant patients.
Two of the most common opportunistic fungal pathogens prevalent in
immunocompromised patients are Aspergillus spp. and Candida spp. Resulting
systemic infections incur an extremely high mortality rate and require
aggressive therapy. The importance of early diagnosis for effectove
therapy, connot be overemphasised. DNA probe technology offers significant
advantages over current testing methods in terms of both speed and
accuracy. The proposed research will involve the identification and
design of specific probes fpr Aspergillus spp. and Candida spp., and
the incorporation of the probes into assay formats which will allow
the clinician to distinguish between different fungal pathogens. Preparation
methods for the extraction of DNA clinical samples will also be examined.
After the development of a Kit, it will be necessary to perform extensive
clinical trials before its sensitivity and specificity can be guaranteed.
Clinical partners will be sought during the exploratory phase to advise
on the appropriate formats on the panel of fungal pathogens and to
perform phase 1 clinical trials. The partners will include experts
in AIDS.HIV and Transplantation fields.
Start Date: 1997-12-01
End Date: 1998-04-08
Project Reference: BMH4979104
Title: Cancer After Transplantation
General Information: Organ transplantation is followed
by an increased risk for development of cancer. Analyses of materials
from transplanted and therefore immunosuppressed patients allow the
possibility to find risk factors for cancer and to evaluate oncogenetic
mechanisms in general.
In our most recent analyses performed using correct cancer epidemiological
methods an increased incidence of 3 - 5 times that in the general
population has been found, including most types of tumours, however
with an uneven pattern with emphasis on lip- cervical-, vulvar-, urological-,
skin-cancers and lymphoproliferative disorders (PTLD). Most tumours
occur early (include. PTLD) after transplantation, tumours of the
skin however later and with an increase with time.
This complication appears to be increasing in degree for all types
of organ transplantation, however a parallel increase in our knowledge
concerning possible risk factors and oncogenetic mechanisms in general.
Many of the tumours appear to be associated in some way with virus
infections, thus opening up for possible new approaches to prophylaxis
and treatment.
Based on previous cancer epidemiological studies in the Nordic countries
it is the aim of this new study to :
1. perform a follow-up on existing files on kidney transplanted patients
in the Nordic countries to latest possible date in the framework of
Scandiotransplant and the Association of the Nordic cancer Registries
2. to analyse the Nordic material concerning all types of organ transplantation
to latest possible date in the framework of Scandiatransplant and
the Association of the Nordic Cancer Registries (ANCR)
3. to start a prospective registry with extensive use of existing
data files in the Scandiatransplant organisation and the Association
of the Nordic Cancer Registries (ANCR) allowing yearly analysis, with
1-3 in a collaborative study including all Nordic transplantation
centres and cancer registries
4. to perform a study of cancer in patients on dialysis in the European
Institute of Oncology, Division of Epidemiology and Biostatistics
in Milano, Italy, which co-operates with centres in many European
countries, since this will be complementary to the transplant study,
as these patients are uremic with depressed immune defence, however
not transplanted and immunosuppressed by drugs.
The cancer epidemiological analysis will allow identification of cases
to be analysed intensively in :
5. specialised laboratories for immune pathology (DK, GB), cytokines
(DK), virology (DK), and tissue typing (DK, FI, N, SE)
6. identified cases with proved Epstein-Barr oncogenetic background
will be treated with a combination of (a) intravenous high-dose aciclovir
and (b) decreased or discontinued immunosuppression.
The overall aim is to bring together cancer epidemiology (in the Nordic
countries and Italy) with new advances in cellular, molecular and
developmental genetics in immunopathology and immunology (cytokines
and tissue types) and virology in order to obtain new biological insights
and improvements in both diagnosis and treatment of interest for the
field of transplantation and thereby also to obtain new insights in
oncogenesis per se.
Start Date: 1996-06-01
End Date: 1999-05-31
Project Reference: BMH4960610
Title: European Research on Cord Blood Banking and Use for Transplantation
General Information: The principal limitations of allegoric
bone marrow transplantation (ABMT) are the lack of suitable HLA-matched
donors for the majority of patients and the complication of graft-versus-host
disease (GvHD). The lack of sibling donors in some cases has been
overcome through the establishment of large panels of potential marrow
donors but these panels are restricted in terms of HLA polymorphism
and of their ethnic diversity. This is most marked in Europe where
each nation has its own ethnic diversity. Limitation is also related
to the fact that results of allegoric bone marrow transplantation
from normal bone marrow donor are dependent of HLA-A, B, C, DR, DP,
DQ identity between donor and recipient. Umbilical cords from full-term
pregnancies have been shown to be a source of haematopoetic progenitors
(1,2,3,5,6). Banks of cord blood samples are being established in
a number of EU member states (47). A number of cord blood transplants
have been performed with encouraging results (3,39,40,41,42,43,44).
Preliminary evidence suggests that these transplants are associated
with less GvHD than comparable unrelated BMT.
The purpose of the research is to advance our understanding of cord
blood transplantation and to establish common criteria and protocols
for the handling of cord blood samples.
Objectives:
- to standardise the methods of collection, testing and cryopreservation
of cord blood
- to study the properties of haematopoietic progenitors present in
cord blood
- to study the immune function of cord blood lymphocytes
- to co-ordinate and facilitate the exchange of sera and cells from
regional cord blood depositories held in member states
- to establish a European Registry of patients treated by cord blood
transplantation and design protocols comparing cord blood transplants
with alternative conventional blood and bone marrow haematopoietic
stem cell transplants.
Start Date: 1996-07-01
End Date: 1999-06-30
Project Reference: BMH4960833
Title: Mantle cell lymphomas (MCL) - Biologic and clinical charaterisation
and prospective evaluation of myeloablative radio-chemotherapy with
blood stem cell transplantation
General Information: Mantle lymphomas (MCL) represent a recently
recognised sub-type of malignant lymphomas which are charaterised
by a specific histology and immunophenotype and an unfavourable clinical
course. Hence, response to chemotherapy is poor and patients with
this disease usually face a median survival of less than three years.
The recent discovery that MCL are associated with a specific chromosomal
abnormality, the translocation t (11;14) that leads to the deregulation
of cyclin D 1 and over-expression of bcl 1 and a consecutive impairment
of cell cycle control has opened new perspectives to better understand
the biology of this lymphoma and also potentially its clinical course.
The current multinational study aims at gaining new insights into
the biology of MCL and its appropriate clinical management and tries
to explore a novel therapeutic strategy comprising myeloablative radio-chemotherapy
with subsequent peripheral blood stem cell transplantation. These
objectives are addressed in three major steps :
- The assessment of clinical and histopathologic features of presentation
as obtained from a retrospective analysis of patients that have been
treated with conventional therapies at the participating institutions;
- The biologic characterisation of MCL by means of modern immunophenotypic
and molecular techniques;
- The prospective evaluation of myeloablative radio-chemotherapy with
subsequent blood stem cell transplantation.
Start Date: 1996-07-01
End Date: 1999-06-30
Project Reference: BMH4961539
Title: Development of a cell transplantation therapy for patients
with parkinson's disease
Objective: The main objective of the present project
is to develop cell transplantation into a clinically useful treatment
for patients with Parkinson's disease.
Other objectives are:
to develop strategies to counteract the degeneration of dopamine neurons
after transplantation in humans;
to study mechanisms of action of dopaminergic grafts in parkinsonian
patients;
to use neural grafting as a tool to clarify the functional topography
of the dopamine system in the human brain and the pathophysiology
of different symptoms of Parkinson's disease;
to better understand the etiology of Parkinson's disease.
Currently available treatments for Parkinson's disease are insufficient,
and a majority of patients become severly incapacited. A transplantation
therapy would improve the quality of life and living conditions for
a large number of patients.
Start Date: 1996-01-01
End Date: 1998-12-31
Project Reference: BMH4950341
Title: Bioartificial liver in vivo
General Information: Research objectives
The development of a liver support system for the treatment of patients
with fulminant hepatic failure and as a bridge to liver transplantation
is a major challenge. Many early attempts focussed on broad detoxification
based on the assumption that liver failure could be reversed if the
associated toxins were removed from the circulation of the patient.
Although improvement of the neurologic status of the patients has
been reported, none achieved long term survival. It was therefore
concluded that an effective liver support system should be able to
perform the liver's multiple synthetic and metabolic functions including
detoxification and excretion . The most logical approach to this problem
is the introduction of active functioning hepatocytes. Different bioreactor
systems are currently under investigation. However, an ideal BAL system
has not yet been invented. We deviced a novel bioreactor (patent pending)
which allows individual perfusion of high density cultured hepatocytes
with low diffusional gradients, thereby more closely resembling the
conditions in the intact liver lobuli. The bioreactor consists of
a spirally wound nonwoven polyester matrix, i.e. a sheet-shaped threedimensional
framework for hepatocyte immobilization and aggregation, and of integrated
hydrophobic hollow-fibre membranes for oxygen supply and CO2 removal.
The bioreactor is seeded with 220.106 freshly isolated porcine hepatocytes
cultured at 20.106 viable cells/ml. Medium (plasma in vivo) is perfused
through the extrafibre space and therefore in direct hepatocyte contact.
In vitro evaluation of the BAL showed that hepatocytes contained cytoarchitectural
characteristics as found in vivo and an even distribution of small
hepatocyte aggregates ( < 75 fm) throughout the three-dimensional
matrix with sufficient space between the aggregates for individual
cell perfusion. The biochemical performance of the bioreactor remains
stable over the investigated period of four days. On day one and day
four galactose elimination was 28.4 + 2.3 fg/106 cells, urea synthesis
was 1.9 + 0.4 fg/106 cells, and lidocaine metabolism 39.2 + 3 .2 fg/106
cells. Low lactate/pyruvate ratios and constant pH values indicated
optimal oxygenation and CO2 exchange by the integrated oxygenator.
Metabolism of a wide range of amino acids as well as protein secretion
was documented. In the first in vivo experiments in rats with acute
liver failure due to complete liver ischemia (porta caval shunt plus
ligation of the hepatic artery) survival time in controls with only
supportive therapy was 5 + 1 hr and in a second control group treated
by plasmapheresis and a BAL without cells in the extracorporeal circuit
6 i 1.5 hr (n=7). The first rats with complete liver ischemia treated
by our BAL in the extracorporeal circuit survived 11 and 12 hrs respectively,
a highly significant improvement.
The next step in the development of a satisfactory BAL for human application
will be evaluation of the BAL in a bigger animal experimental setting.
In collaboration with the group of Dr. Calise in Napoli we will treat
pigs with complete liver ischemia by a BAL scaled up for the pigs
circulation. Our expertise for the group in Italy will be the application
of the upgraded BAL, the knowledge of pig hepatocyte isolation and
plasmapheresis. The pig experiments are essential as a bridge to human
application. Since the group of Dr. Calise has already sufficient
experience with the liver ischemia model in pigs our collaboration
can be very fruitful. Production of a scaled up BAL for the pig will
be performed by The Spectrum Companies La Cadena Drive, Laguna Hills
in the United States. The price of these BAL's will be $ 300 to 400
per device. Other expences of this in vivo study will be the costs
of the pigs and the plasmapheresis apparatus.
Start Date: 1997-03-22
End Date: 1998-03-21
Project Reference: FMBI961547
Title: In vitro system for enhanced and tumor specific graft
versus leukemia effect provided by tumor antigen specific donor cytotoxic
t lymphocytes
General Information: Allogeneic bone marrow transplantation
for the treatment of leukemia in patients with acute lymphocytic leukemia
(ALL) is used with increasing frequency. However, one of the major
shortcomings remains the risk of leukemic relapse. In ALL of mature
T-cells (T-ALL) the variable region of the T-cell receptor (VB) is
unique for all monoclonal tumor cells, thus representing a 'tumor
defining antigen'. In order to induce a graft-versus-leukemia reaction
directed specifically against these tumor cells, HLA-matched, CD8+
T-cells will be primed in vitro by autologous dendritic cells presenting
recombinant VB tumor antigen. In vitro primed cytotoxic CD8+ T-cells
will subsequently be tested for their ability to specifically kill
the T-ALL cells from which the recombinant VB was derived. If so,
this in vitro model would open new avenues in the protection from
leukemic relapse of T-ALL patients after allogeneic bone marrow transplantation.
Start Date: 1996-01-12
End Date: 1998-02-11
Project Reference: FMBI950013
Title: Genetic Diversity of HLA in Europe : Impact on Transplantation
and Preventive Medicine
General Information: The histocompatibility antigens play a
crutial role in normal and pathological immune processes. There are
two classes of the antigens. The class I is expressed by every cell
and present the endogen peptides. to immune cells for eliminate malignant
or infected cells. The class II antigens serve for presentation of
processed exogen peptides and is expressed in restricted number of
cells - antigen presenting cells. Both classes are coded by several
gens, which cluster in two regions, according to their functions.
This two clusters are divided by only one megabase gap and however
have different patterns of expression: while class I is ubiquitous,
class II is expressed by particular cell at particular developmental
stage.
There are some examples of multilevel regulation by chromatine conformation
of gens clusters in man, beta-globin claster is the better known.
Chromatin folding and unfolding accomplished during cell development
is the mechanism of "opening" or "shut douw" of
expression, and precede its initiation. The changes in chromatin conformation
are regulated by locus control region, already described in several
human clasters, but not in the class I or II region.
Taking in account the pathology, followed by complete absence of class
II expression we proposed to study the process of normal and pathological
inactivation of class II gens in several molecular models.
The knowledge of class II regulation at the chromatin level will promote
our comprehension of bare lymphocyte syndrom and autoimmunity, will
also fernish new approach of improvement of immune response against
infection.
We propose also a new and simple method to test the locus control
region capacity, which can be applied in any situation, when gen transfection
is needed.
Start Date: 1995-04-01
End Date: 1997-03-31
Project Reference: CIPD940297
Title: Bioartificial pancreas
General Information: About 80 million people in the world,
among whom 4 to 5 million in Europe suffer from insulino-dependant
diabetes (type I), characterised by a hyperglycemia resulting from
a deficiency in insulin secretion. The current ways of administration
of insulin do not reproduce the physiological secretion essential
in maintaining the glycemic equilibrium. This project is devoted to
the development of a prototype of bioartificial pancreas usable in
the human. This bioartificial pancreas will be made of pancreatic
islets packed in a capsule made of a complex support and membranes.
Membranes should exhibit specific permeability to insulin, glucose
and nutrients and be a barrier to immunoglobulins and cells. The prototype
will be tested in diabetic mice and should restore, in the absence
of any insulin injection, normoglycemia immediately after transplantation.
About 80 million people in the world, among whom 4 to 5 million in
Europe suffer from insulino-dependant diabetes (type I), characterised
by a hyperglycemia resulting from a deficiency in insulin secretion.
The current ways of administration of insulin do not reproduce the
physiological secretion essential in maintaining the glycemic equilibrium.
This project is devoted to the development of a prototype of bioartificial
pancreas usable in the human. This bioartificial pancreas will be
made of pancreatic islets packed in a capsule made of a complex support
and membranes. Membranes should exhibit specific permeability to insulin,
glucose and nutrients and be a barrier to immunoglobulins and cells.
The prototype will be tested in diabetic mice and should restore,
in the absence of any insulin injection, normoglycemia immediately
after transplantation.
About 80 million people in the world, among whom 4 to 5 million in
Europe suffer from insulino-dependant diabetes (type I), characterised
by a hyperglycemia resulting from a deficiency in insulin secretion.
The current ways of administration of insulin do not reproduce the
physiological secretion essential in maintaining the glycemic equilibrium.
This project is devoted to the development of a prototype of bioartificial
pancreas usable in the human. This bioartificial pancreas will be
made of pancreatic islets packed in a capsule made of a complex support
and membranes. Membranes should exhibit specific permeability to insulin,
glucose and nutrients and be a barrier to immunoglobulins and cells.
The prototype will be tested in diabetic mice and should restore,
in the absence of any insulin injection, normoglycemia immediately
after transplantation.
About 80 million people in the world, among whom 4 to 5 million in
Europe suffer from insulino-dependant diabetes (type I), characterised
by a hyperglycemia resulting from a deficiency in insulin secretion.
The current ways of administration of insulin do not reproduce the
physiological secretion essential in maintaining the glycemic equilibrium.
This project is devoted to the development of a prototype of bioartificial
pancreas usable in the human. This bioartificial pancreas will be
made of pancreatic islets packed in a capsule made of a complex support
and membranes. Membranes should exhibit specific permeability to insulin,
glucose and nutrients and be a barrier to immunoglobulins and cells.
The prototype will be tested in diabetic mice and should restore,
in the absence of any insulin injection, normoglycemia immediately
after transplantation.
Start Date: 1996-12-12
End Date: 1997-05-31
Project Reference: BMH4969059
Title: Transplantation of muscular satellite cells into the
myocardium for heart muscle regeneration
General Information: The hypothesis of this project is that
adult muscle satellite cells cultured in vitro and implanted into
injured myocardium are thought to develop into neomyocardium. Satellite
cells will be isolated from adult rat laussimns dorsi muscle and cultured
in vitro. To allow confirmation of their presence after implantation
into myocardium, an E. coli plasmid pCMVlacZ coding for B-galactosidase
and neomycin resistance will be used to label the satellite cells.
Transfection will occur by lipofection technique. Prior to implantation,
myocardial injury will be inflicted in the same rats which had their
muscle explanted by performing a surgical ligature of coronary artery
branch. Control, culture medium only, and implant channels will be
created into the injured myocardium. The morphology of implanted cells
will be analysed microscopically, in addition to functional parameter
investigations of whole heart explauts. This technique of cellular
eardiomyoplast may present a significant advance in the eure for myocardial
infarction.
Start Date: 1996-10-14
End Date: 1999-10-13
Project Reference: FMBI961264
Title: Low-temperature preservation of isolated liver cells
for transplantation
General Information: Cryopreservation of hepatocytes
remains an important issue in view of possible transplantation for
treatment of metabolic deficiencies and acute liver diseases. However,
the process of freezing and thawing inflicts considerable structural
and metabolic damage to the cells. Cellular injury becomes even more
pronounced with the removal of the cryoprotectants.
Not only intact and viable hepatocytes are essential but long-term
survival after transplantation is also necessary to sustain enzyme
production. If isolated hepatocytes could be successfully cryopreserved,
major liver transplant operations may be avoided and replaced by regular
intrahepatic or intrasplenic transplantations of isolated hepatocytes.
Preliminary experiments on animal hepatocytes indicate that viability
of the cells could be stimulated by the utilisation of a mono-layer
culturing technique of cryopreserved hepatocytes, allowing the cells
to recuperate from cryo-stress and regaining their full metabolic
activity, thus being ideal1y suited to be used for subsequent transplantation.
In this project the aim is to examine the essential metabolic parameters
and to determine liver enzyme activity levels during the experimental
procedures in order to establish optimal conditions ensuring metabolic
and structural integrity of low-temperature preserved liver cells
Optimal survival being assured, these cryopreserved cells will thus
be transplanted to perform active liver functions.
Start Date: 1994-08-01
End Date: 1995-07-31
Project Reference: INTAS-93-0014
Title: Information technology for national and international
cooperation in transplantation
General Information: Clinical transplantation is a broadly used therapeutic
approach in life-threatening diseases. There are two major problems
for which a national and international co-operation is condition sine
qua non. One is scarcity of (donor) organs and the second is the diversity
and multiplicity of genetic factors regulating donor/recipient matching.
Therefore, information and communication technology became an inherent
part of transplantation medicine. In organ transplantation the patient
waiting list, organ allocation, patient selection (etc...) demands
challenging software systems; in bone marrow transplantation excessive
donor register, rapid and effective inter-centre communication, very
sophisticated donor/recipient pair selection, etc..., are demanding
information and communication technology. E.g. for a patient "somewhere"
in Europe a bone marrow donor has to be selected amongst more than
2,300,000 volunteers listed by 25 national registers. In Central Europe,
transplantation activities started at the level of medical care and
laboratory work. The number of kidney transplantations in Prague reached
in 1994 the West-European level and Czech and Hungarian bone marrow
registers are on the European list of national registers (with 4000
and 2000 donors registered, respectively). However, there are major
obstacles in controlling the growing complexity of the situation.
This project proposes information and communication technology transfer
to Central Europe, namely by:
education of specialist(s),
transfer and adaptation of software systems,
appropriate systems for linking to European network(s),
purchase of durable equipment needed for this project.
Co-ordination of the project will be helped by the Information Processing
Department of the University Hospital Leiden; there is expertise par
excellence because there are the centres for Eurotransplant (organ
transplantation) and Eurodonor (bone-marrow transplantation).
Implementation:
improvement of information technology for national transplant system,
link with European Donor Secretariat (EDS) and Bone Marrow Donors
World-wide (BMDW),
link with European Marrow Donor Information System (EMDIS),
link with International Transplant Waiting Lists (kidney).
The result of this project would be participation in the European
Transplant-Network organisation with important consequences for medical
care. The potential extension of these results to further (East and
Central Europe) countries is also an important consequence for the
future. Finally, the proposal is useful for "both sides"
because enables organ and cell exchange for genetically matched combinations.
Start Date: 1995-12-01
End Date: 1998-11-30
Project Reference: 0166/37863
Title: In vitro cellular correlates in allograft recipients
Objective: The objectives were:
1) To find tests in vitro to predict the risk of graft rejection after
transplantation organ or of graft versus host disease (GvHD) after
Bone Marrow Tranplantation (BMT).
2) To study the mechanisms of action of new immunosuppressive compounds
(monoclonal antibodies, and peptides) or of immunological manoevers
(such as pegraft blood transfusions) aimed at decreasing allogeneic
immune response. The primary approach was to use graft recipient blood
cells or cells extracted directly from the graft (rejection/tolerance)
or skin (GvHD) to study their characteristics and functions in vitro.
Start Date: 1993-01-01
End Date: 1996-06-30
Project Reference: BIO2920300
Title: Treatment of hematological malignancies by bone marrow
transplantation from volunteer donors
Objective: The goal of the Concerted Action is to increase
the number of patients with haematological malignancies and pre-malignancies
that can be cured by using unrelated volunteer donor bone marrow transplantation.
This is done by promoting the establishing of new registers of volunteer
donors as well as increasing the number in existing registries. A
coordination of the system for finding an HLA-compatible donor is
made. The goal is also to find search prognosis indices that would
help to shorten the time to find a donor. The patients will be recruited
from more than 100 European Centers to a study that will compare results
of transplantation with marrow from unrelated HLA-matched volunteer
donors to conventional transplantation with marrow from HLA-matched
sibling donors and to autologous bone marrow transplantation.
Start Date: 1990-01-01
End Date: 1992-06-30
Project Reference: MR4*0216
Title: The Management of End-Stage Renal in Europe-Approching
a consensus
General Information: Kidney dialysis and transplantation are
life saving but expensive forms of treatment for patients with End
Stage Renal Disease. Increasingly older patients and more importantly
those with coexisting illnesses (eg heart disease) are receiving such
Renal Replacement Therapy (RRT) in most Western and some Eastern European
countries. Since the prevalence of such comorbidity varies from country
to country, published data comparing survival on RRT are open to misinterpretation.
The main aim of RRT is preservation of life, however the control of
associated medical conditions is also important. Our current Biomed
1 project aims to determine, using a risk stratification protocol,
the effect of age and comorbidity on survival on RRT and to establish
and monitor protocols for the clinical management of such patients
in centres in five countries in Western Europe. We now wish to include
St petersburg and Sofia in our study and determine their acceptance
rate of patients for RRT and whether the proportions in the low, medium
and high risk categories (according to age and comorbidity) are different
from those in the five Western European countries in the study. our
current Biomed 1 project is developing and monitoring protocols for
the management of anaemia, bone disease and CMV infection in patients
with End Stage Renal Disease. In view of the time constraints the
participants from St petersburg and Sofia will fill up data collection
forms for the data required before the implementation of the protocols.
In this way their basic data will be available for comparison with
those of the other centres. In addition they will attend the Plenary
meeting at which results are discussed with aview to considering developing
such guidelines for the care of the patients in their own centres.
Overall the inclusion of these Eastern European centres will a) allow
us to improve-our risk stratification protocol for use throughout
Western and Eastern Europe b) allow us to strengthen the results obtained
from the centres (Tirana and Budapest) incorporated during the PECO
93 initiative and c) enable our clinical management guidelines to
have wider relevance throughout Europe and permit our health care
systems to be better organised, managed and financed, particularly
in the areas working within financial constraints.
Start Date: 1995-05-01
End Date: 1996-07-31
Project Reference: CIPD940226
Title: An European Multicentre Study of Transplantation of Organs
from Living Donors : the Ethical and Legal Dimensions
General Information: Globally the supply of cadaveric solid
organs for transplantation is failing to meet demand, despite this
the use of living donor transplantation (LDT) is highly variable and
in many European states, in decline. Living donor transplantation
remains the most efficient, most durable and most economical method
of treating endstage renal failure. It provided the basis for the
majority of successful cadaveric transplant programmes in Western
Europe and for that reason is likely to be a corner stone of effective
renal replacement services in the developing Central and Eastern European
countries. The potential for growth in organ transplantation in Central
and Eastern European states is great and the need is pressing. With
limited dialysis facilities, increased annual transplantation rates
are likely to be the only means of avoiding excessive mortality and
morbidity. The newly formed independent territories in particular
would benefit greatly from the experience of Western jurisdictions
with respect of LDT. Sharing of data and experience would however
be mutually beneficial to all participants and the project would for
the first time generate reliable and comprehensive data for these
states. The project will help establish and develop databases covering
three key areas which would be accessible to all participants (1)
professional and community attitudes (surveyed by questionnaires and
interviews of clinical staff, patients and families) (2) Donor Health
Registry, containing long-term and short-term pre-operative and postoperative
morbidity data on living donors (3) Legisearch, a database of laws
governing transplantation in general and LDT in particular. Experience
with existing legal regimes would be of particular value to the many
Central and Eastern states contemplating legislation in this area.
The EUROTOLD project is an ideal vehicle for dissemination of information
and the sharing of experience. In addition expansion of the project
will permit a fuller evaluation of the ethics and practice of LDT
generally and the use of marginal donors in particular. It is anticipated
that this Central and Eastern European liaison will lead to the enhanced
use of LDT within these states, leading to higher transplant rates
overall. In countries with limited health care budgets and technological
support, LDT offers much hope for the future.
Start Date: 1995-04-01
End Date: 1997-06-30
Project Reference: CIPD940266
Title: Transplantation of nerve cells to the amygdala in a rat
model of Alzheimer's disease
Start Date: 1992-01-01
End Date: 1994-12-31
Project Reference: CI1*910921
Title: The use of ultraviolet light in clinical bone marrow
transplantation to modify graft-versus and host-versus-graft reactions
and to facilitate successful transplantation of non identical bone
marrow without immunodepressive drugs
Start Date: 1992-01-01
End Date: 1994-12-31
Project Reference: SC1*0722
Title: Development of safe procedures for transplantation of
mismatched bone marrow
Start Date: 1981-01-01
End Date: 1984-12-31
Project Reference: BI5*0357
Title: Suppression of transplantation response against h-2 compatible
grafts containing products of transferred genes
Start Date: 1994-03-01
End Date: 1996-02-29
Project Reference: CIPA930098
Title: Bone marrow transplantation a search for molecular matching
and cellular monitoring of donor and patient
Start Date: 1994-02-01
End Date: 1997-01-31
Project Reference: CIPA930199
Title: The effects of dietary fish oil on eicosanoid production
and renal function in cyclosporine A-treated renal allograft recipients
Start Date: 1991-10-01
End Date: 1993-12-31
Project Reference: SC1*0710
Title: Maintenance of the international bone marrow transplantation
registry and carry out of analysis connected with bone marrow transplantation
Start Date: 1982-07-01
End Date: 1984-12-31
Project Reference: BI5*0520
Title: Promoting of engraftment and preventionof gvh disease
following allogeneic bone marrow transplantation in rhesus m
Start Date: 1983-01-01
End Date: 1984-12-31
Project Reference: BI5*0535
Title: European Marrow Donor Information System
Objective: 1) To decrease the waiting time for the EC registered
patients also augmenting their expectancies of life, independently
of their origin countries, by means of networking Distributed Data
Bases 2) To define EC standards and adopt common ethical rules and
procedures to the access to the Network, also to avoid illegal traffic
in transplants.
Start Date: 1992-01-01
End Date: 1994-12-31
Project Reference: A2006
Title: Human bone marrow stem cell
Objective: In January 1990, at the beginning of the
Human Bone Marrow Stem Cell Concerted Action (CA), no laboratory in
Europe was planning to develop large scale purification methods for
isolating the hematopoietic stem cell for either cell or gene therapy.
In 1993, staff in various European laboratories have become acquainted,
and have interacted with each other. This has allowed us to organize
stem cells, to meet regularly and to compare various clinical devices
to purify stem cells, and to organize gene therapy or clinical groups
at a European level.
Start Date: 1990-01-01
End Date: 1993-06-30
Project Reference: MR4*0189
Title: Treatment of diabetes by islet cell transplantation
Objective: The long-term goal of this programme is
to cure diabetic patients by implantation of insulin-producing islet
cells.
Start Date: 1989-07-01
End Date: 1990-06-30
Project Reference: MR4*0194
Title: Treatment of diabetes by islet cell transplantation
Objective: The long-term goal of this programme is to cure
diabetic patients by implantation of insulin-producing islet cells.
Start Date: 1990-07-01
End Date: 1992-06-30
Project Reference: MR4*0277
Title: A Multicentre Effort Aimed at Improving Matching Criteria
in Bone Marrow and Renal Transplantation
Project Reference: BMH1921781
Title: Treatment of Diabetes by Islet Cell Transplantation
Project Reference: BMH10805
Title: European Network for Striatal Transplantation in Huntington's
Disease (NEST-HD): Preclinical Development and Clinical Trial Methodology
Project Reference: BMH11621
Title: Genetic Diversity of HLA in Europe: Impact on Transplantation
and Preventive Medicine
Project Reference: BMH11699
Title: European Multicentre Study of Transplantation of Organs
from Living Donors : the Ethical and Legal Dimensions
Project Reference: BMH11841
Title: Rapid techniques for graft assessment following bone
marrow transplantation designed for large scale use following acci-
dental lethal exposure to radiation
General information: Bone marrow transplantation (bmt) is now the
treatment of choice for many haematological disorders and it is also
the only method of treatment available for those accidentally exposed
to otherwise lethal doses of ionising radiations. this situation has
already occured following the recent russian reactor accident. Current
methods for monitoring engraftment are labour-intensive, expensive
and time-consuming, requiring either karyotypic analysis or analysis
of the genetic material using conventional polymorphic dna probes
and would seriously over titrate existing analytical facilities if
required for use on a large scale. Both procedures have the additional
disadvantage that they will permit the discrimination of host and
donor cells only at the level of 10 %.
The availability of a rapid, simple and reliable process which could
be easily used for the simultaneous assessment of multiple grafts
is therefore highly desirable. We have developed one such procedure,
based upon the use of y-chromosome-specific repetitive elements for
use in sex-mismatched transplantations and propose the further development
of a simple method, applicable to all transplant situations, which
will vastly increase the speed and efficiency with which engraftment
following bone marrow transplantation can be monitored by amplifying
in-vitro polymorphic loci which will permit the discrimination of
host and donor cells at efficiencies thousands of times greater than
those achievable by current analytical procedures.
While in principle any polymorphic loci would suffice, those containing
short, variable number tandem repeat sequences will be of most use
in view of their high degree of polymorphism. Loci with variable sequences
contained within restriction fragments of less than two kilobases
will be selected initially. Where necessary, genomic dna segments
will be sequenced and short oligonucleotide primers flanking the variable
regions will be synthesised. These will be used for the in-vitro amplification
of polymorphic loci in donors and recipients of bone marrow transplants
using thermostable dna polymerase. Amplified dna will be analysed
by conventional southern blotting (or by direct analysis in acrylamide
gels). Since in-vitro amplifications in excess of 100,000 fold are
now achievable, the assay, at its limits, should detect fewer than
one host cell in 10 to the power 6 donor cells (and vice versa). In
practice, this means that analyses will be performable on very small
quantities of material and with great speed.
Start Date: 1988-07-01
End Date: 1989-12-31
Project Reference: BI6*0309
Title: Transplant Euro Computer Network
Objective: The major objectives of TECN were to design and
implement an open information system for Organ Exchange Organisations
(OEO), Registries and Tissue Banks. TECN is a European development
which address the communications related problems of transplant facilities
and health administrations.
Start Date: 1992-01-01
End Date: 1993-12-01
Project Reference: E2006
Title: Esculape: use of computer techniques for tissues matching
and analysis as an aid to human transplantation
General Information: Early research has created a prototype software system with real possibilities
for use in the problems of transplant histocompatibility. Based on
this the project will seek to develop hla (human leucocyte antigens)
referencing computer systems and software packages which could become
the standard for human tissue typing. Because of its importance the
project will involve a wide variety of medical, health service and
research organisations. The definition phase will include checking
existing data against a prototype system and the evolution of a common
data structure.
Project Reference: SP036
Title: Donors for bone marrow transplantation: HLA a mismatched
related versus hla matched unrelated
Achievements: The safety and efficacy of bone marrow transplantation
using donors other than human leucocyte antigen (HLA) identical siblings
was investigated. The results of analyses conducted are preliminary.
Nonetheless a substantial proportion of leukemia patients were disease
free, alive and well following transplantation of HLA incompatible
bone marrow donated by family members.
Start Date: 1985-07-01
End Date: 1987-06-30
Project Reference: BI6*0084
Title: Bone marrow transplant bank interoperability
Objective: MARGRITE will link national bone marrow donor information
with the European databanks for patient information (EBMT) through
the use of telematics, ensuring interoperability and interconnectivity,
as recommended in the G7 Global Healthcare Applications project. It
will thereby help increase the number of donors and consequently the
number of potential beneficiaries. Work will be based on Internet
with data encrypted during transmission, and will adhere to the EU
regulations on data protection and confidentiality of patient records.
It is designed for use by national bone marrow databases, hospital
administrators, physicians specialising in bone marrow grafting, and
cancer specialists, and will function on team, national and European
levels. Additional benefits include the provision of continuously
updated medical records, and new access to Europe-wide population
data for improved analysis of results.
Project Reference: HC78970
|
|
|
|
