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Endothelial injury, F-actin and vitamin-D binding protein
tion and changes in expression of genes related to macrophage polarization associated with VDBP levels. For example, marked up-regulation of ADORA3 would pro- mote IL6 production which would favor epithelial healing. We propose that higher levels of VDBP at later timepoints serve to modulate immune recovery, while at early time- points, prior to donor cell recovery, there are few if any macrophages to modulate and so no effect is apparent.
Figure 4 shows in schematic form our proposal for VDBP function after HSCT. We envisage that in the early days after transplant VDBP functions as an actin scav- enger, protecting the endothelium and preventing early complications such as TA-TMA. VDBP is depleted in this process, but rebounds around day 30. VDBP has little opportunity to act as an immunomodulator in the early weeks after HSCT as donor cell counts have not yet recov- ered. Between days 30 and 60 after HSCT donor cell counts recover and tissue healing takes place, and VDBP can modify macrophage phenotype to favor tissue heal- ing. Taken together, these data indicate important benefit for higher levels of VDBP after HSCT, and further work will clarify whether there would be potential benefit from strategies to increase or infuse additional VDBP.
Disclosures
SMD has served as a consultant for Novartis and has received research support from Prolacta and Alexion pharmaceuticals; SJ has received research support from Alexion pharmaceuticals; NL and SMD are holders of a provisional US patent regarding vita- min D-binding protein as a modifier of transplant outcomes.
Contributions
NL, SA, DL, ND, JR, NG, EMRP, KL, BL, AD performed experiments and reviewed and approved the manuscript; AL per- formed statistical analyses; NL, MH, SJ, CED and SMD designed experiments, analyzed and interpreted data and reviewed and approved the manuscript.
Acknowledgments
We gratefully acknowledge financial support from the Mueller Family Foundation and technical assistance from Edith Janssen, PhD and Joseph Qualls, PhD.
Funding
This work was supported by R01 HD093773 to SJ and SMD.
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