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Theme 1: Immunity, Infection and Information

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. Regenerative Medicine 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.

RIMLS research connected to the theme "Infection, Immunity and Regenerative Medicine/ Immunity-related Disorders and Immunotherapy" involves:

  • Inflammatory diseases, some of which may have an autoinflammatory or autoimmune mechanism

The aim is to identify disease mechanisms that encompass both the innate and adaptive immune system and the identification of modifier genes and posttranslational modifications, including autoantigens, to explain tissue specificity of these conditions such as rheumatoid arthritis, systemic sclerosis, gouty arthritis, psoriatic arthritis, psoriasis, diabetes, systemic lupus erythematosus and hyper IgD syndrome.

  • Infectious diseases with a high societal burden

The focus lies on the role of the innate immune system in pathogen recognition and host defence (fungal, bacterial and viral infections), on pathogen-host interactions (e.g., immune evasion mechanisms of pathogens), vector biology (e.g. interaction malaria and Dengue virus with mosquitos), anti-microbial drugs and development of drug-resistance (e.g. invasive aspergillosis), vaccine development (e.g. malaria, Strepto-coccus pneumoniae, Haemophilus influenzae,Moraxella catarrhalis), and the role of pathogens in the development of (chronic) inflammatory diseases (e.g. role enteroviruses in type 1 diabetes development).

  • Immunological and haematological research in three major biomedical fields:

1) Molecular and functional analysis of normal and malignant blood cell development and immune control. Including analysis of dendritic cells, regulatory T-cells and natural killer cells and aims at defining regulatory circuits effective in tolerance and immunity.
2) Immunotherapy of cancer. Development and clinical application of vaccination and imaging strategies for solid and haematopoietic malignancies and their microenvironment.
3) Organ transplantation. Development and clinical application of novel immune monitoring and intervention approaches in kidney transplantation.

Research focuses on fundamental studies on dendritic cells (DC), regulatory T-cells, NK cells and other haematopoietic stem cells to expand existing and define novel regulatory circuits and differentiation routes. Understanding and imaging the microenvironment of hematopoietic and solid malignancies as well as in transplantation is an essential component in developing personalized medical treatments for patients.

In the area of DC-targeted cancer vaccines, studies in mouse tumour models as well as clinical trials will focus on i)in situtumour antigen loading of DC and maturation of DC by pattern recognition receptor ligands and ii) combining vaccination with other immune modulating and targeted therapy approaches, including the elimination of the immune-suppressive effects of myeloid suppressor cells and regulatory T-cells and their molecular pathways. Induction, modulation and assessment of regulatory immune cells will be a major focus in the context of organ transplantation.

Ultimately knowledge gained regarding the immune regulatory roles of DC subsets, regulatory T-cells, and NK cells will contribute to our understanding of tissue microenvironment and the rational design of novel, personalized immune-therapeutic treatment modalities in cancer and transplantation.

  • Regenerative medicine

Regenerative medicine is a multidisciplinary field of science combining concepts and methodologies from a number of different scientific fields. Obviously, clinical sciences like surgery are important, and in the year 2010, the subtheme was greatly reinforced by the incorporation of dedicated surgeons. In the subtheme tissue-engineered constructs, based on extracellular matrix molecules, polymers and effector molecules (e.g. growth factors), are designed and fabricated, and analysedin vitroandin vivo.Smart organ-specific bioscaffolds are prepared in such a way that they provide appropriate signals to the cells to proliferate, migrate of differentiate. Focus is on ceramics, calcium phosphates, collagens, glycosaminoglycans and effector molecules like growth factors and cytokines. Emphasis is on a selected number of tissues, viz. cartilage/bone, skin, kidney and blood vessels and urogenital organs.

  • Microenvironment in health and disease

The microenvironment consists of a large number of (structural) biomolecules. In the subtheme focus is on collagens, glycosaminoglycans, matrix metalloproteinases and a number of effector molecules (BMPs, TGF beta). The role of these components in cancers, nephropathies and degenerative cartilage diseases is studiedin vitroas well asin vivo. Strategies to restore homeostasis in deranged and disease-associated microenvironments are pursued, including the use of glycomimetics.