Commensal Fungi in Health and Disease.

Pattern recognition receptors in fungal immunity.

Pattern recognition receptors: immune targets to enhance cancer immunotherapy.

Glucans are part of a group of biologically active natural molecules and are steadily gaining strong attention not only as an important food supplement, but also as an immunostimulant and potential drug. This paper represents an up-to-date review of glucans (β-1,3-glucans) and their role in various immune reactions and the treatment of cancer. With more than 80 clinical trials evaluating their biological effects, the question is not if glucans will move from food supplement to widely accepted drug, but how soon.

Beta Glucan: Supplement or Drug? From Laboratory to Clinical Trials.

Background β-Glucans are polysaccharides constructed of glucose monomers linked by β-glucosidic bonds, which mainly exist in cereals (barley and oat), yeast and mushrooms. Some physiological functionalities of β-glucans have been confirmed, consequently, their development and utilization in the biomedical, pharmaceutical, food, and cosmetic industries have received increasing interest. Foods and dietary supplements containing β-glucans are very popular. Scope and approach This review summarizes recent findings regarding the physiological functionalities of β-glucans and details the action mechanisms of β-glucans upon the present knowledge. The prospects for future research on these topics are also discussed. Key findings and conclusions β-Glucans are effective in many aspects of human health, including cancer prevention, reducing glycemia and serum cholesterol, anti-inflammation, as well as improving immunity. The modification of β-glucans contributes to better solubility, viscosity and gelation, which can change the bioactivities of β-glucans. The action mechanisms of β-glucans and their derivatives are considered to be mainly mediated by some cytokines and hormones in subjects. Human health is supported by various mechanism researches. Although certain action mechanisms remain unclear, the clarification of how β-glucans exhibit biological effects is beneficial for our understanding of complicated biochemical reaction in living organisms.

Physiological functionalities and mechanisms of β-glucans

Vaccination with heat-killed Saccharomyces cerevisiae (HKY) protects against experimental infection by pathogenic fungi of five genera. Here we tested whether purified Saccharomyces cell wall β-glucan could induce protection against systemic aspergillosis. CD-1 mice were given three weekly vaccine doses subcutaneously prior to intravenous infection with Aspergillus fumigatus. Mice received PBS, 2.5 mg HKY, whole glucan particles (WGP), WGP conjugated to BSA (0.06 to 12 mg per dose), a soluble medium molecular mass (MMW) β-glucan alone or MMW–BSA (≤24 mg per dose). Survival and c.f.u. were determined, and cytokine induction and anti-β-glucan antibodies were assessed in vaccinated mice. Neither soluble MMW glucan, nor MMW–BSA was effective. HKY protected in two studies (survival and c.f.u. were reduced in brain and kidney organs, P<0.004). Six or 12 mg WGP or WGP–BSA prolonged survival (P≤0.004) and reduced c.f.u. in each organ (P≤0.015) in both experiments; 0.6 mg WGP or WGP–BSA prolonged survival (P≤0.015) and reduced c.f.u. (P≤0.015) in one experiment. Cytokine profiles in serum and bronchoalveolar lavage from uninfected vaccinated mice showed an innate and adaptive immune profile (i.e. upregulation of colony stimulating factors, interferons, TNF-α, chemokines such as MCP-1, MIP-1α, RANTES and KC, and Th17-activating cytokines such as IL-6, IL-1β, IL-17). No anti-β-glucan antibodies were in the sera, suggesting an adaptive T cell-mediated, not a B cell-mediated, protective response. Vaccination with WGP or WGP–BSA proved protective against systemic aspergillosis, equivalent to that of HKY, supporting the potential of particulate β-glucans, alone or conjugated, as vaccines against aspergillosis.

Whole glucan particles as a vaccine against murine aspergillosis

Imprime PGG (Imprime), an intravenously-administered, soluble β-glucan, has shown compelling efficacy in multiple phase 2 clinical trials with tumor targeting or anti-angiogenic antibodies. Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly activating innate immune effector cells, triggering a coordinated anti-cancer immune response. Herein, using whole blood from healthy human subjects, we show that Imprime-induced anti-cancer functionality is dependent on immune complex formation with naturally-occurring, anti-β glucan antibodies (ABA). The formation of Imprime-ABA complexes activates complement, primarily via the classical complement pathway, and is opsonized by iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcg Receptor IIa, eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the generation of reactive oxygen species and antibody-dependent cellular phagocytosis. Importantly, these innate immune cell changes were not evident in subjects with low ABA levels but could be rescued with exogenous ABA supplementation. Together, these data indicate that pre-existing ABA are essential for Imprime-mediated anti-cancer immune activation and suggest that pre-treatment ABA levels may provide a plausible patient selection biomarker to delineate patients most likely to benefit from Imprime-based therapy.

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Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.

We reported previously that yeast-derived whole glucan particles (WGPs), with or without conjugation to BSA, used as a vaccine protected against systemic aspergillosis in mice. Here, we examined their utility as a potential vaccine against coccidioidomycosis. WGPs were prepared from Saccharomyces cerevisiae; conjugation with BSA (WGP–BSA) was done using 1-cyano-4-dimethylaminopyridinium tetrafluoroborate-mediated conjugation. Heat-killed S. cerevisiae (HKY) was used as a positive-control vaccine. CD-1 mice were vaccinated with WGPs or WGP–BSA, HKY or PBS once weekly, beginning 21 days prior to infection. Mice were infected intravenously with arthroconidia of Coccidioides posadasii. In the low-mortality study, 50 % of PBS-treated controls died. Only WGP–BSA at 0.6 mg per dose induced significant protection compared with PBS treatment. All surviving mice were infected in all three organs examined. Those given WGP–BSA at 0.6 mg per dose had fewer c.f.u. in liver and lungs (P = 0.04), and those given WGPs at 6 mg per dose had fewer in lungs (P < 0.02), compared with PBS. In the high-mortality study, 90 % of PBS mice died. Vaccination with HKY, and WGPs or WGP–BSA at 6 or 12 mg per dose significantly prolonged survival (P ≤ 0.05). No surviving mice were free of infection. HKY and WGP–BSA at 12 mg per dose reduced c.f.u. in the liver and lungs (P < 0.05) and WGP–BSA at 6 mg per dose reduced c.f.u. in the lungs (P < 0.05); unconjugated WGPs did not reduce infection. WGPs or WGP–BSA acted as a vaccine that protected against mortality caused by coccidioidomycosis. Thus, WGP protection against coccidioidomycosis and aspergillosis provides the basis for development of a pan-fungal vaccine.

Whole glucan particles as a vaccine against systemic coccidioidomycosis

Modified and/or derivativized β-glucans with an enhanced capacity to modulate human immune response as compared to the parent, unmodified and/or underivatized β-glucans are demonstrated.

MODIFIED AND DERIVATIZED β-GLUCAN COMPOUNDS, COMPOSITIONS, AND METHODS

This disclosure describes, in one aspect, a method for identifying β-glucan binding to immune cells of a subject. Generally, the method includes obtaining a blood sample from the subject, the blood sample comprising immune cells, adding soluble β-glucan to at least a portion of the blood sample and incubating the mixture under conditions allowing the soluble β-glucan to bind to the immune cells, and detecting soluble β-glucan bound to the immune cells. In another aspect, this disclosure describes a method that generally includes identifying the subject as a low binder of β-glucan, and co-administering to the subject a soluble β-glucan and an antibody preparation capable of converting the subject from a low binder to a high binder.

Kyle S. Michel

Papers

Whole glucan particles as a vaccine against murine aspergillosis

Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation.

Whole glucan particles as a vaccine against systemic coccidioidomycosis

MODIFIED AND DERIVATIZED β-GLUCAN COMPOUNDS, COMPOSITIONS, AND METHODS

Beta-glucan immunotherapeutic methods