Recipient vitamin A levels influence the risk of graft-versus-host disease after experimental allogeneic stem cell transplantation

Abstract

Abstract Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Retinoic acid (RA), the active metabolite of vitamin A, has been implicated in GVHD pathogenesis. However, whether recipient vitamin A levels modulate GVHD risk remains controversial based upon recent clinical data. To gain insights into this clinically relevant question, Balb/c mice were kept on diets containing normal (VAN) or excessive (VAH) amounts of vitamin A. Lethally irradiated VAN and VAH mice were then transplanted with bone marrow and splenic T cells from MHC-mismatched C57BL/6 mice to induce GVHD. There was no significant difference in the expansion of donor CD4 and CD8 T cells in the spleen and CD4 T cells in the mesenteric lymph nodes between the two groups early after HSCT. There was also no significant difference in the expression of gut-homing molecule α4β7 on donor T cells in VAN versus VAH mice. However, there was a significant reduction in serum LPS levels in VAH mice compared with those of VAN mice in later stage of GVHD development, indicating a better maintained intestinal barrier integrity. Gene expression of proinflammatory cytokines including IFN-γ and TNF-α was also significantly decreased in the colon tissues of VAH mice compared with that of VAN mice. Despite reduced intestinal inflammation, VAH mice unexpectedly died significantly faster than VAN mice after transplantation. Collectively, our studies indicated that higher vitamin A levels are associated with accelerated GVHD-associated mortality after experimental HSCT. Therefore, some caution should be exercised when considering high dose vitamin A supplementation for GVHD prevention as proposed in recent clinical trials.