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.
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.
Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Joseph
J
Dodge
Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Allison
A
Stephans
Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri.
Jinping
J
Lai
Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
William R
WR
Drobyski
Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: xchen@mcw.edu.
Xiao
X
Chen
D064591:Allografts / Q000166:cytology; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D006086:Graft vs Host Disease / Q000209:etiology* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000378:metabolism; D014019:Tissue Donors; D014212:Tretinoin / Q000378:metabolism*; D014802:Vitamin A Deficiency
D015704:CD4 Antigens; D018168:Receptors, Retinoic Acid; D014212:Tretinoin
GVHD; HSCT donor; Retinoic acid; Retinoic acid receptor; Vitamin A