ABSTRACT
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.
Subject(s)
Dendritic Cells/immunology , Gene Expression Regulation/drug effects , Graft vs Host Disease/prevention & control , Immunologic Factors/administration & dosage , Pyrimidines/administration & dosage , Triazoles/administration & dosage , Administration, Oral , Animals , Antigens, CD/biosynthesis , Antigens, CD/immunology , B7-2 Antigen/biosynthesis , B7-2 Antigen/immunology , Dendritic Cells/metabolism , Dendritic Cells/pathology , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Histocompatibility Antigens Class I/biosynthesis , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/biosynthesis , Histocompatibility Antigens Class II/immunology , Humans , Immunoglobulins/biosynthesis , Immunoglobulins/immunology , Immunologic Factors/adverse effects , Immunologic Factors/chemistry , Interleukin-12/biosynthesis , Interleukin-12/immunology , Interleukin-12 Subunit p35 , Membrane Glycoproteins/biosynthesis , Membrane Glycoproteins/immunology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Molecular Structure , Protein Subunits/biosynthesis , Protein Subunits/immunology , Pyrimidines/adverse effects , Triazoles/adverse effects , CD83 AntigenABSTRACT
We have established a convenient, two-step procedure to solubilize the yeast cell wall (1-->3)-beta-D-glucan using the combination of NaClO oxidation and DMSO extraction. Candida soluble beta-D-glucan (CSBG) was mainly composed of a linear beta-1,3 glucan with a linear beta-1,6-glucan moiety. In this study, we screened for several immunopharmacological activities of CSBG and found the following activities: (1) interleukin-6 synthesis of macrophages in vitro; (2) antagonistic effect for zymosan mediated-tumor necrosis factor synthesis of macrophages; (3) augmentation for lipopolysaccharide mediated tumor necrosis factor and nitrogen oxide syntheses of macrophages; (4) activation of alternative pathway of complement; (5) hematopoietic response on cyclophosphamide induced leukopenia; (6) the antitumor effect on ascites form tumor; (7) Enhanced vascular permeability; (8) priming effect on lipopolysaccharide triggered TNF-alpha synthesis; and (9) adjuvant effect on antibody production. These results strongly suggested that CSBG possessed various immunopharmacological activity.
Subject(s)
Candida/chemistry , Glucans/pharmacology , beta-Glucans , Animals , Antibody Formation/drug effects , Antigen-Presenting Cells/drug effects , Capillary Permeability/drug effects , Cell Line , Cyclophosphamide/pharmacology , Glucans/toxicity , Interleukin-6/biosynthesis , Leukocyte Count , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred ICR , Sarcoma 180/drug therapy , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The limulus test is a well-established method for the diagnosis of both Gram-negative sepsis and invasive fungal infection. To diagnose fungal infections, a beta-(1-->3)-D-glucan-specific chromogenic kit (Fungitec G test MK) has been developed and applied clinically. We are concentrating our main efforts on developing a better standard to improve the precision of this method. To this end, we have successfully developed a protocol to obtain a soluble Candida spp. beta-(1-->3)-D-glucan (CSBG) by sodium hypochlorite (NaClO) oxidation and subsequent dimethyl sulfoxide (Me2SO) extraction (yield of 9.6 +/- 4.1%) of acetone-dried whole-cell preparations. The beta-glucan fraction is free from the cell-wall mannan, gives a symmetrical peak by gel filtration, and is soluble in dilute NaOH. The product is composed mainly of beta-(1-->3)- and beta-(1-->6)-D-glucosidic linkages. The specific activity of the beta-glucan is comparable with pachyman when combined with the Fungitec G test as the standard glucan and reacted as low as 10(-11) g/mL.