Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract

Application of anti-thymocyte globulin (ATG) is a widely used strategy for the prevention of graft-versus-host disease (GvHD). As vitamin D3 serum levels are also discussed to affect hematopoietic stem cell transplantation (HSCT) outcome and GvHD development, we analysed a possible interplay between ATG treatment and serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in 4 HSCT cohorts with different vitamin D3 supplementation. ATG is significantly associated with higher serum level of 1,25-dihydroxyvitamin D3 around HSCT (day -2 to 7, peri-transplant), however only in patients with adequate levels of its precursor 25-hydroxyvitamin D3. ATG exposure had no impact on overall survival in patients supplemented with high dose vitamin D3, but was associated with higher risk of one-year treatment-related mortality (log rank test p=0.041) in patients with no/low vitamin D3 supplementation. However, the difference failed to reach significance applying a Cox-model regression without and with adjustment for baseline risk factors (unadjusted P=0,058, adjusted p=0,139). To shed some light on underlying mechanisms, we investigated the impact of ATG on 1,25-Dihydroxyvitamin D3 production by human dendritic cells (DCs) in vitro. ATG increased gene expression of CYP27B1, the enzyme responsible for the conversion of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3, which was accompanied by higher 1,25-dihydroxyvitamin D3 levels in ATG-treated DC culture supernatants. Our data demonstrate a cooperative effect of 25-hydroxyvitamin D3 and ATG in the regulation of 1,25-dihydroxyvitamin D3 production. This finding may be of importance in the context of HSCT, where early high levels of 1,25-dihydroxyvitamin D3 levels have been shown to be predictive for lower transplant related mortality and suggest that vitamin D3 supplementation may especially be important in patients receiving ATG for GvHD prophylaxis.

Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment

“…Extraction of RNA, reverse transcription and quantitative real-time PCR for gene expression analysis in myeloid cells was performed as described elsewhere ( 24 ). Primer sequences (all from Eurofins MWG Operon, Ebersberg, Germany) were as follows (-5’-3’): 18S rRNA: sense, 5′-ACCGATTGGATGGTTTAGTGAG-3′ and antisense, 5′-CCTACGGAAACCTTGTTACGAC-3′.…”

LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid

“…Purification of RNA, Reverse Transcription and quantitative Real-Time PCR for gene expression analysis in transduced T cells was performed as described elsewhere [ 54 ]. Primer sequences (all from Eurofins MWG Operon, Ebersberg, Germany) were as follows (-5′-3′); (F-Forward; R-Reverse): 18s rRNA F-ACCGATTGGATGGTTTAGTGAG, R-CCTACGGAAACCTTGTTACGAC; LDHA F-GGTTGGTGCTGTTGGCATGG, R-TGCCCCAGCCGTGATAATGA; LDHB F-GATGGTGGTTGAAAGTGCCTATGAAGTC, R-AGCCACACTTAATCCAATAGCCCA.…”

Nutritional interventions in patients with graft-versus-host disease

“…The study by Macedo et al [33] accurately described the immunomodulatory role of vitamin D, reporting that high levels may downregulate T cell proliferation via epigenetic gene modulation (EZH2 and ID3), whereas vitamin D deficiency may induce high production of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 2 (IL-2), IL-4, or interferon γ (INF-γ). Furthermore, vitamin D could have a synergistic action with antithymocyte globulin (ATG) serum administered to prevent GvHD: in vitro , ATG increases gene expression of CYP27B1, the enzyme responsible for the conversion of 25-hydroxyvitamin D3 into 1,25-dihydroxy vitamin D3, known to induce tolerogenic dendritic cells and T regulatory cells [34]. Apart from the immunomodulatory effect of vitamin D, the vitamin D receptor (VDR) plays a role in intestinal homeostasis.…”