title: Regulatory roles of NKT cells in the induction and maintenance of cyclophosphamide-induced tolerance.
abstract: We have previously reported the sequential mechanisms of cyclophosphamide (CP)-induced tolerance. Permanent acceptance of donor skin graft is readily induced in the MHC-matched and minor Ag-mismatched recipients after treatment with donor spleen cells and CP. In the present study, we have elucidated the roles of NKT cells in CP-induced skin allograft tolerance. BALB/c AnNCrj (H-2(d), Lyt-1.2, and Mls-1(b)) wild-type (WT) mice or Valpha14 NKT knockout (KO) (BALB/c) mice were used as recipients, and DBA/2 NCrj (H-2(d), Lyt-1.1, and Mls-1(a)) mice were used as donors. Recipient mice were primed with 1 x 10(8) donor SC i.v. on day 0, followed by 200 mg/kg CP i.p. on day 2. Donor mixed chimerism and permanent acceptance of donor skin allografts were observed in the WT recipients. However, donor skin allografts were rejected in NKT KO recipient mice. In addition, the donor reactive Vbeta6(+) T cells were observed in the thymus of a NKT KO recipient. Reconstruction of NKT cells from WT mice restored the acceptance of donor skin allografts. In addition, donor grafts were partially accepted in the thymectomized NKT KO recipient mice. Furthermore, the tolerogen-specific suppressor cell was observed in thymectomized NKT KO recipient mice, suggesting the generation of regulatory T cells in the absence of NTK cells. Our results suggest that NKT cells are essential for CP-induced tolerance and may have a role in the establishment of mixed chimerism, resulting in clonal deletion of donor-reactive T cells in the recipient thymus.
authors.affiliation: Department of Cardiovascular Surgery, Department of Pathology, Greaduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Iwai
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tomita
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shimizu
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Yasunami
authors.forename: Takashi
authors.initials: T
authors.lastname: Kajiwara
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Kikuo
authors.initials: K
authors.lastname: Nomoto
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasui
mesh_terms: D000818:Animals; D017637:Clonal Deletion; D003520:Cyclophosphamide / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016038:Skin Transplantation / Q000276:immunology / Q000379:methods; D013950:Thymus Gland / Q000166:cytology; D014184:Transplantation, Homologous
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D003520:Cyclophosphamide