Increased Vitamin D Binding Protein Levels Are Associated with Improved Overall Survival Following Bone Marrow Transplant in Children

Vitamin D-binding protein (DBP) transports vitamin D metabolites. DBP is present in molar excess of vitamin D, leading to identification of non-vitamin D dependent immunomodulatory functions. DBP is a negative acute phase reactant, typically decreased in acute illness and inflammatory states. DBP is highly polymorphic, and affinity for vitamin D metabolites varies by genotype. We hypothesized that DBP levels would decrease after transplant, ameliorating the effect of vitamin D deficiency by increasing levels of bioavailable vitamin D. DBP was measured in serum at days 0, 100, and 1 year in 134 transplant recipients using a polyclonal DBP ELISA kit. Surprisingly, DBP levels increased markedly following HSCT (Figure 1), and had not returned to baseline at one year. We noted bimodal peaks at both day 0 and 100, with a shift in both peaks toward the right by day 100. To determine if the bimodal peak was due to genotypic differences we compared change in DBP from day 0 to 100 by genotype, and found that DBP increased in those with no Gc2 allele, but did not increase in those with at least one Gc2 allele (P = .0005). DBP levels were significantly lower in those with acute GVHD, (462 vs 734 mg/mL, P = .026) and 1-year survival (OS) was significantly increased in patients with higher DBP levels at day 100 (83% vs 73% P = .03; Figure 2). We expected that the biological effects of DBP would be due to changes in levels of bioavailable vitamin D, which we calculated using reported formulas, combining 25OHD level, DBP level, genotype, and albumin level. OS was higher in patients with day 0 bioavailable vitamin D levels above the median compared to patients with bioavailable vitamin D levels below the median (OR 2.7, P = .006). However, there was no association between bioavailable vitamin D levels and cumulative incidences of acute GVHD, bacteremia, or viral infections at 1 year. Median bioavailable vitamin D level was lower in patients with a fracture post-transplant (.94 vs 1.21 ng/mL, P = .12). We examined the immunomodulatory effect of DBP by looking at the effect of patient serum from 18 cases on expression of the anti-microbial protein cathelicidin (CAMP), an innate immune system gene regulated by vitamin D in cultured normal human monocytes. We found a significant negative correlation between total 25OHD and DBP levels with fold increase in CAMP expression (r = −.7, P = .001, Figure 3; r = −.5, P = .03), but no correlation with bioavailable vitamin D (r = −.01, p = 1.0). We report the novel finding of increased DBP levels after HSCT, sustained for more than a year, and associated with improved survival, likely due to association with freedom from GVHD. Our functional CAMP assay indicated a strong correlation with total 25OHD levels and DBP. These data indicate a complex and clinically significant relationship between DBP and transplant outcomes. We are further exploring immunomodulatory activity of DBP in this context.