Immune deficiency and aging

Research agenda

Lines of research

I General and specific antibody preparations.
IVIg are antibodies that are purified from the plasma of a large pool of donors, used to protect patients who lack the right antibodies themselves. In this research line, Sanquin investigators focus on the question of how these antibodies can best be administered and how they act in the patients. It is clear that the immunity of patients who do not have the right antibodies themselves recovers as a result of antibody therapy. However, IVIg is also administered to patients with certain auto-immune diseases. In these cases it is often not clear why giving IVIg contributes to recovery from the disease. More insight into the relationship between the structure and function of the purified antibodies is required. It is also important to unravel how specific B cells differentiate, and how the formation of antibodies with specific structure-function relationships (sub-classes and specific glycosylation) are regulated. An insight into these questions will contribute to the possibility of producing specific antibodies that have an optimum therapeutic effect in different auto-immune diseases.
In addition to IVIg, Sanquin also produces antibody preparations that are enriched with specific antibodies, for instance against Rhesus D, tetanus, Hepatitis A and Varicella Zoster viruses. The Rhesus D antibodies are administered to pregnant Rhesus D-negative women in order to prevent them from producing harmful antibodies against a Rhesus D-positive child during the pregnancy. The other antibodies are administered to prevent specific infections in people at risk of these infections, and who have no or insufficient antibodies against the specific pathogens. The specific antibody preparations are made by Sanquin from the plasma of voluntary donors who are specifically immunised to make these antibodies. Sanquin carries out considerable research into the question of how antibody formation is regulated in humans. More insight is necessary to make an immunisation scheme required for each antibody, to lead to the formation of high-affinity antigen-specific antibodies, also in donors who have not encountered the specific antibody before. How short-lived and long-lived plasma cells contribute to the antibody response after re-immunisation is also a major question, as is the question of whether antibodies of short-lived plasma cells are possibly less effective (less high affinity, differently glycosylated) than those of long-lived plasma cells.

II Complement disorders

The complement system is a collection of proteins in plasma that plays a significant role in the initial immune reaction against intruders in the blood. Activation of the complement system can give rise to a severe inflammatory reaction, and the complement system is therefore strictly regulated by proteins such as Factor H and C1 esterase inhibitor. Deficiencies in complement proteins can be congenital (genetic mutations) or acquired as a result of excessive consumption in diseases with strong complement activation. Complement deficiencies are associated with an increased chance of infections or the development of auto-immune diseases, depending on which complement protein is missing. In collaboration with Sanquin Diagnostics Services, Sanquin Research investigates the balance between complement activation and regulation. Amongst other aspects, the research is focused on the function of complement regulation protein Factor H (FH). It is also investigated whether plasma-purified FH could be a therapeutic option for the treatment of complement mediated disorders such as atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH). Sanquin also investigates the possible therapeutic application of a monoclonal antibody that intensifies the function of FH on the body’s own cells.

For many years, Sanquin has produced C1 esterase inhibitor for the treatment of Hereditary Angio-oedema (HAE), a disease that is characterised by oedema as a result of C1 esterase inhibitor deficiency. Much research is carried out into the exact action of C1 esterase inhibitor and into the question of whether C1 esterase inhibitor can also be used effectively in other (inflammatory) disorders, such as in patients showing undesired immunity against red blood cells (autoimmune hemolytic anemia).

III Stem cell transplantation
Allogenic hematopoietic stem cell transplantation (HSCT) is one of the most effective ways to fight certain tumors. The normal cells of the immune system of the patient are also eliminated after eradication of the hematological malignancy by means of chemotherapy and/or radiotherapy. After HSCT, the donor cells will make new immune cells and restore the patient’s immune system. These cells can also produce an immune reaction against possible remaining cancer cells. This is called the Graft-versus-leukemia (GvL) effect. The success of this therapy is limited by the development of immune reactions of the donor cells against other cells of the patient (including skin, intestines). This is called the Graft-versus-host-disease (GvHD). This research line is focused on understanding why some patients show a better balance between GvL and GvHD than others. The answer to this question can lead to strategies to induce GvL in each patent, whilst GvHD is prevented.

IV The less active immune system in aging and disease

Sanquin carries out a considerable number of research projects on the question of why immune reactions are suboptimal during illnesses, and into the role of aging in these processes.
Immune molecules are depleted during some disease processes. If the disease persists it can cause the patient to become deficient in such immune molecules. Sanquin investigates whether this depletion of immune molecules can be prevented, and whether these immune molecules can be given as therapy.

As one becomes older, it seems that some immune cells are formed less efficiently, and some undesired immune cells seem to accumulate. Sanquin investigates how these processes occur and whether these are general phenomena, or that certain people show these phenomena more or less as a result of specific pathogens encountered during one’s life. Or as a result of specific genetic predisposition. Answers to these questions may provide an insight into ways to increase the immunity with specific vaccins, or by other therapies that can modulate the action of the immune system.

National Science Agenda cluster questions

The NSA cluster questions shown below are linked to Sanquin’s research lines for the medical need Immune deficiency:
I. Improving diagnostics and therapy of congenital and acquired immune deficiencies.
II. Drafting new guidelines for the hyperimmunisation of voluntary donors, and optimising donor selection for hyperimmunisation to obtain effective and safe specific antibodies.
III. Improvement of the efficacy and the reduction of undesired immunity by stem cell transplantations
IV. Improving the efficacy of the immunity of elderly persons

34 In light of the changing population (aging, shrinking in some places and affected by migration), what is the sustainability of the welfare state? IV
76 What are the consequences of chronic disorders, stress and handicaps, and how can humans handle these as well as possible? I, II, III, IV
77 What is the contribution of non-genetic factors to personal characteristics and disease processes? I, II, III, IV
80 Can we understand the factors better that play a role in the development and maintenance of incomprehensible protracted physical disorders and therefore treat these disorders better I, II, III, IV
81 How will the knowledge of genetics play a role in the understanding of, screening for and treatment of (rare) illnesses? I, II, IV
91 Pregnancy, giving birth to a child and the menopause: can we improve these?    II
95 How can healthcare be focused on the uniqueness of a person, amongst other things by making use of biomarkers? I, II, III, IV
98 How can we convert breakthroughs in basic biomedical research better into the development of new drugs? I, II, III, IV
99 Using a better understanding of life, how can we identify new targets for molecular therapy, antibiotics and antiviral drugs? I, II, III, IV
100 Using (stem) cells and biomaterials, how can we promote the formation and recovery of tissues and organs? III
101 Can we develop models of the human body and use smart technology for health, food and toxicities research while simultaneously reducing the use of experimental animals drastically? II, IV
102 How can we develop new medicines and therapies in order to remain as vigorous and healthy as possible? I, II, III
104 How do we develop minimally invasive techniques and interventions for the diagnosis, prognosis and treatment of patients? I, II, III, IV
105 How can big data and technological innovation (e-health) contribute to healthcare? I, II, III, IV
112 Big data: can we utilise big datasets and their gathering for the realisation of values, gaining insights and obtaining answers? I, II, III, IV
135 How can we understand the properties, the functionalities and the interaction of molecules in living systems better and, for instance, in this way develop systems that are inspired by life? I, II, III, IV
136 Cells are the building blocks of life. How do they work and what can they teach us about the processes of life? I, II, III, IV