Inkyu Hwang

Mechanisms of tumor-induced T cell immune suppression and therapeutics to counter those effects.

The theory of tumor immune surveillance states that the host immune system has means to recognize transformed cells and kills them to prevent growth and spreading of those cells. Nevertheless, cancer cells often survive and outgrow to form a tumor mass and metastasize to other tissues or organs. During the stage of immune evasion of tumor, various changes takes place both in the tumor cells and the tumor microenvironment to divert the anti-tumor immune responses by T cells and natural killer cells. Advances in the basic science in tumor immunology have led to development of many creative strategies to overcome the immune suppression imposed during tumor progression, a few of which have been approved for the treatment of cancer patients in the clinic. In the first part of this review, mechanisms of tumor-induced T cell immune suppression resulting in immune evasion of tumors will be discussed. In the second part, emerging methods to harness the immune responses against tumors will be introduced.

A new rearranged abietane diterpene from Clerodendrum inerme with antioxidant and cytotoxic activities

Abstract Eight compounds were isolated from the leaves of Clerodendrum inerme, including one new rearranged abietane diterpene, crolerodendrum B (1). Their structures were determined by means of spectroscopic methods including one-dimensional and two-dimensional nuclear magnetic resonance (1-D and 2-DNMR), high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) and circular dichroism (CD). The DPPH radical scavenging and cytotoxic activities of isolated compounds against MCF7 (breast), HCT116 (colon) and B16F10 (melanoma) cancer cell lines were evaluated. Compounds 1, 3 and 4 exhibited strong DPPH radical-scavenging effects (ED50 values of 17.6 ± 2.1, 10.1 ± 0.8 and 11.3 ± 0.3 μM, respectively) and 4 showed strong cytotoxicity against the HCT116 cell line (IC50 = 3.46 ± 0.01 μM).

Anti-allergic effects of the ethanol extract of Syzygium formosum (Wall.) Masam leaves and its immunoregulatory mechanisms

ETHNOPHARMACOLOGICAL RELEVANCE As documented in a Vietnamese traditional medical encyclopedia, Syzygium formosum (Wall.) Masam leaves have been routinely used among indigenous Vietnamese people for treatment of various allergy-like symptoms including dermatitis and rhinitis. AIM OF THE STUDY Anti-allergic activity of S. formosum leaves was examined with a mouse model of chicken ovalbumin (cOVA)-induced food allergy, and mechanisms underlying the anti-allergic effect were explored. MATERIAL AND METHODS BALB/c mice were administered i.p. cOVA (20μg) plus alum (2mg) twice on day 0 and 14 for sensitization (immunization). Two weeks after the second immunization, the mice were administered cOVA (50mg) p.o. 5 times every 3 days to induce food allergy symptoms (i.e., anaphylaxis, diarrhea, and drop in the body temperature). Ethanol extract of dried leaves of S. formosum (80mg/kg or 200mg/kg body weight) was administered p.o. daily during the induction (challenge) period. RESULTS Treatment with the S. formosum leaves ethanol extract ameliorated the allergic symptoms to a significant extent and in a dose-dependent manner. The treatment also resulted in a significant improvement in the inflammatory lesion in the small intestine and reduction in the numbers of mast cells and eosinophils recruited to the lesion. The treatment also brought about a significant reduction in the levels of Th2 cytokines produced by the mesenteric lymph node cells cultured ex vivo with cOVA. The passive anaphylaxis experiment also showed that the extract treatment impaired the mast cell function. CONCLUSION Our study provides a scientific basis for the traditional (indigenous) use of the S. formosum leaves extract for the treatment of various allergy symptoms in Vietnam. In addition, the results show that the extract has activities to suppress antigen-specific Th2 T cell immune responses and the mast cell function, which are directly related with its anti-allergic effect.

Chemical components from Aloe and their inhibition of indoleamine 2, 3-dioxygenase

Background: In Korea, Aloe is routinely ingested as a traditional medicine or as a component of health beverages. Objective: To research the inhibition of indoleamine 2, 3-dioxygenase (IDO) activities of components from Aloe. Materials and Methods: the compounds were isolated by a combination of silica gel and YMC Rp-18 column chromatography, and their structures were identified by analysis of spectroscopic data (1D, 2D-NMR, and MS). All of the isolated compounds were examined for their ability to inhibit IDO, which actively suppresses immune functions by catalyzing the rate limiting reaction in the conversion of tryptophan to kynurenine. Results: In this phytochemical study, 18 known compounds were isolated from aqueous dissolved Aloe exudates. All of the isolated compounds were examined for their ability to inhibit IDO activities for a series of anthraquinone derivatives (1-7) isolated from the Aloe extract; the IC50 values of these compounds ranged from 39.41 to 53.93 µM. Enzyme kinetic studies of their modes of inhibition indicated that all of the compounds were uncompetitive inhibitors. Conclusion: The aqueous dissolved Aloe exudate can be used as a source of novel natural IDO inhibitors and merit testing as therapeutic agents in the treatments of cancer and immunopathologic diseases, such as autoimmune, inflammatory, and allergic disorders. Abbreviation used: IDO: inhibit indoleamine 2, 3-dioxygenase, TMS: tetramethylsilane, HMQC: heteronuclear multiple quantum correlation, HMBC: heteronuclear multiple bond correlation, COSY: 1H-1H correlation spectroscopy, ESI-MS: Electrospray ionization mass spectrometry, DMSO: dimethyl sulfoxide

Anti-allergic effects of Rosae multiflorae fructus via inhibition of T cell proliferation and the mast cell function

Anti-allergic effects of the hot water extract of Rosae multiflorae fructus (Rosae extract), which has long been used in oriental medicine for treatment of various diseases, were explored with a chicken ovalbumin (cOVA)-induced mouse model of food allergy. Compared to the sham mice to show severe allergic symptoms (i.e., anaphylaxis, diarrhea and decrease in the body temperature) following oral cOVA challenge, the Rosae extract-treated mice showed a marked improvement in those symptoms. Histology data demonstrated that Rosae extract treatment resulted in a amelioration in the intestinal inflammatory lesion and a reduction in the numbers of mast cells and eosinophils in the small intestine. Studies using DO11.10 TCR transgenic T cells indicated that Rosae extract had an activity to subdue the antigen-specific T cell activation/proliferation in vivo and thereby to lower the level of Th2 cytokine production by T cells during the antigen-specific immune response. Moreover, passive systemic anaphylaxis study showed that the extract also had an activity to inhibit the mast cells function in vivo, i.e., release of granules triggered by specific IgE-antigen interaction. Altogether, the results from this study not only imply a potential clinical application of Rosae extract in prevention and treatment of food allergy but also clearly elucidate the immunoregulatory mechanisms of Rosae extract underlying its anti-allergic effect.

Development of an oral immunoadjuvant from cheonggukjang that is efficacious for both mucosal and systemic immunity

Immunological properties of a 50% ethanol/aqueous extract of cheonggukjang (CGJ), a fermented soybean product, were investigated as a potent, orallyavailable, and cost-effective immunoadjuvant. Different from cholera toxin, a widely used experimental oral adjuvant with effects limited to mucosal immunity in the gut, oraladministration of the CGJ extract had positive effects on both mucosal and systemic immunity. Administration of keyhole limpet hemocyanin (KLH) with the CGJ extract resulted in hyper-production of KLH-specific IgA in the gut and KLH-specific IgG in the serum. Oral-administration of the CGJ extract resulted in promotion of both Th1 and Th2 immune responses, thus eliminating concerns over an imbalanced Th1 and Th2 immune bias that is often observed upon administration of other commonly used immunoadjuvants. Ethanol/aqueous extraction of CGJ resulted in enrichment of polyphenolic compounds, including flavonoids, providing a potential extra health benefit.

Beneficial effects of the mixed adjuvant of CpG plus monophosphoryl lipid a in immunization with a recombinant protein vaccine for hepatitis A

In an effort to develop a new vaccine for hepatitis A, which is mainly transmitted via contaminated foods and water, recombinant virus protein 1 (VP1) of hepatitis A virus was used as an antigen. Several adjuvants in a single or a mixed form, i.e., alum, CpG oligodeoxynucleotide, monophosphoryl lipid A (MPL), alum plus MPL, and CpG plus MPL, were also tested for their immunological properties. When their effects on the production of VP1-specific IgG relative to that of total IgG and the levels of and balance between Th1- and Th2-type cytokine productions were compared, CpG plus MPL was found to have highly beneficial effects, providing a new insight in selection of adjuvant for development of a new vaccine.

Cytotoxic triterpene saponins from the mangrove Aegiceras corniculatum

Abstract Using various chromatographic separations, sixteen compounds, including one new triterpene saponin named aegicoroside A (1), were isolated from the leaves of the Vietnamese mangrove Aegiceras corniculatum. Their structures were determined by spectroscopic methods such as 1D and 2D NMR and HR-ESI-MS. The cytotoxic activities of the isolated compounds against MCF7 (breast), HCT116 (colon), B16F10 (melanoma), and A549 (adenocarcinoma) cancer cell lines were also evaluated. Strong cytotoxicity was observed for sakurasosaponin (2) against all four cancer cell lines and for sakurasosaponin methyl ester (3) against MCF7, A549, and HCT116 cell lines with IC50 values ranging from 2.89 ± 0.02 to 9.86 ± 0.21 μM.