Immunoassay and Regulation of Traditional Chinese Medicine on Cancer Patients
Immunoassay and Regulation of Traditional Chinese Medicine on Cancer Patients
The immune system is our body's defense mechanism, which helps us to resist foreign pathogens
 and cancer cells in the body. However, if the immune system is too weak, too strong, or
 unbalanced, it will be susceptible to get bacterial and viral infections, unable to fight
 cancer, or cause allergies, autoimmune and rheumatic diseases. At present, there is no good
 western medicine to strengthen immunity when the body is insufficient immunity. However,
 strong immunity causes autoimmune diseases and need to be treated by steroids and
 immunosuppressive agents. These drugs have limited efficacy and often have many side effects.
 In the clinical practice of traditional Chinese medicine, tonify qi, supplement blood and
 nourish yin are often used to enhance immunity. However, there is no clinical test to
 demonstrate the modulation of immune response after traditional Chinese medicine treatment.

 In our preliminary study, the investigators identified that the basic immune response of
 cancer patients is weaker than healthy people by testing the level of IFN-r (promoting T cell
 activity, anti-tumor, anti-viral), TNF-a (promoting B cell proliferation, producing
 antibodies, anti-tumor, anti-viral) and IL-2 (regulate the proliferation and
 differentiation). Besides, some Chinese herbal extracts can significantly stimulate the
 immune response higher than the general average basic immunity of cancer patients. Further,
 we will use the stimulatory Chinese medicine extract to administer to cancer patients and
 examine the immune response of cancer patients after taking them. Therefore, this test can
 provide actual data on the basic immunity of healthy people or cancer patients and the
 modulation of immune response by traditional Chinese medicine treatment. This analysis
 platform provides patients to select the medicines that can enhance the immune response for
 individuals and analyze the changes of the immune response after conditioning with the
 candidate Chinese medicines. Therefore, this test could be applied clinically to validate the
 immunological regulation of Chinese herbal medicine as well as analyze the immunological
 modulation against different cancer by various Chinese herbal medicine.
Traditional Chinese medicine (TCM) and dendritic cells (DCs) activation/maturation One of the
 important approaches to successful cancer immunotherapy is generation of specific T cell
 responses by dendritic cells (DCs). DCs are the most potent antigen-presenting cells for
 naive T cells, because their high expression of MHC and co-stimulatory molecules. DCs
 comprise several subsets, and their roles in the presentation of antigens derived from
 pathogens, vaccines and self tissues are now beginning to be elucidated. Immature DCs (iDCs)
 resided in periphery have a high ability to endocytose antigens and become to mature DCs
 (mDCs) upon a variety of stimuli through Toll-like receptors (TLRs). However, iDCs facilitate
 immune tolerance and fully mDCs can promote immune responses. Until now, there are some
 studies have demonstrated that TCM could promote the activation status of DC to enhance
 immune responses through TLR, which are characterized by increased expression of
 co-stimulatory moleculars, MHC class II and several cytokines. Ganoderma lucidum and
 Cordyceps sinensis have been widely used in Asian countries to have beneficial effects on
 human health. Ganoderma lucidum polysaccharides have been reported to induce DCs maturation
 and promote the cytotoxicity of specific CTL. Moreover, Ganoderma lucidum polysaccharides
 were able to induce DC activation markers production and cytokines expression through TLR-4
 signaling pathway. However, this character about TCM acted as TLR agonists could apply to
 develop safe and effective adjuvant in vaccine generation.

 Traditional Chinese medicine (TCM) and T cell activation T cells are the master regulators of
 adaptive immune responses. Proper T cell responses are essential for the hosts to orchestrate
 sufficient adaptive immunity. Classically, the TH1/TH2 hypothesis has served the immunology
 community well, particularly in understanding infectious and allergic diseases. Regulatory T
 cells (Treg) are suppressive T cells that regulate effector T cell immunity. Nevertheless,
 this model dose not fit all systems when it comes to the study of organ-specific autoimmune
 diseases. It has also become more and more clear, however, that many complicated pathological
 situations cannot be simply explained by the TH1 cell and TH2 cell paradigm. Efforts to
 resolve these issues in recent years have resulted in the discovery of TH17 cells.

 T cell immunity is crucial for anti-tumor immunity. Given their importance in immune
 responses and diseases, it is important to understand the regulation of T cell immunity. In
 immune system, different lineages of immune cells were conventionally distinguished by the
 morphology and expression of a cluster of differentiation markers on the cell surface. TH1
 cells that make IL-2 and IFN-r are important for delayed-type hypersensitivity reactions,
 whereas TH2 cells that make IL-4 promote IgE production and allergic reaction. The
 differentiation of TH1 and TH2 cells mainly through the induction of distinct transcriptional
 programs. Activation of Signal Transducers and Activators of Transcription 1 (STAT1) by IFN-r
 and STAT4 by IL-12 drives expression of T-bet for TH1 programming. On the other hand,
 activation of STAT6 by IL-4 promotes GATA3 expression in TH2 cells. A revise of the TH1/TH2
 hypothesis was proposed until the discovery and IL-23 and IL-17. TH17 cell is a distinct T
 helper cell population that plays a crucial role in CD4+ T cell-mediated adaptive immunity.
 Commitment to the TH17 pathway requires the presence of both IL-6 and TGF-a during in vitro
 culture. These cells, different from the classical TH1 and TH2 cells, do not produce IFN-r or
 IL-4 but on the other hand express the IL-23 receptor and IL-21, IL-22, and IL-17F. ROR-rt ,
 ROR-rt are also highly expressed in TH17cells and can be induced by TGF-a and IL-6. Our
 previous studies showed for the first time an in vivo requirement for STAT3 in TH17 mediated
 autoimmunity. In addition, the investigators found that STAT3 is required for the maintenance
 of endogenous TH17 cells. In a more recent report, the investigators also found that CD8 T
 cells, like their CD4 counterparts TH17, can be skewed toward IL-17 production in vitro and
 in vitro.

 Manipulating T cell immunity by Chinese herbs is a promising field to explore. Many herbs
 were reported to regulate the T cell activation. Tanshinlactone A from Salvia miltiorrhiza
 Bunge significantly decreased the IL-2 and IFN-γ gene expression through reduction of MAPK
 activation in phytohemagglutinin-activated peripheral blood mononuclear cells. Periplocoside
 E (PSE) was shown to dose-dependently inhibit anti-CD3 induced primary T cell proliferation,
 activation for IL-2R (CD25) expression, and IFN-γ and IL-2 production at the transcriptional
 level by inhibited the activation of ERK and JNK. Furthermore, kurarinol was reported to
 increase level of HBV specific CTL by down-regulating peripheral blood HBV specific CTL
 surface PD-1 expression of CHB patients.

 All of these will support investigators' hypothesis that modulation of dendritic cell and T
 cell immunity by Chinese herbs or cytokines may be an applicable intervention to modulate
 immunity, for example, to promote anti-tumor immunity against cancer. The successful
 completion of the proposed studies will provide a strong support for future development of
 anti-cancer immunotherapy by Chinese herbs.

 Traditional Chinese herbs as a pharmacologic approach to modulate immunity Cancer
 immunotherapy, allergy, and autoimmune diseases are among the chronic illness that accounts
 for the death and economic burdens in Taiwan and other modern countries. Diseases such of
 Rheumatoid arthritis (RA), SLE, multiple sclerosis, ankylosing spondylitis, vasculitis,
 psoriasis and Sjogren's syndrome are common autoimmune diseases that cause not only life-long
 discomfort but also disabilities of the patients. Cancer immunotherapy is promising. Many of
 autoimmune disease and difficult-to-treat allergies are now found to be associated with IL-17
 mediated pathology. However, the current treatment is limited. Recently, targeted therapy
 such as Etanercept (trade name Enbrel), a biopharmaceutical that interferes with tumor
 necrosis factor (TNF; a soluble inflammatory cytokine), has been developed to treat some of
 the autoimmune diseases. However, nhibition of TNF has substantially advanced the treatment
 of inflammatory diseases. Because TNF and IL-17 have shared functions, the rationale for
 testing IL-17 inhibitors in the clinic is often based on the concept that patients who do not
 respond to TNF inhibitors may have an IL-17-driven disease. Autoimmune diseases such of
 rheumatoid arthritis and multiple sclerosis are common autoimmune diseases that cause not
 only life-long discomfort but also disabilities of the patients. The current treatment for
 these autoimmune diseases is limited to analgesia, anti-inflammatory drugs, steroids,
 disease-modifying antirheumatic drugs (DMARDs), and immunosuppressants. Recent studies in
 mouse models and in humans have identified a key role of IL-17 and TH17 cells in the
 pathogenesis of inflammation and autoimmunity as well as in host defense against certain
 pathogens.

 Meanwhile, there are some studies using Chinese herbs to modulate CD4 TH17 immunity. Compound
 extracted from Chinese herbs, such as berberine exhibited potent efficacy inhibiting TH17 in
 the EAE model. Triptolide also inhibited collagen-induced arthritis (CIA), a model of
 rheumatoid arthritis, through inhibition of CD4 TH17 cells. Periplocoside A was found to
 ameliorate EAE by suppressing IL-17 production and inhibited the differentiation of Th17
 cells in vitro. Eriocalyxin B was also found to be effective to inhibit TH17 and EAE through
 targeting Janus Kinase/Signal Transducer and Activator Of Transcription and Nuclear
 factor-kappaB signaling pathways. TCM formula such as Qingkailing injection was found to
 ameliorate rat experimental autoimmune uveitis (EAU). Qingkailing injection can alleviate
 autoimmune uveitis in rats, inhibit the differentiation toward Th1 and Th17 effector cells
 and the relevant cytokines secretion. Pure compound from Daphne odora var. marginata (D.
 marginata) was also found to inhibit TH17 and thus exhibit inhibitory effects in CIA model.

 One of the landmark study published in Science and Nature Chemical Biology is the example of
 halofuginone, an active component of traditional Chinese herb hydrangea root (Dichroa
 febrifuga), used to treat malaria for thousands of years. A collaborative research team led
 by Dr. Mark Sundrud at the Department of Pathology, Harvard Medical School and Immune Disease
 Institute, Boston, MA, has reported that halofuginone halted the progression of experimental
 autoimmune encephalomyelitis (EAE) mice and TH17. Importantly, unlike other therapies for
 autoimmune diseases, halofuginone does not have the undesirable effect of suppressing the
 other immune system.

 The investigators have established some platforms for screening Chinese herbs not only for
 modulating PD-1/PD-L1, IL-17, but also for detection of dendritic cell and T cell activation
 (Immunogen Test Panel).

 The hypothesis is that modulation of dendritic cells and T cells by traditional Chinese
 medicine may be an applicable intervention to treat some of the immunologic diseases such as
 cancer, allergy, and autoimmune diseases. Studies that can fit the niche, understanding the
 function and mechanism of Chinese herbs on immune cells and its pathway, will have broad
 clinical and immunological significance. The successful completion of the proposed studies
 will provide a strong support for a clinical trial of traditional Chinese medicine to treat
 patients with immunologic diseases.
Inclusion Criteria:

 -  Patients diagnosed with ovarian cancer and endometrial cancer (cancer patients treated
 with chemotherapy, radiotherapy, and surgery) can be included.

 -  Breast cancer: Diagnosed by pathological diagnosis of biopsy, without chemotherapy or
 radiotherapy.

 -  Colorectal cancer: Diagnosed by pathological diagnosis of slices, without chemotherapy
 or radiotherapy.

 Exclusion Criteria:

 -  Pregnant women

 -  Minors under the age of 20.

 -  Those who are currently using traditional Chinese medicine