Ph.D. Student, Autoantibody formation in patients with TTP, Sanquin Research, Amsterdam
Ph.D. Student, Research department of Plasma Proteins, Amsterdam Plesmanlaan, 36 hours
The Research Group:
The research program of the Department of Plasma Proteins focuses on the biology and function of blood coagulation factors that include Von Willebrand factor (VWF) and ADAMTS13. A multidisciplinary approach involving cell biological and immunological approaches is used within the different lines of research. Recently, MHC class II tetramer technology has established in our department in order to characterize CD4+ T cell responses to blood coagulation factors in patients with bleeding or thrombotic disorders.
Project:
Thrombotic thrombocytopenic purpura (TTP) is a microvascular occlusive disorder that is characterized by systemic aggregation of platelets in the brain, kidney and other organs. Systemic clumping of platelets is due to a deficiency of the VWF cleaving protease ADAMTS13 which results in accumulation of platelet-reactive ultra-large VWF multimers in the circulation of patients with TTP. In the majority of patients with TTP antibodies directed towards ADAMTS13 develop. Over the past few years we have shown that B cell responses are directed towards a single domain on ADAMTS13 that is crucial for its interaction with VWF. At present we do not know why antibodies directed towards ADAMTS13 develop in apparently healthy individuals. The triggering
events may comprise a foreign antigen such as a pathogen expressing a T cell epitope resembling ADAMTS13 (molecular mimicry). Presently ADAMTS13 specific CD4+ T cell responses in patients with acquired TTP have not been defined. MHC class II tetramers will be used to analyse CD4+ T cell responses at the clonal level in patients with acquired TTP. The data evolving from these studies may provide a basis for further improvement of therapeutic approaches for this thrombotic disorder which will involve generation and administration of tolerogenic antigen presenting cells or alternatively promote the formation of regulatory T cells by targeting immunodominant T cell epitopes to APC's in vivo.
Additional information:
Luken BM, Turenhout EA, Hulstein JJ, van Mourik JA, Fijnheer R, Voorberg J (2005) The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. Thromb. Haemost. 93, 267-274.
Luken BM, Kaijen PH, Turenhout EA, Kremer-Hovinga JA, van Mourik JA, Fijnheer R, Voorbegr J (2006) Multiple B-cell clones producing antibodies directed to the spacer and disintegrin/ thrombospondin type-1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 4(11):2355-64.
Requested:
* university graduate;
* ample intellectual and experimental skills;
* a highly motivated candidate with expertise in cell biology and/or immunology.
Offered:
* a temporary position as a Ph.D student for 4 years in a challenging research environment;
* salary and conditions are conform CAO Sanquin.
Further information:
For further information please contact mr. dr. J.J. Voorberg, tel.
020-5123151 or by e-mail j.voorberg@sanquin. nl.
Your written application, accompanied with Curriculum Vitae, can be addressed to the department Human Resource Management, attentions to Ms T.M.E. Verduijn, PO Box 9190, 1006 AD Amsterdam or by e-mail werk@sanquin. nl, under indication of job opening number TV 09-08. U kunt ook solliciteren via het sollicitatieformuli er (in Dutch)
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