APCO Science of Balancing Immunity

The Science of Balancing Immunity
By Prof.Dr.Watchara Kasinrerk
“BIM product induces the activation of Th1 and Th17 cells, but not Th2 cells”
Biomedical Technology Research Center, Chiang Mai University, Thailand
General information

Th1 and Th2 cells
The immune system is an important system for protection body from infections and destroying cancer cells. The immune system consists of a sophisticated array of cells that have developed to recognize and eradicate a wide variety of microorganisms and cancers. T lymphocytes are important players in this process. They can be stimulated by peptide antigen presented on major histocompatibility complex (MHC) molecules expressed on antigen-presenting cells (APCs). Upon T cell stimulation, they secrete IL-2 and express surface IL-2 receptors. Binding of IL-2 to its receptors, through the autocrine mechanism, induces clonal expansion of T lymphocytes. The activated T lymphocytes are then subsequently differentiated to the effector cells for generating immune functions.

T helper cells (also known as Th cells or CD4+ lymphocytes) are a subpopulation of T lymphocytes that play an important role in establishing and maximizing the capabilities of the immune system. These cells have no cytotoxic or phagocytic activity. They cannot kill infected host cells or pathogens. T helper cells, however, are involved in activating and directing other immune cells to function. They are essential for the induction of antibody production by B lymphocytes and determining B cell antibody class switching. The T helper cells also involved in the activation and growth of cytotoxic T cells (also known as Tc cells or CD8+ lymphocytes) for the killing of virus-infected and cancer cells. In addition, T helper cells can activate and maximize the bactericidal activity of phagocytes such as macrophages, monocytes, and granulocytes. It is this diversity in function and their role in influencing other cells that give T helper cells their name.

T helper (Th) cells express the CD4 molecule and, after activation, can differentiate into at least two subsets, Th1 and Th2 cells (Fig. 1). The Th1 and Th2 cells have different function and produce different cytokines. Th1 cells are important for the eradication of intracellular pathogens, including bacteria, parasites, yeasts, and viruses. The hallmark cytokines of Th1 cells is IFN- which can activate microbicidal activity as well as cytokine production in macrophages.

These cytokines also involved in the activation of CD8+ lymphocytes and NK cells which play a major role in destroying cancer cells. TNF-, a potent pro-inflammatory cytokine, was also demonstrated to be produced by the Th1 cells.

The primary role of TNF- is participating in the regulation of immune cells. TNF is able to induce inflammation, to induce apoptotic cell death, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, as well as cancer. Other cytokines, such as IL-2, tumor necrosis factor- (TNF- or lymphotoxin) and IL-10 have also demonstrated to be Th1 cytokines, but none defines this lineage as clearly. It is noted that IL-2 is classically associated with Th1 cells, but this association may be misleading; IL-2 is produced by all helper T cells early in their activation. A Th1 response is often accompanied by the production of complement-fixing antibodies of the IgG2a isotype, as well as the activation of natural killer (NK) cells and cytotoxic CD8+ T cells expressing IFN- and perforin.

Taken together, the activation and induction of Th1 cells are of importance for the generation of a powerful cell-mediated immunity. In contrast to the Th1 cells, Th2 cells produce a different type of cytokines. After activation, Th2 cells secrete cytokines IL-4, IL-5, and IL-13 and can activate mast cells and eosinophils. Depending on their secreted cytokines, the Th2 cells function mainly to mediate humoral immunity, eradicate helminths and other extracellular parasites. These cells also mediate allergic and atopic manifestations, which is in keeping with findings that Th2-derived cytokines can induce airway hyperreactivity as well as the production of IgE. Both Th1- and Th2-specific cytokines can promote growth or differentiation of their own respective T-cell subset but additionally might inhibit the development of the opposing subset.

BIM A Product: Study of the Operation BIM Product on the Modulation of the Immune System
During the last decades, development of specific agents affecting T helper cell subpopulations, i.e., Th1, Th2 and Th17, differentiation has drawn special attention. Many natural products were reported as a good agent for modulating the immune response by regulating the differentiation of T helper cell subpopulations. These products are potential to be the immunomodulators for treatment of various diseases including infectious diseases, cancers, autoimmune diseases and also arthritis.
In this study, we aim to study the immunomodulatory effects of the Operation BIM product. We investigate the possible effect of an Operation BIM product, Arthrinox, on the controlling of T helper cell subpopulation differentiation.

Objectives

The objective of this study is to investigate the possible effects of the BIM A Product on the regulation of T helper cell subpopulations. The levels of various cytokines of blood collected from healthy donors before and after taking Operation BIM product (Arthrinox capsule) for 15 days were compared.

Study approaches:

1. Study subjects
• 12 healthy volunteers: 6 males and 6 females
• Age: 20-55 years old
• The recruited volunteers were separated into 2 groups:
Group 1: taking placebo; 6 subjects
Group 2: taking Arthrinox capsule; 6 subjects
2. Blood collections
Blood (5 ml. using heparin as anticoagulant) were collected from each subject at day 0. According to their groups, subjects took Arthrinox capsule or placebo (4 capsules/day) every day for 15 days. Afterward, blood was collected (5 ml. using heparin as anticoagulant) for the second time at day 16.
3. Study of the effect of the Arthrinox capsule on the regulation of T helper cell subpopulations
Peripheral blood mononuclear cells (PBMCs) were isolated from the collected blood by using Ficoll-Hypaque gradient centrifugation. PBMCs were in vitro stimulated with or without anti-CD3 monoclonal antibodies (clones OKT3) and cultured for 24 hours at 37oC in a CO2 incubator. The cell culture supernatant was collected and centrifuged 20,000 rpm, 2 min. The cell-free supernatants were separated and stored at -70°C for determination of cytokines.
Results
The stimulation indexes of various cytokines in subjects taking the Arthrinox capsules and placebo were calculated and compared. By normalization using subjects taking placebo, % enhancement and reduction of subjects taking Arthrinox capsule were shown in Figure below. The results indicate that Arthrinox capsule reduced the production of IL-2 and IL-17 and significantly reduced the production of TNF-a.
Additional Resources:
Topic: Innate Immunity and Rheumatoid Arthritis
Ref: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937347/
Topic:  Blocking the immune system in rheumatoid arthritis
Ref: https://www.pharmaceutical-journal.com/news-and-analysis/infographics/blocking-the-immune-system-in-rheumatoid-arthritis/20201090.arti

BIM D Product: Study of the Operation BIM Product on the Modulation of the Immune System
During the last decades, development of specific agents affecting T helper cell subpopulations, i.e., Th1, Th2 and Th17, differentiation has drawn special attention. Many natural products were reported as a good agent for modulating the immune response by regulating the differentiation of T helper cell subpopulations. These products are potential to be the immunostimulants for treatment of various diseases including infectious diseases, cancers, autoimmune diseases and also diabetes.
In this study, we aim to study the immunomodulatory effects of the Operation BIM product. We investigate the possible effect of the Operation BIM product on the controlling of T helper cell subpopulation differentiation.

Objectives

The objective of this study is to investigate the possible effects of the Operation BIM product on the regulation of T helper cell subpopulations. The levels of various cytokines of blood collected from healthy donors before and after taking Operation BIM product for 15 days were compared.

Study approaches:

1. Study subjects
• 12 healthy volunteers: 7 males and 5 females
• Age: 20-50 years old
• The recruited volunteers were separated into 2 groups:
Group 1: taking placebo; 6 subjects
Group 2: taking Operation BIM product; 6 subjects
2. Blood collections
Blood (5 ml. using heparin as anticoagulant) were collected from each subject at day 0. According to their group, subjects took Operation BIM product or placebo (4 capsules/day) every day for 15 days. Afterward, blood was collected (5 ml. using heparin as anticoagulant) for the second time at day 16.
3. Study of the effect of the Operation BIM products on the regulation of T helper cell subpopulations
Peripheral blood mononuclear cells (PBMCs) were isolated from the collected blood by using Ficoll-Hypaque gradient centrifugation. PBMCs were in vitro stimulated with or without anti-CD3 monoclonal antibodies (clones OKT3) and cultured for 24 hours at 37oC in a CO2 incubator. The cell culture supernatant was collected and centrifuged 20,000 rpm, 2 min. The cell-free supernatants were separated and stored at -70°C for determination of cytokines.
4. Determination of T helper cell cytokines
Cytokines in the cell culture supernatant were determined by Flow cytomixÒ (eBioscience, Inc. San Diego, CA, USA) followed the manufacturer’s protocol. Comparison of the cytokine levels from un-stimulated PBMC and stimulated PBMC in term of Stimulation Index on day 0 and day 15 were performed.
Results
The stimulation indexes of various cytokines in subjects taking the BIM product and placebo were calculated and compared. By normalization using subjects taking placebo, % enhancement and reduction of subjects taking BIM product were shown in Figure below. The results indicate that Operation BIM product reduced the production of TNF-a, IFN-g, IL-4, IL-5, IL-9, IL-10, IL-12, and IL-17.
Lab Data of BIM Capsule 

A decrease of TNF-α, IL-6, and IL-17 lower the severity of inflammation. The remedy for arthritis, SLE, atopic dermatitis.

The decrease of TNF-α and INF-ɣ lower attack on pancreas β-cell, more insulin is secreted, the blood sugar level is lowered, diabetes type-I is improved. Insulin-resistant is also decreased, blood sugar level is lowered, diabetes type-II is improved.

A decrease of IL-17 lowers the severity of autoimmunity and diabetes.

Xanthones are natural substances found in the Genus Garcinia, particularly in mangosteen.

Scientific studies, particularly by the scientists of the Thai Mangosteen Research and Development Center (TMRDC) at Asian Phytoceuticals Public Company Limited (APCO) have established the following activities of xanthones :
These statements have NOT been approved by the US FDA:
1. Growth inhibition and may have the ability to kill antibiotic-resistant gram-positive bacteria, the effectiveness equals that of vancomycin.
2. May have Anti-inflammatory properties
3. Analgesic (pain relieving) and anti-allergy.
4. Anti-oxidant – preventing heart diseases from LDL cholesterol oxidation.
5. Might be able to Kill breast cancer cells, leukemia cells, liver cancer cells, kidney cancer cells, stomach/intestinal cancer cells, and lung cancer cells (based on laboratory testing).
6. Show signs to Kill tuberculosis bacterium (based on laboratory testing).
7. May be able to Inhibit the propagation of HIV (based on laboratory testing).
8. Potential to Increase the phagocytosis, the cellular process of eliminating foreign matters and bacteria.
9. Might be able to Inhibit cartilage deterioration and increase bone mass (based on laboratory testing)
GM-1 is found, by scientists at TMRDC, to be the most active amongst 41 xanthones in mangosteen.
References :
1. J. Nat.Prod. 1987 May-June 50(3) 474-8
2. J. Sci. Soc. Thailand, 12(1986) 239-242.
3. Free Radic Res. 2000 Nov;33(5):643-59.
4. Planta Med. 1996 Aug;62(4):381-2
5. Free Radic Res. 1995 Aug;23(2):175-84.
6. J Pharmacol Sci. 2004 May;95(1):33-40.
7. J Med Assoc Thai. 1997 Sep;80 Suppl 1:S149-54.
8. Chem Pharm Bull(Tokyo) 2003 Jul; 51(7):857-9.
9. M.Sc. in Pharmacology Thesis, Chiang Mai University 1998. (Ajchara Chaikaeo)
10. M.Sc. in Organic Chemistry Thesis, Prince of Songkla University 1985.

Topic: 
Th17 cytokines and vaccine-induced immunity.
Ref: www.ncbi.nlm.nih.gov/pubmed/20112107Topic: Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin
Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707624/Topic: Utilizing TH9 cells as a novel therapeutic strategy for malignancies
Ref:  http://www.tandfonline.com/doi/abs/10.4161/onci.23084Topic: Synergy between CD8 T Cells and Th1 or Th2 Polarised CD4 T Cells for Adoptive Immunotherapy of Brain Tumours
Ref: 
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063933 (Th1)

Topic: Rapid Generation of Potent and Tumor-specific Cytotoxic T Lymphocytes by Interleukin 18 Using Dendritic Cells and Natural Killer Cells
Ref: http://cancerres.aacrjournals.org/content/60/17/4838

Topic: Th17 cells promote cytotoxic T cell activation in tumor immunity
Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787786/

Topic: Th9 cells promote antitumor immune responses in vivo
Ref: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484462/

Topic: Rapid Generation of Potent and Tumor-specific Cytotoxic T Lymphocytes by Interleukin 18 Using Dendritic Cells and Natural Killer Cells
Ref: http://cancerres.aacrjournals.org/content/60/17/4838

Topic: What is Interleukin 5?
https://en.wikipedia.org/wiki/Interleukin_5

Topic: Th2 cytokines and asthma — The role of interleukin-5 in allergic eosinophilic disease
Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC59571/

Topic: IL5 interleukin 5 [ Homo sapiens (human)
Ref: https://www.ncbi.nlm.nih.gov/gene/3567
Ref: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277955/

Topic: TNF-a, IFN-g IL17

Diabetes. 1996 Feb; 45(2) : 183-9 = https://www.ncbi.nlm.nih.gov/pubmed/8549863

Diabetes Med. 1998 May; 15(5) : 435-6 = https://www.ncbi.nlm.nih.gov/pubmed/9609368

Immunity. 2008 Oct 17;29(4):628-36. = https://www.ncbi.nlm.nih.gov/pubmed/18848474

Immunology and Cell Biology 91,393-401 (July 2013)

Arthritis Research&Therapy 2006, 8(Suppl 2)

American Journal of Pathology Vol167, No.1, July 2005

Topic: Alzheimer The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ
Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822284/

Topic: Increased serum levels of interleukin-18, -23 and -17 in Chinese patients with Alzheimer’s disease.
Ref: https://www.ncbi.nlm.nih.gov/pubmed/25138786

Topic: Interleukin-17 inhibits Adult Hippocampal Neurogenesis
Ref: https://www.nature.com/articles/srep07554

Topic: Study of interleukin-6 production in Alzheimer’s disease.
Ref: https://www.ncbi.nlm.nih.gov/pubmed/22026253

Topic: Nanoformulated alpha-mangostin ameliorates Alzheimer’s disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.
Ref: http://www.sciencedirect.com/science/article/pii/S0168365916300529

Topic: Natural Xanthones from Garcinia mangostana with Multifunctional Activities for the Therapy of Alzheimer’s Disease.
Ref: https://www.ncbi.nlm.nih.gov/pubmed/27038926

Topic: Heavy metal overload has been linked to serious problems like liver disease and brain disorders like Alzheimer’s disease.
Ref: https://thedailyhealth.co.uk/malic-acid-chronic-fatigue-syndrome-00974/

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