Enhancing effects of (2S,3S,4R)-1-O-(alpha-D-galactopyranosyl)-2-(N-hexacosanoylamino) -1,3,4-octadecanetriol (KRN7000) on antigen-presenting function of antigen-presenting cells and antimetastatic activity of KRN7000-pretreated antigen-presenting cells.
(2S,3S,4R)-1-O-(alpha-D-galactopyranosyl)-2-(N-hexacosanoylamino)- 1,3, 4-octadecanetriol (KRN7000), with an alpha-galactosylceramide structure, is an immunomodulator showing potent antimetastatic activities. In an in vitro study, KRN7000 potently stimulated proliferation and enhanced natural killer activity in spleen cells from BALB/c euthymic mice, but not BALB/c athymic (nu/nu) mice, suggesting that T cells play an important role in these activities. To study the detailed immunostimulatory mechanisms of KRN7000, syngeneic mixed leukocyte reactions were then performed using dendritic cell-enriched fractions (DCEFs) from spleens of BALB/c euthymic and athymic mice. In these studies, KRN7000 enhanced the antigen-presenting cell activities of the DCEFs. In addition, marked production of interleukin-2 and interferon-gamma in BALB/c euthymic mice was observed following treatment with KRN7000 in vitro and in vivo. Because of these strong immunostimulating effects of KRN7000, its antimetastatic effects were also evaluated. Adoptively transferred KRN7000-treated DCEF markedly prolonged the survival time of mice bearing B16 pulmonary metastases. These results demonstrate that KRN7000 may be useful for cancer therapy not only as an antitumor agent but also as an activator of antigen-presenting cells such as dendritic cells, which can be used for adoptive cellular therapy.
Yamaguchi
Y
Y
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Motoki
K
K
Ueno
H
H
Maeda
K
K
Kobayashi
E
E
Inoue
H
H
Fukushima
H
H
Koezuka
Y
Y
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007959:Lymphocyte Culture Test, Mixed; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D005699:Galactosylceramides; D007376:Interleukin-2; D007371:Interferon-gamma; C103873:KRN 7000