NK026680, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft-versus-host reaction in mice.
A role for dendritic cells (DCs) has been emphasized in the onset of acute graft-versus-host disease (GVHD). We have made efforts to develop a new strategy for suppression of DC functions with a chemical compound in the treatment of acute GVHD. We here describe the immunological characterization of the new chemical compound NK026680. It was found that NK026680 significantly suppressed (1) expression of CD83, CD86, and major histocompatibility complex (MHC) class I and II antigens on human monocyte-derived DCs, (2) excretion of interleukin-12p40 on activation of monocyte-derived DCs, (3) allogeneic responses of human and mouse T cells and (4) mortality in mice with acute GVHD evoked across MHC class I or II. The beneficial effect of NK026680 administered orally was without any recognizable adverse effects. Early intervention in acute GVHD was required for this effect, indicating that an early event in acute GVHD is a critical target of NK026680. We propose the use of NK026680 as a prophylactic for acute GVHD.
Saiga
K
K
Pharmaceutical Group, Nippon Kayaku Co., Ltd, Tokyo, Japan.
Toyoda
E
E
Tokunaka
K
K
Masuda
A
A
Matsumoto
S
S
Mashiba
H
H
Kuramochi
H
H
Nemoto
K
K
Abe
F
F
Kawagishi
N
N
Furukawa
H
H
Ono
M
M
D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D053765:Interleukin-12 Subunit p35; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D015394:Molecular Structure; D021122:Protein Subunits / Q000096:biosynthesis / Q000276:immunology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects; D000097802:CD83 Antigen
D015703:Antigens, CD; D051940:B7-2 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D007155:Immunologic Factors; D018664:Interleukin-12; D053765:Interleukin-12 Subunit p35; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D011743:Pyrimidines; D014230:Triazoles; D000097802:CD83 Antigen; C509974:(S)-1-(5-hydroxy-1,5-dimethylhexyl)-3-(7-(4-methoxyphenyl)-(1,2,4-triazolo(1,5-a)pyrimidin-2-yl))urea; C497965:Cd86 protein, mouse; C508858:IL12A protein, human