Immunomodulating substances, biological response modifiers, and biotherapy, including immunotherapy, are important for the treatment of cancer. Some β-glucans are well-known biological response modifiers, and the mushrooms from which they are derived are widely distributed in nature and are used as medicine and food. Among the β-glucans, the 6-branched 1,3-β-glucan is the best characterized. Lentinan from Lentinus edodes (40) and Sonifilan (SPG) from Schizophyllum commune (9) have been used clinically for cancer therapy in Japan. We have analyzed the mechanism of β-glucanmediated immunopharmacological activity, and demonstrated the conformation-dependent and -independent activity of β-glucan (48, 49). Recent data indicated that orally administered β-1,3-glucan potentiated the activity of antitumor monoclonal antibody, leading to enhanced tumor regression and survival (20,21). Thus, cancer immunotherapy using β-glucan is a promising possibility.Sparassis crispa is a medicinal mushroom that recently became cultivatable in Japan. The primary component of the major cold NaOH-extracted polysaccharide fraction from S. crispa was found to be 6-branched 1,3-β-glucan, having one branch approximately every third main chain. This fraction showed strong antitumor activity against the solid form of Sarcoma 180 in ICR mice (34). In our recent study, we used S. crispa to treat several cancer patients in combination with lymphocyte transplantation immunotherapy and obtained a good response (35). To examine the pharmacological usefulness of S. crispa β-glucan Mechanism of Enhanced Hematopoietic

SCG is a major 6-branched 1,3-beta-D-glucan in Sparassis crispa Fr. showing antitumor activity. We recently found that the splenocytes from naive DBA/1 and DBA/2 mice are potently induced by SCG to produce interferon- gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-12p70 (IL-12p70), and that GM-CSF plays a key biologic role among these cytokines. In this study, we investigated the contribution of cell-cell contact and soluble factors to cytokine induction by SCG in DBA/2 mice. Cell-cell contact involving intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) was an essential step for the induction of GM-CSF and IFN-gamma by SCG but not for the induction of TNF-alpha or IL-12p70 by SCG. SCG directly induced adherent splenocytes to produce TNF-alpha and IL-12p70. GM-CSF was required for the induction of TNF-alpha by SCG, and in turn, TNF-alpha enhanced the release of GM-CSF and thereby augmented the induction of IL-12p70 and IFN-gamma by SCG. Neutralization of IL-12 significantly inhibited the induction of IFN-gamma by SCG. We concluded that induction of GM-CSF production by SCG was mediated through ICAM-1 and LFA-1 interaction, GM-CSF subsequently contributed to further cytokine induction by SCG, and reciprocal actions of the cytokines were essential for enhancement of the overall response to SCG in DBA/2 mice.

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Soluble β-glucan preparation from the cold NaOH extract of Sparassis crispa (SCG) is a six-branched 1,3-β-D-glucan that is a major cell-wall structural component in fungi. Leukocytes from DBA/2 mice are highly sensitive to SCG, producing cytokines in vitro. We previously reported that the intraperitoneal (i.p.) administration of β-glucan decreased cytokine induction by SCG in vitro in DBA/2 mice. In this study, we examined the effects of the oral (p.o.) administration of polysaccharide fractions extracted from S. crispa, using hot water (SCHWE), a β-glucan from S. crispa, to DBA/2 mice on cytokine induction by SCG in the spleen in vitro. The level of induction of IFN-γ and GM-CSF by SCG was significantly increased in SCHWE-treated mice. This activity was more clearly observed when chlorpromazine was administered as a pretreatment in SCHWE-treated mice. The production of GM-CSF, IFN-γ, and IL-6 by immune cells in Peyer's patches was higher in SCHWE-treated mice than in control mice. These results suggest that orally administered β-glucan may modulate cytokine induction by SCG in the spleen through the activation of Peyer's patches.