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A mannose-rich polysaccharide biological response modifier (BRM), derived from Aloe vera L. var. chinensis (Haw.) Berg., was demonstrated to be a potent murine B- and T-cell stimulator in our previous study. We here report the stimulatory activity of PAC-I on murine peritoneal macrophage. The polysaccharide when injected into mice enhanced the migration of macrophages to the peritoneal cavity. Peritoneal macrophage when treated by PAC-I in vitro had increased expression of MHC-II and FcgammaR, and enhanced endocytosis, phagocytosis, nitric oxide production, TNF-alpha secretion and tumor cell cytotoxicity. The administration of PAC-I into allogeneic ICR mice stimulated systemic TNF-alpha production in a dose-dependent manner and prolonged the survival of tumor-bearing mice. PAC-I is thus a potent stimulator of murine macrophage and the in vitro observed tumoricidal properties of activated macrophage might account for the in vivo antitumor properties of PAC-I. Our research findings may have therapeutic implications in tumor immunotherapy.

Biological response modifiers (BRMs) are substances which augment immune response. BRMs can be cytokines which are produced endogenously in our body by immune cells or derivatives of bacteria, fungi, brown algae, Aloe vera and photosynthetic plants. Such exogeneous derivatives (exogeneous BRMs) can be nucleic acid (CpG), lipid (lipotechoic acid), protein or polysaccharide in nature. The receptors for these exogeneous BRMs are pattern recognition receptors. The binding of exogeneous BRMs to pattern recognition receptors triggers immune response. Exogenous BRMs have been reported to have anti-viral, anti-bacterial, anti-fungal, anti-parasitic, and anti-tumor activities. Among different exogeneous BRMs, polysaccharide BRMs have the widest occurrence in nature. Some polysaccharide BRMs have been tested for their therapeutic properties in human clinical trials. An overview of current understandings of polysaccharide BRMs is summarized in this review.

Three purified polysaccharide fractions designated as PAC-I, PAC-II, and PAC-III were prepared from Aloe vera L. var. chinensis (Haw.) Berg. by membrane fractionation and gel filtration HPLC. The polysaccharide fractions had molecular weights of 10,000 kDa, 1300 kDa, and 470 kDa, respectively. The major sugar residue in the polysaccharide fractions is mannose, which was found to be 91.5% in PAC-I, 87.9% in PAC-II, and 53.7% in PAC-III. The protein contents in the polysaccharide fractions was undetectable. NMR study of PAC-I and PAC-II demonstrated the polysaccharides shared the same structure. The main skeletons of PAC-I and PAC-II are beta-(1-->4)-D linked mannose with acetylation at C-6 of manopyranosyl. The polysaccharide fractions stimulated peritoneal macrophages, splenic T and B cell proliferation, and activated these cells to secrete TNF-alpha, IL-1 beta, INF-gamma, IL-2, and IL-6. The polysaccharides were nontoxic and exhibited potent indirect antitumor response in murine model. PAC-I, which had the highest mannose content and molecular weight, was found to be the most potent biological response modifier of the three fractions. Our results suggested that the potency of aloe polysaccharide fraction increases as mannose content and molecular weight of the polysaccharide fraction increase.

Alkaline-soluble antitumor polysaccharide was prepared from the cell wall of the mushroom Flammulina velutipes. The backbones) of the polysaccharide is mainly composed of beta-(1-->3)-D-linked glucose and its molecular weight was estimated to be about 200 kD. The polysaccharide was found to be non-toxic by brine shrimp assay. When injected into mice intraperitoneally, the polysaccharide triggered proliferation of splenic lymphocytes and also vascular dilation and hemorrhage (VDH) response. The polysaccharide exhibited potent anti-tumor activity against sarcoma SC-180 in vivo but not in vitro.