Sanquin Research Program Grant

Molecular and Cellular Haematology Research Program Sanquin Blood Supply
Towards rational improvements in transfusion medicine, adoptive cellular therapy and the treatment of clotting disorders. (LSBR 2013-0628)

Project leader: Prof. Dr. René A.W. van Lier, scientific director Sanquin Research, Amsterdam

Overall aim and key objectives of the program
Covering the complete spectrum of blood and blood transfusion research, Sanquin aims to perform original science on not only basic and clinical but also applied topics. As a consequence our research departments deal with a complementary range of subjects including fundamental biology and biochemistry of mature blood cells and plasma proteins, hematopoiesis, immunohematology, coagulation, immunopathology, blood-borne infections, blood transfusion technology, transfusion monitoring, transfusion medicine, and donor studies.
The program grant consisted of 5 novel fundamental projects that form a coherent program. First, they all dealt with the core of Sanquin research, i.e. the improvement of the properties of cells and plasma proteins for the treatment of patients. Second, they were aimed on including novel technologies into our research activities. This innovation was not only necessary to improve our products but is also essential to maintain Sanquin’s position as a leading research institute in the field of transfusion medicine, cell biology, immunology and hemostasis. Next to these 5 fundamental projects, the 6th project dealt with the translational activities of the stem cell laboratory and was a necessary extension of the work that was started in the previous LSBR program grant.
The highlights of the different work projects are briefly summarized below:

1 – It takes two to tango: the endothelium as scaffold and gatekeeper in blood cell transfusion.
J. van Buul Biologist
Our work in project 1 showed the importance and the potential of the vasculature to act as a therapeutic target to intervene in inflammation-based diseases including translation-related pathophysiological events such as TRALI (transfusion-related acute lung injury) and TACO (transfusion-related circulatory overload). By understanding in more detail the specific dependency of cellular responses and the consequent contributions of the vasculature for these processes, we can start to develop dedicated and personalised medicine to overcome inflammation-based diseases.

2 – Humoral immune responses against non-infectious antigens.
M. van Ham Biologist, E. van der Schoot MD/Immunohematologist, L. Aarden Biochemist
We have generated a pipeline to isolate and characterise alloantibodies against non-infectious agents (project 2).
Using this novel technological and bioinformatic platforms we have demonstrated that these antibodies exhibit unique Fc and Fab glycosylation patterns, which determines their pathogenicity. We are presently translating these findings into predictive diagnostic tests. In future this knowledge is important for prevention and intervention of the alloimmune response to blood cells.

3 – Dissecting the molecular architecture and dynamics of haemostatic networks by functional proteomics (‘HEMO-INTERACTOMICS’).
J. Voorberg Biochemist, A.B. Meijer Biochemist, K. Mertens Biochemist
In project 3, functional proteomics have been successfully employed to study the molecular architecture of enzymecofactor complexes. In addition, interactions of hemostatic proteins with cell surface receptors have been defined at the molecular level using mass spectrometry-based approaches generating novel insight into the clearance, immunogenicity and signalling properties of blood coagulation factors within the hemostatic system.

4 – Influence of cells on HSC function upon transplantation.
M. Nolte Biologist
Focussing on the interaction between the immune system and the blood-forming system, we have in project 8.4, studied the cellular and molecular mechanism by which T cells can regulate the function of HSCs in the bone marrow. Unravelling how T cells enter the bone marrow and subsequently influence HSCs and their supportive niches, both in the steady state and upon inflammation, provided valuable insight for the field of HSC transplantation, but also
contributed to our understanding of why chronic inflammation impairs bone marrow output and induces anaemia.

5 – Regulation of cell effector functions.
R. van Lier MD/Immunologist, M. Wolkers Medical Biologist
Unraveling the role of transcription factors and of post-transcriptional events to govern T cell effector function provided novel mechanistic insights in T cell biology. The outcomes have proven instrumental to design our current research lines that are aimed at improving the quality of T cell products for clinical purposes.

6 – Production of cellular therapies in the Stem Cell Laboratory of Sanquin Research
C. Voermans Medical Biologist
The last project of the LSBR program grant enabled the implementation and validation of the production of two ATMPs for clinical trials and subsequent GMP licensing by the competent authority. This valuable output paves the way for the exploration and development of future therapeutic cellular products within the laboratory for cellular therapies.

The funding of this program by LSBR has strongly strengthened collaborative research within Sanquin. In part this is because we have had the ability to invest in technology platforms (imaging, proteomics) that allowed (and allow) us to perform state of the art research. Researchers of the molecular and cellular research program share common interests and knowledge of the physiological role of cells and proteins and have the ambition to employ this for the continuous improvement of transfusion practices.