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Effects of Donor Vitamin A Deficiency and Pharmacologic Modulation of Donor T Cell Retinoic Acid Pathway on the Severity of Experimental Graft-versus-Host Disease. Biol Blood Marrow Transplant 2016 12;22(12):2141-2148

Date

09/07/2016

Pubmed ID

27596131

DOI

10.1016/j.bbmt.2016.09.001

Scopus ID

2-s2.0-85003032776   8 Citations

Abstract

Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). A combination of genetic and nongenetic factors dictates the incidence and severity of GVHD. Recent studies have identified the potential role of the retinoic acid (RA)/retinoic acid receptor (RAR) pathway in the pathogenesis of GVHD. RA is the active metabolite of vitamin A. Thus, a clinically relevant question is whether HSCT donor and/or recipient vitamin A status affects the development of GVHD. It has been previously reported that recipient vitamin A deficiency is associated with reduced intestinal GVHD and prolonged overall survival after experimental allogeneic HSCT. However, it is still unknown whether donor vitamin A status influences GVHD development. In the current study, we report that chronic vitamin A deficiency changes the composition of T cell compartment of donor mice with a reduction in the percentage of CD4+ T cells. We showed that although vitamin A deficiency does not affect donor T cell alloreactivity on a per cell basis, a decreased proportion of donor CD4+ T cells in marrow graft inoculums leads to reduced incidence and severity of GVHD. Furthermore, our proof of principle studies using a pan-RAR antagonist demonstrated that transient inhibition of donor T cell RAR signaling can reduce T cell alloreactivity and their ability to cause lethal GVHD. Our studies provide preclinical evidence that donor vitamin A deficiency may be a nongenetic factor that can modulate the severity of GVHD and pharmacologic interfering RA/RAR pathway in donor T cells might be a valuable approach for mitigating GVHD after allogeneic HSCT.

Author List

Dodge J, Stephans A, Lai J, Drobyski WR, Chen X

Authors

Xiao Chen MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Allografts
Animals
CD4 Antigens
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Mice
Receptors, Retinoic Acid
T-Lymphocytes
Tissue Donors
Tretinoin
Vitamin A Deficiency