Vascular diseases and Inflammation

Problems and questions from clinic and practice

Inflammations play an important role in clearing invading micro-organisms or damaged tissue. Inflammations are characterised by pain, local redness and an increase in temperature as a result of vasodilation, and by swelling as a result of oedema formation. An inflammatory reaction is a interaction of proteins with cells in the blood and cells of the vessel wall, the endothelial cells. These endothelial cells are activated as a result of the local inflammation mediators, causing the cells to become more permeable for plasma proteins, and thereby giving the leukocytes the opportunity to leave the blood stream at that position. This process leads in most cases to an effective removal of the micro-organism, and recovery of the damaged tissue that was the cause of the inflammation. However, inflammation reactions are not always benign, but can also cause damage to the tissues. Damaged and dead cells, derived as a result of the initial inflammation, can exacerbate the inflammation reaction as a result of the released histones and/or DNA for instance, resulting in a vicious circle. The inflammation can also become chronic when the infection cannot be completely cleared, and this can lead to organ damage.

With many diseases, such as sepsis, vasculitis, GvHD and TRALI, the negative effect of the inflammation reaction seems to dominate and provide a significant contribution to the morbidity and mortality of the disease. It is therefore of utmost importance to understand the exact role of the various inflammation mediators in such diseases, in order to be able to intervene specifically in the inflammation process. The question is how complex interactions of proteins (for instance complement, cytokines, acute phase proteins, histones) and leukocytes (for instance neutrophiles, monocytes, T and B cells) with the endothelial cells of the vessel wall are regulated. A complicating factor is the fact that inflammatory reactions in all organs and tissues do not follow the same path, and this contributes to organ-specific complications of certain diseases. A better understanding of the underlying mechanisms would enable us to intervene in a specific manner in various diseases, where inflammation plays an important role in the disease process.

Inflammation can also occur specifically in the vessel wall, better known as vasculitis. Every blood vessel can be affected. This can lead to serious leakage and oedema formation, as well as uncontrolled loss of leukocytes and, eventually, the development of atherosclerosis as well. This can be induced by certain viruses, especially hepatitis viruses. Certain infections and reactions to some drugs and vaccines also seem able to cause this disorder. The infection presumably develops when the immune system regards the blood vessels or parts of the blood vessels as foreign tissue, and attacks them. Cells of the immune system that cause the inflammation surround and infiltrate the affected blood vessels and destroy them. Vasculitis can be limited to the veins, large arteries, small arteries or capillaries, or it can be limited to the blood vessels in a certain part of the body, such as the head, a leg or a kidney. Disorders like the Henoch-Schönlein syndrome, erythema nodosum, polyarteritis nodosa, arteriitis temporalis (reuscelarteriitis) and Takayasu’s arteriitis, are characterised by vasculitis that is limited to the blood vessels of a certain size or position. The direct treatment and improvement of the quality of the blood vessels and thereby limiting bleeding and white blood cell infiltration, is an attractive therapy that can provide better health for the particular organs, and eventually total well-being. In this way it is also possible to diminish the possibility of developing atherosclerosis. In terms of bleeding, this medical need will therefore also collaborate closely with the medical need Bleeding & hemostasis.
    
Additionally, one of the complications of blood transfusions in intensive care patients is the acute reaction of the pulmonary vessels. In this situation, the blood vessels of the lungs are affected seriously, as shown by increase of oedema formation in the lungs, and the presence of a very high white blood cell count in the lungs. In some cases this may even cause death. It is not yet well known how the lungs eventually become so damaged.

The last point of attention is the quality of the blood vessels during aging. The blood vessels last a whole lifetime and are essential for the transport of nutritional supplements such as oxygen to all organs. However, aging has a substantial impact on the quality of our blood vessels, and hence on the transport system of our body. The quality of the blood vessels deteriorates especially as a result of the changing composition of the underlying tissue. This causes a dormant inflammation of the blood vessels that manifests itself under certain conditions as substantial vascular inflammation. Making the blood vessels healthy and especially keeping them healthy during the aging process is something that concerns us all, and is therefore one of the spearheads of this medical need, so we will collaborate with the medical need Immune deficiency and aging.

Solutions: Sanquin products and services

It is our objective to develop new (diagnostic) tests to determine the inflammatory mediators in patient material (biopsies/plasma). These tests can be used to identify new bio-markers. These can lead to better monitoring of the disease in patients, possibly having a predictive value, and can be a way to follow response to therapy.
We will study the inside of a blood vessel, regarding its behaviour after contact with the risk factors as described above. We can focus more directly on therapeutic starting points on the wall of the blood vessel, by improving the mutual attachment of the endothelium and thereby being able to influence the permeability and bleeding. This also includes improving the quality of the blood vessel, as well as the reaction of the endothelium to the aforementioned factors with respect to inflammations.

Research is also carried out at various levels into organ-specific migration processes that allow leukocytes to enter and/or leave a certain organ. Modulation of leukocyte migration could be a very attractive method for influencing disease processes.
Research into plasma proteins such as pGelsolin, complement inhibitor Factor H and C1 esterase inhibitor are tested as a possible therapeutic application in inflammatory diseases. IVIg, already produced by Sanquin for many years, is used not only as subsitution therapy in patients who make no or hardly any antibodies, but is also used in various inflammatory diseases (such as ITP, Kawasaki disease and Guillain Barre syndrome) to inhibit the symptoms of inflammation. The investigations into IVIg are carried out in collaboration with the medical need Immune deficiency and aging. There is also a focus on the identification of new plasma proteins with possible therapeutic applications.
Within this medical need, we concentrate on organ and tissue specific blood vessels, so as to be able to administer future treatments as accurately as possible. And we concentrate on the possible application to culture the body’s own endothelial cells for possible therapeutic applications. This is based on the BOEC (blood-outgrowth-endothelial-cells) isolation and culture methods.

Coordinators

Martijn Nolte PhD
Prof Jaap van Buul PhD
Ilse Jongerius PhD

Research groups

Antigen specific B cell responses (Prof Marieke van Ham PhD)
Blood Cell Research (Product and Process Development, Blood Bank) (Dirk de Korte PhD)
Blood-borne Infections (Prof Hans Zaaijer MD PhD)
Cell adhesion and migration (Coert Margadant PhD)
Cellular Hemostasis (Prof Jan Voorberg PhD)
Complement Research (Ilse Jongerius PhD)
Inflammation  (Prof Sacha Zeerleder MD PhD)
Laboratory for Cell Therapy (Carlijn Voermans PhD)
Methodology of etiologic clinical transfusion research (Rutger Middelburg PhD)
Molecular Cell Biology Lab (Jaap van Buul PhD)
Phagocyte Laboratory (Prof Timo van den Berg PhD, Prof Taco Kuijpers MD PhD)
Plasma Proteins & Research Facilities (Maartje van den Biggelaar PhD)
Red Cell Laboratory (Robin van Bruggen PhD)
Structure & function of antibodies (Theo Rispens PhD)
Transfusion support in cancer therapies (Prof Jaap Jan Zwaginga MD PhD)
Transfusion Technology Assessment (Mart Janssen PhD)