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Studies on the differentiation of inflammatory and regulatory T-cells

Jeffery, Louisa Elizabeth (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve T\(_R\)\(_e\)\(_g\) and T\(_h\)17 dysregulation. Thus, understanding how vitamin D modifies CD4\(^+\) T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH)\(_2\)D\(_3\), the active form of vitamin D, upon human CD4\(^+\) T-cell differentiation. 1,25(OH)\(_2\)D\(_3\), acted directly upon human CD4\(^+\) T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFN\(_y\) and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH)\(_2\)D\(_3\)-treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH)\(_2\)D\(_3\)reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH)\(_2\)D\(_3\)modified immunity. Furthermore, pro-regulatory effects of 1,25(OH)\(_2\)D\(_3\)were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH)\(_2\)D\(_3\) was observed, supporting ability of 1,25(OH)\(_2\)D\(_3\)to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D\(_3\)to drive 1,25(OH)\(_2\)D\(_3\)-modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH)\(_2\)D\(_3\)in serum. Whether dysregulation of the T\(_R\)\(_e\)\(_g\)/T17 balance or response to 1,25(OH)\(_2\)D\(_3\) was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH)\(_2\)D\(_3\) were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH)\(_2\)D\(_3\)might be useful in the treatment of synovitis.

Type of Work:Ph.D. thesis.
Supervisor(s):Sansom, David and Raza, Karim
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of immunity and infection
Subjects:RC Internal medicine
RA Public aspects of medicine
Institution:University of Birmingham
ID Code:1551
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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