title: Graft-versus-host disease targets ovary and causes female infertility in mice.
abstract: Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used.
authors.affiliation: Center for Cellular and Molecular Medicine and.|Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Shimoji
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and.
authors.forename: Daigo
authors.identifier: 0000-0001-9489-9704
authors.initials: D
authors.lastname: Hashimoto
authors.affiliation: Department of Life Science, Okayama University of Science, Okayama, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Tsujigiwa
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Miyawaki
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and.
authors.forename: Reiki
authors.initials: R
authors.lastname: Ogasawara
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Jiromaru
authors.affiliation: Center for Cellular and Molecular Medicine and.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Center for Cellular and Molecular Medicine and.|Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and.
authors.forename: Takanori
authors.identifier: 0000-0002-0941-271X
authors.initials: T
authors.lastname: Teshima
mesh_terms: D000818:Animals; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D007247:Infertility, Female / Q000209:etiology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000473:pathology*; D016133:Polymerase Chain Reaction