Shift of graft-versus-host-disease target organ tropism by dietary vitamin A.
Gut-homing of donor T cells is causative for the development of intestinal GvHD in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Expression of the gut-specific homing receptors integrin-α4β7 and chemokine receptor CCR9 on T cells is imprinted in gut-associated lymphoid tissues (GALT) under the influence of the vitamin A metabolite retinoic acid. Here we addressed the role of vitamin A deficiency in HSCT-recipients for donor T cell migration in the course of experimental GvHD. Vitamin A-deficient (VAD) mice were prepared by feeding them a vitamin A-depleted diet. Experiments were performed in a C57BL/6 into BALB/c model of acute GvHD. We found that expression of integrin-α4β7 and CCR9 in GALT was reduced in VAD recipients after HSCT. Competitive in vivo homing assays showed that allogeneic T cells primed in VAD mice did not home as efficiently to the intestine as T cells primed in mice fed with standard diet (STD). The course of GvHD was ameliorated in VAD HSCT-recipients and, consequently, their survival was prolonged compared to recipients receiving STD. However, VAD-recipients were not protected and died of clinical GvHD. We found reduced numbers of donor T cells in the intestine but increased cell counts and tissue damage in other organs of VAD-recipients. Furthermore, we observed high IFN-γ(+)CD4(+) and low FoxP3(+)CD4(+) frequencies of total donor CD4(+) T cells in VAD as compared to STD recipients. Taken together, these results indicate that dietary vitamin A deficiency in HSCT-recipients changed target organ tropism in GvHD but also resulted in fatal inflammation after HSCT.
Institute of Immunology, Hannover Medical School, Hannover, Germany. koenecke.christian@mh-hannover.de
Christian
C
Koenecke
Immo
I
Prinz
Anja
A
Bubke
Alina
A
Schreder
Chun-Wei
CW
Lee
Oliver
O
Pabst
Reinhold
R
Förster
D000818:Animals; D002452:Cell Count; D004032:Diet; D005786:Gene Expression Regulation / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism* / Q000601:surgery; D018380:Hematopoietic Stem Cell Transplantation; D016023:Integrins / Q000378:metabolism; D007422:Intestines / Q000276:immunology*; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism; D051379:Mice; D054388:Receptors, CCR / Q000378:metabolism; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous / Q000009:adverse effects; D014801:Vitamin A / Q000378:metabolism*; D014802:Vitamin A Deficiency / Q000276:immunology / Q000378:metabolism
C119309:CC chemokine receptor 9; D016023:Integrins; D054388:Receptors, CCR; C071777:integrin alpha4beta7; D014801:Vitamin A