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Sub-themes: Infection and autoimmunity (Prof. J Schalkwijk), Immune regulation (Prof.
G. Adema), and Tissue engineering and pathology (Dr
A. van Kuppevelt).
The immune system has the dual task of eliminating pathogens and eradicating
incipient tumours, while preventing auto-reactive responses harmful to the host.
In maintaining this balance, there is a complex interplay between immune and
tissue cells and many stimulatory and inhibitory circuits operate simultaneously.
Outcomes are further shaped by genetic and environmental factors. Deregulation
of this intricate balance is associated with human diseases, ranging from inflammatory
and autoimmune disorders to cancer, infection and transplantation disorders.
In each case, prolonged deregulation can initiate a cascade of events ultimately
leading to tissue damage and destruction. Tissue engineering is a relatively
new field of research aimed at repairing or replacing damaged tissues by implanting ‘smart’ synthetic
bio-matrices or stem cells. Immune control is intrinsically involved both in
tissue acceptance and in preventing autoimmune attacks on engineered tissues.
A multi-disciplinary approach (molecule-mouse-patient) is taken to define the
molecular basis of immune regulatory circuits, events that trigger or fuel immune-related
disorders and infectious diseases, and tissue pathology & regeneration as well
as stem cell behaviour & differentiation.
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This sub-theme covers two important areas of biomedical research:
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Multifactorial chronic inflammatory diseases with a presumed autoimmune mechanism and a complex polygenic inheritance.
Examples include: rheumatoid arthritis, psoriasis, diabetes and SLE.
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Infectious diseases with complex disease mechanisms and/or a high societal burden.
Examples include: persistent fungal infections, virus/host interactions leading to carcinogenesis or chronic inflammation, and malaria.
The aim of this sub-theme is to develop a comprehensive education and research programme that produces excellent science and advanced technology in these two areas.
Traditionally, the etiology and pathogenesis of many of the above mentioned diseases has been studied from the perspective of adaptive immunity, and this has led to important advances both in understanding and diagnostics of these conditions, but not necessarily in improved treatment.
The past decade has witnessed a major shift of paradigm with regard to the earlier mentioned diseases.
This involved two important conceptual changes: firstly, the importance of the genetic background in the susceptibility to multifactorial conditions and infectious diseases, and secondly, the role of the innate immune system as an important first line of host defence and modulator of adaptive immunity.
This shift of paradigm will have a strong impact on the way that current and future research is focused.
Using genomics, transcriptomics or proteomics strategies, novel candidate disease genes (both in host and pathogen) have been identified and serve as a starting point for drug discovery, vaccine development and improved diagnostics.
The identification of primary cytokines, signalling pathways and effector molecules of the innate immune system as pivotal inflammatory mediators will have a strong impact on future therapies as already witnessed by the use of ‘biologicals’ in various inflammatory diseases.
In the area of multifactorial inflammatory diseases, the strategies for the near future will include, from a scientific point of view, the identification of disease mechanisms that encompass both the adaptive and innate immune system and the
identification of modifier genes and posttranslational modifications to explain tissue specificity of these conditions (joint, skin, pancreas, kidney).
In the area of infectious diseases, the focus will be on the role of the innate immune system in pathogen recognition and host defence (fungal and bacterial infections), on pathogen/host interactions (RNA-viruses) and vaccine development (malaria). The technologies
used in these areas will include sophisticated in vitro tissue culture models, transgenic and knockout models, gene delivery/knockdown in vitro and in vivo by adeno and lentiviral vector systems, and proteomic technology.
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This sub-theme covers basic immunological/haematological research and has three major biomedical application fields.
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Immune control by leukocytes, including dendritic cells and regulatory T-cells.
The sub-theme includes the molecular and functional analysis of these immune cells and aims at defining regulatory circuits effective in tolerance and immunity.
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Immunotherapy of Cancer.
Development and clinical application of vaccination strategies against solid and haematopoietic malignancies.
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Organ transplantation.
Development and clinical application of novel immune intervention approaches in kidney transplantation.
Traditionally, the immune system’s role in diseases like cancer and transplantation has been largely studied from the perspective of the disease. This
has led to important advances and detailed knowledge regarding the diagnostics and immune-pathology of
transplantation and cancer. The identification of tumour-associated antigens has boosted immunological
research in the cancer field. Strategies aiming at eradication of solid tumours by vaccination approaches,
or in case of haematological malignancies by donor lymphocyte infusion, have been developed. In the
last decade, genomics/proteomics efforts combined with fundamental immunological studies has uncovered
common immune regulatory mechanisms and two key players, dendritic cells and regulatory T-cells, which control
the immune balance. They affect both immunity against tumours and transplantation tolerance. The finding
that common regulatory pathways, molecules and regulatory cell types effectively determine the outcome of both
anti-cancer vaccines and transplantation has an impact on the way current and future research is focused.
Likewise, genes and proteins identified in normal and malignant haematopoietic differentiation further
boost fundamental studies and design of clinical treatment modalities for leukaemia.
Future research within this sub-theme will focus on fundamental studies
of dendritic cells, regulatory T-cells and other haematopoietic cells to define novel- and expand
existing regulatory circuits and differentiation routes. Broad genomic profiling approaches will gradually
be replaced by pathway oriented profiling approaches, like semi-quantitative, micro-fluidic based PCR technology
and sensitive proteomic profiling of purified protein complexes. Genes and proteins identified in these
cells will be analysed at the functional level in vitro and in vivo mouse models. Studies aiming at
elucidating the organisation and dynamics of individual proteins and protein complexes at the ultra-structural
level will continue and include advanced microscopical methodology (e.g. FRET, CLSM, NSOM).
In cancer vaccine development, focus will be on adenovirus mediated gene-therapy and DC. In the area of DC-based cancer vaccines, studies in mouse tumour models as well
as clinical trials will focus on i) in situ tumour antigen loading of DC and maturation of DC by toll
like receptor ligands and ii) combining vaccination with other immune modulating approaches, including
the elimination of the immune-suppressive effects of regulatory T-cells. Induction of T regulatory
cells will be a major focus in the context of organ transplantation.
We envisage that in this stimulating scientific environment pivotal knowledge regarding
the role of DC and regulatory T-cells in immune regulation will also find their way to the sub-themes within
theme 1, ‘Inflammation and infection’ and ‘Tissue engineering and Pathology’. In turn, knowledge developed
in these sub-themes as well as in the other themes within the NCMLS will be highly beneficial for the
further development of the sub-theme immune regulation and contribute to the rational design of novel immune-therapeutic
treatment modalities in cancer and transplantation.
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This sub-theme covers a holistic approach to tissue engineering that includes:
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The construction of molecularly-defined scaffolds;
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The application of cells, notably stem cells;
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The patho-histological, physiological and molecular analysis of (engineered) tissues.
The challenge of every biomedical researcher is to understand the basic phenomena of disease, and to use this knowledge for treatment. In some cases,
a disease has progressed in such a way that the only option for treatment is to regenerate/replace the affected organ. This is the point where pathology
and tissue engineering meet. Tissue engineering aims at no less than to create new tissues and organs.
Its basis is the steadily increasing need for the replacement of lost or malfunctioning tissues and
organs, and the limited availability of donor transplants.
The costs associated with the treatment of patients with organ or tissue failure are high and account
for approximately 50% of the total health-care budget.
Hence, tissue engineering is expected to become a multi-billion market.
Tissue engineering is a multidisciplinary field of science combining concepts and methodologies
from a number of different scientific fields. In particular, tissue pathology provides information
regarding the integrity and complex cellular/molecular interactions within tissues. In addition, cell biology,
biochemistry, histology, immunology, molecular biology and material science are instrumental for tissue-engineering.
Obviously, clinical sciences like surgery are equally important. It is therefore the ultimate aim of
this sub-theme to combine fundamental (molecular-driven) and applied (medical-driven) research in such a
way that tissue-engineered constructs can be rationally designed, fabricated, and analysed in vitro, in
animal models, and ultimately in patients. Within the NCMLS focus is on a selected number of tissues,
viz. cartilage, bone, skin, kidney and blood vessels.
Tissues and organs are composed of cells surrounded by extracellular matrices. As much as cells signal
to their surroundings, the surroundings give signals to cells. In this sub-theme both entities will be
addressed. Stem cells and more differentiated, organ-specific, cells (e.g. chondroblasts, keratinocytes, podocytes)
will be probed for their capacity to form new tissue and organs. In parallel, smart organ-specific biomatrices
will be constructed in such a way that they will provide appropriate signals to the cells to proliferate,
migrate of differentiate. Focus will be on ceramics, calcium phosphates, collagens, glycosaminoglycans
and effector molecules like growth factors and cytokines.
In order to rationalise the choice of cells as well as the biomatrices, an in depth understanding of
the signal pathways that have to be (de)activated in order to direct a cell into the desired phenotype
is necessary.
The subtheme brings together both a number of fundamental groups with clear biomedical
focus (e.g. Depts. Biomaterials, Biochemistry, Tumor Immunology) , and a number of medical groups with
a clear fundamental focus (e.g. Departments of Pathology, Nephrology and Rheumatology and Dermatology). Use
is made of the extensive (knowledge) infrastructure of the NCMLS, including modern technological facilities
like the DNA microarray core facility, the microscopy image centre, and the central animal facility. The
holistic approach of the theme may appeal to international students, which will be trained to study complex
features using a variety of experimental approaches. |
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Contact
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Postal address:
259 NCMLS
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Visiting address:
Geert Grooteplein 28
6525 GA Nijmegen
T: +31 (0)24 361 07 07
F: +31 (0)24 361 09 09
E: Info@ncmls.ru.nl
I: www.ncmls.eu
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