In vivo modelling of normal and pathological human T-cell development

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In vivo modelling of normal and pathological human T-cell development

Type: Doctoral Thesis
Title: In vivo modelling of normal and pathological human T-cell development
Author: Wiekmeijer, A.S.
Issue Date: 2016-09-08
Keywords: T-cell development
Human
NSG mouse
SCID
T-ALL
Abstract: This thesis describes novel insights in human T-cell development by transplanting human HSPCs in severe immunodeficient NSG mice. First, an in vivo model was optimized to allow engraftment of hematopoietic stem cells derived from human bone marrow. This model was used to study aberrant human T-cell development in severe combined immunodeficiency (SCID) and leukemia. For SCID with known mutations as well as with atypical clinical presentation, stages of developmental arrest were determined. Using cellular barcoding, severe restriction of hematopoietic clonality during T-cell development was observed but the limited number of clones still makes up a very diverse polyclonal T-cell receptor repertoire. The restriction points coincided with arrests in development for SCID. In addition, new mechanisms whereby LMO2 causes aberrant human T-cell development, which eventually could lead to leukemia, were identified. The provided model can further aid in both fundamental studies, optimization of gene therapy approaches and stem cell expansion. Furthermore, it illustrates the need for more in depth understanding of human T-cell development, which could help improvement of T-cell reconstitution after transplantation and might aid in the diagnosis and future treatment of patients with T-ALL. Overall, the xenograft model has proven useful to advance our understanding of human T-cell development.
Promotor: Supervisor: F.J.T. Staal Co-Supervisor: K. Pike-Overzet
Faculty: Faculty of Medicine, Leiden University Medical Center (LUMC)
University: Leiden
Uri: urn:isbn:9789402802542
Handle: http://hdl.handle.net/1887/42846
 

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