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Title: Functional consequences of TGFB1 polymorphims and their role in haematopoietic stem cell transplantation
Author: Arrieta Bolanos, E. R.
ISNI:       0000 0004 5358 4986
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Haematopoietic stem cell transplantation (HSCT) is used to treat malignant and non-malignant diseases. Apart from clinical and human leukocyte antigen (HLA)-related factors, non-HLA Immunogenetics is increasingly recognized to play a role in the outcome of HSCT. A gene that may be relevant for the outcome of HSCT is TGFB1, which encodes transforming growth factor β-1 (TGF-β1), a cytokine that is central in the regulation of numerous immune processes. In order to understand the role of TGFB1 polymorphism in HSCT, I studied the effect of this variation in the production of this cytokine by regulatory T cells (Treg) and also in the outcome of a cohort of HSCT patients and donors. This study has found evidence of differential surface expression of TGF-β1 by activated Treg bearing TGFB1 +29C as compared with those lacking this variant. Also, the analysis of a cohort of HSCT patients and donors revealed that patients carrying TGFB1 allele p001 had reduced overall survival and increased non-relapse mortality. Interesting additional discoveries include the lack of induction of TGFB1 messenger ribonucleic acid upon T cell receptor-mediated activation in Treg, the presence of preformed intracellular latent TGF-β1 both in Treg and effector cluster of differentiation (CD)4+CD25- cells, and the kinetics of transient surface latent TGF-β1 expression on Treg in the context of an in vitro suppression assay. The typing of TGFB1 alleles in more than 1000 unrelated samples gives the first large-scale glimpse of the diversity of TGFB1 polymorphism in the population. Likewise, this study discovered the presence of novel polymorphic positions and novel alleles of the human TGFB1 gene, adding to the current knowledge on the diversity associated with it. Additional contributions are also the design of a novel TGFB1 regulatory region and exon 1 sequencing-based typing strategy and the generation of an informatics tool for the easy assignment of allelic genotypes for this ~3000 base region based on the individual variant genotypes at 18 polymorphic positions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available