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Title: Immunomodulatory actions of 1,25-dihydroxyvitamin D3 and its analogs: focus on T lymphocytes
Other Titles: Immuunmodulerende werking van 1,25-dihydroxyvitamine D3 en analogen: focus op T lymfocyten
Authors: Baeke, Femke; M9927386
Issue Date: 5-Jul-2011
Abstract: The bioactive form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and its synthetic analogs are known as immunomodulators, which are able to prevent the development of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Up to now, the disease-modifying actions of these compounds were believed to rely on their ability to modulate dendritic cell function, thereby indirectly shifting T cell responses from an immunogenic towards a tolerogenic profile. Importantly, receptors for vitamin D (VDR) are also expressed by T lymphocytes. However, when we initiated this work, effects involving direct T cell modulation were controversial and poorly characterized. Therefore, we focused in this work on the potential role of T cells as direct targets of 1,25(OH)2D3 and potent analogs. The data obtained in Chapter 4 clearly unveil human T cells as direct targets for 1,25(OH)2D3 in the immune system. T cell activation, triggered by distinct activation stimuli, strongly elevated the expression of genes related to vitamin D metabolism, including VDR and the vitamin D-activating enzyme 1-α-hydroxylase. In accordance, pre-activated T cells that feature maximal VDR expression levels exhibited an enhanced sensitivity to the actions of active vitamin D as compared to resting T cells, and this effect was even further amplified by chronic exposure to the ligand. Thus, with the appreciation that both timing and frequency of 1,25(OH)2D3-treatment represent critical factors for efficient activation of VDR signaling pathways, we developed an in vitro protocol that can be used as screening system to identify new immunomodulatory actions of 1,25(OH)2D3 or synthetic agonists on T cells. In Chapter 5, we then used this optimized in vitro protocol to study the direct impact of TX527, a structural vitamin D analog, on human T cell responses. A microarray analysis demonstrated that TX527 affected T cell responses in an integrated manner, revealing a preferential regulation of genes involved in growth and proliferation, cell death, cellular development, cellular movement and cell-to-cell signaling and interaction. Additional analysis confirmed these findings at a phenotypical and functional level, showing that TX527 decreased T cell activation and proliferation, as well as pro-inflammatory cytokine expression. At the same time, this vitamin D analog triggered the induction of a functional CD4+CD25highCD127low regulatory T cell (Treg) population and imprinted T cells with a unique migratory signature which would target them to sites of inflammation. Together, these findings markedly improve our understanding of the role of vitamin D analogs as direct regulators of T cell responses and further complement our current knowledge on the mechanisms by which these compounds can modulate the immune system in vivo. In the second part of this thesis (Chapter 6), we exploited the immunomodulatory effects of TX527 in vivo in the model of syngeneic islet transplantation in diabetic NOD mice. As previously shown, vitamin D analogs can prevent autoimmune diabetes development in NOD mice, but co-administration of other immunomodulating agents such as cyclosporine A (CsA) is needed to intervene in established diabetes. Here, we chose to combine TX527 also with anti-CD3 monoclonal antibodies (mAb) because to date, anti-CD3 mAbs represent one of the most promising immune therapies to revert recent-onset T1D, but their clinical use encounters important side effects. Given the ability of vitamin D analogs to cooperate with other immunomodulators, we here investigated whether TX527, either alone or combined with CsA, could enhance the therapeutic efficacy of anti-CD3 mAbs to prevent diabetes recurrence upon syngeneic islet transplantation in diabetic NOD mice. Remarkably, combining the three agents at low, subtherapeutical doses strongly prevented immune-mediated islet destruction and subsequent recurrence of diabetes, by far exceeding the therapeutic efficacy of each of the mono- and duo-therapies. Despite the clear improvement of the clinical outcome by the combination therapy, the observed alterations in T cell numbers, Treg frequencies and expression of inflammatory homing receptors were predominantly mediated by anti-CD3 at the early time point of analysis. Here, additional analysis at later time points will further clarify the exact contributions of TX527 and CsA in this experimental setting.In conclusion, this work provides novel insights into the immunomodulatory mechanisms of active vitamin D and structural analogs, clearly identifying T cells as prominent and direct targets for these compounds. In addition, we propose that VDR agonists should be considered as dose-reducing agents in combination therapies for autoimmune diseases, in which low doses of other immunomodulatory compounds such as anti-CD3 mAb and CsA are inefficacious whereas high doses can be efficacious but cause side-effects.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Clinical and Experimental Endocrinology
Medical Clerkships Centers
Clinical Residents Medicine
Laboratory of Experimental Transplantation

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