Vitamin A Deficiency Is Associated with Increased Risk of Acute Graft Versus Host Disease in Children

Vitamin A and its metabolite retinoic acid directly influence the development and function of the immune system, enhancing differentiation of regulatory T-cells, and is a crucial factor in development of tolerance and maintenance of intestinal homeostasis. In a mouse model, vitamin A deficiency increased inflammatory cytokines in the GI-associated lymphoid tissue and draining lymph nodes. In contrast, other mouse models have shown that exogenous vitamin A exacerbated GI GVHD, increasing trafficking of T-cells to the gut and that genetic ablation of retinoic acid receptor signaling from donor T-cells also reduced severity of GVHD in the GI-tract and liver, suggesting that vitamin A can be pro and anti-inflammatory depending on context. We hypothesized that lower levels of vitamin A will lead to increased incidence of GVHD. We conducted a cohort study of 114 children receiving allogeneic HSCT between April 2013 and July 2015, prospectively enrolled into our BMT repository (Table 1). Blood samples and clinical data were collected prospectively, once weekly, from admission until 100 days post-transplant. Vitamin A levels were measured in patient plasma at baseline and Day 30 using the Human Vitamin A ELISA kit from MyBiosource. Univariate and multivariate analyses were performed with primary endpoints of development of GVHD and TRM. The cumulative incidence of grades 2-4 GVHD was increased in children with a vitamin A level below the median compared with those above (38.6 vs 12.4% at 100 days, p=0.0008, Figure 1). Moreover, the rate of GI GVHD was also increased (30.4 vs 7% at 100 days, p=0.002, Figure 2). In a multivariate analysis including diagnosis, stem cell source and HLA-match, vitamin A level remained an independent risk factor for GVHD. TRM was also increased in children with lower than median vitamin A levels (17.7 vs 7.4% at 1 year, p=0.03, Figure 3). Baseline vitamin A levels were not associated with any outcome. Our data show that vitamin A deficiency is associated with increased risk of acute GVHD, including GI GVHD. It is possible that this is due to a direct effect of vitamin A deficiency on the immune system, or that GVHD itself leads to reduced vitamin A levels. To attempt to address this, we looked at change in vitamin A level from baseline to day 30, expecting that if GVHD caused a marked drop in vitamin A levels, a big change would be strongly associated with GVHD but no association was seen (p=0.15). In future studies we will seek to replicate these current data in independent datasets and explore the mechanism of this finding.Table 1Patient DemographicsAll (n=124)No GVHD (n=74)Grade 2-4 GVHD (n=40)GI GVHD (n=30)Age Median (year)861112Range (year)0.4-320.4-270.6-320.8-32Diagnosis Malignancy33141711Immune Deficiency45291211Bone Marrow Failure4732118Stem Cell Source BM106603728PBSC141122UCB4310Match Matched101583324Mismatched231676 Open table in a new tab Figure 2Cumulative Incidence of GI GVHD based on vitamin A level above and below the median at day +30.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3TRM based on vitamin A levels above and below the median at Day +30.View Large Image Figure ViewerDownload Hi-res image Download (PPT)