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* Department of Cardiovascular Surgery and
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciencies, Kyushu University, Fukuoka, Japan;
Department of Surgery I, Fukuoka University School of Medicine, Fukuoka, Japan;
Department of Infection Control and
¶ Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and
|| Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
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-2d, Lyt-1.2, and Mls-1b) wild-type (WT) mice or V
14 NKT knockout (KO) (BALB/c) mice were used as recipients, and DBA/2 NCrj (H-2d, Lyt-1.1, and Mls-1a) mice were used as donors. Recipient mice were primed with 1 x 108 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 V
6+ 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.
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1 This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Health and Welfare, Japan (to Y.T.). Y.T. was also the recipient of a Surgical Research Foundation Grant from the Japanese Surgical Association.
2 Address correspondence and reprint requests to Dr. Yukihiro Tomita, Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: tomita{at}heart.med.kyushu-u.ac.jp
3 Abbreviations used in this paper: CP, cyclophosphamide; GalCer, -galactosyl ceramide; BMC, bone marrow cell; Gy, gray; KO, knockout; LMNC, liver mononuclear cell; MST, mean survival time; SC, spleen cell; WBC, white blood cell; WT, wild type.
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