Samento – Immunological Mechanisms of Action
By Svetlana Ivanova, MD, PhD
Presented at the International Samento Conference in Brighton, England, September 9-10, 2004
Many conditions known to be successfully treated with Samento can be associated with three major effects of this medicinal plant: anti-infectious (including anti-bacterial, anti-viral, anti-fungal), anti-inflammatory, and anti-cancer effects. The critical link with all these effects is the modulating effect of Samento on the Immune System.
To better understand the immunological mechanisms of action of Samento, we need to recall and highlight some structural and functional features of the human immune system.
The immune system comprises the collection of cells, tissues, and molecules that mediate resistance to infections. Coordinated action of all these components is called the immune response. The normal (balanced) immune response is a fundamental feature of the healthy immune system. Abnormal (imbalanced, functionally impaired) immune responses are the causes of many diseases with serious morbidity and mortality.
The major function of the immune system is to develop the concept of “self” and eliminate what is “non-self”, no matter what it is. Although the microorganisms are the principal “non-self” entities encountered every day, the healthy immune system also recognizes and eliminates neoplasms and transplants. Imbalanced and functionally impaired immune response in discrimination between “self” and “non-self” is the basis for allergic reactions, autoimmune disorders, and cancer.
The Immune System consists of two parts: the older, non-specific part called the “innate” immunity, which mediates the initial protection against infection; and the younger, specific part, called the “acquired” or “adaptive” immunity, which develops more slowly and mediates the later, even more effective, defense against infections.
The innate immunity (also called natural or native immunity) is always present in healthy individuals prepared to block the entry of microbes and to rapidly eliminate those who succeeded in entering host tissues. The mechanisms of innate immunity exist prior to infection; they recognize structures shared by classes of microbes and react similarly to all encountered antigens, providing the initial defense against infections. Some of the mechanisms function to prevent infections, for instance, the epithelial barriers (skin and mucosal linings) with their peptide antibiotics and specialized cells (intraepithelial T lymphocytes, B1 lymphocytes in the peritoneal cavity). Another mechanisms function to eliminate the invading microbes and include: phagocytic cells (granulocytes, monocytes, macrophages), natural killer (NK) cells (specialized in killing infected cells at early stages of a primary viral infection, and in anti-cancer activities), dendritic cells (DCs) specialized in antigen presentation , the complement system (a collection of circulating and membrane-associated proteins, mostly with enzymatic functions), the acute-phase proteins (the major of them are: C-reactive protein, ceruloplasmin, serum amyloid A), prostaglandins (substances of inflammation - a class of lipid inflammatory mediators), and cytokines – intercellular signaling polypeptides secreted by activated cells (mostly, mononuclear phagocytes, NK cells, and DCs), that function as the chief stimulators of the production of acute-phase proteins and mediators of the inflammatory and the immune reactions.
The inflammatory response, the initial response of the innate immunity to the harmful external stimuli (including the infectious microorganisms), is tightly regulated by various cytokines, involving mediators that initiate and maintain inflammation and the mediators that shut the process down. The patterns of cytokine production and the acute-phase response differ in different pathophysiologic states. In the state of acute inflammation, the balanced cooperation of both types of mediators (normal inflammatory response) provides fast restoration of homeostasis and precludes the dissemination of infection. In the state of chronic inflammation, there is an imbalance between two types of mediators that leaves inflammation unchecked, resulting in cell and tissue damage, and possible dissemination of infection.
Adaptive immune responses develop later, and are mediated by lymphocytes (B- and T-cells) and their products (antibodies and cytokines, respectively). In contrast to the innate immunity, the adaptive immunity has two special features: immunologic “memory”, which is the ability to respond more vigorously to repeated exposures to the same microbe, and the exquisite “specificity” for distinct antigens. Both the T- and B-lymphocytes express receptors that specifically recognize not only different substances produced by microbes, but also various noninfectious molecules. The mechanisms of adaptive immunity are specialized to combat different types of infections: for example, specific antibodies function to eliminate extracellular microbes, and activated T lymphocytes help to eliminate microbes living inside the cells.
Although the two parts of the immune system assume very specific duties, they work closely together and provide optimal immune response through numerous positive and negative feedback mechanisms. The adaptive immune responses often use the cells and molecules of the innate immunity to eliminate microbes, at the same time greatly enhancing those mechanisms. For example, the antibodies (a component of the adaptive immunity) bind to microbes, and these coated microbes bind to and activate phagocytes (a component of the innate immunity), which ingest and destroy the microbes. In another example, antibodies bind to microbes and to the proteins of the complement system (a component of the innate immunity), triggering the “complement cascade,” which is the chain of reactions resulting in the complete destruction of microbes.
The cytokines (intercellular messengers of the immune system) play the central role in balancing all the parts of the immune system and orchestrating the normal immune response. The cytokines bridge the innate and adaptive immunities via various feedback mechanisms and affect the magnitude of inflammatory and immune responses. Based on their mechanisms of action, all cytokines can be divided into three primary groups: pro-inflammatory cytokines, anti-inflammatory cytokines, and regulatory cytokines. Combinations of various cytokines may have additive, inhibitory, or synergistic effects. The effects of cytokines on target cells may be inhibited or enhanced by other cytokines, various hormones, circulating cytokine receptors and cytokine-receptor antagonists.
Balanced production and proper action of various cytokines is the key mechanism that provides structural integrity and normal functional activity of the healthy immune system.
Multiple clinical and research data show that Samento (Pentacyclic Oxindole Alkaloids Chemotype of Uncaria tomentosa) has powerful immunomodulating and stimulating properties. Taking into consideration that multiple healing effects of Samento have one common basis – the modulating effect on the immune system, it can be assumed that the Pentacyclic Oxindole Alkaloids (POAs), the chief immunomodulating compounds in Samento, influence the immune system by special ways: they do not generally stimulate all immunocompetent cells of the immune system, but rather specifically influence various feedback mechanisms of the innate and adaptive immunities, strengthening the immune system and bringing it into balance. The immunomodulating activities of POAs most likely involve stimulation of regulatory cytokines and down-regulation of pro-inflammatory cytokines, thus balancing the inflammatory and the immune reactions via multiple feed-back mechanisms, and restoring normal homeostasis. This statement can be supported by the fact that in any pathological condition the earlier Samento is used, the faster clinical improvement can be seen, and the less time is needed to restore normal homeostasis. In chronic long-lasting inflammatory and infectious disorders, the early signs of improvement upon the use of Samento can be seen in the blood test indexes which reflect the key elements of homeostasis (acid-base balance, various metabolic activities, regulating enzymes). For example, in the Pilot study on Samento for chronic Lyme disease (Texas, 2003), the patients with chronic neuroborreliosis demonstrated not only significant clinical improvement, but also had the early positive changes in various blood test indexes (decrease in initially high Triglycerides, Cholesterol and LDL levels, normalization of the HDL/LDL ratio, normalization of initially elevated liver enzymes, normalization of the body fluid pH, stabilization of the normal blood glucose level, improvement in the red blood indexes, normalization of the white blood indexes).
The POAs enhance the non-specific immune response at the early stage of infection by increasing the phagocytic activities of granulocytes (neutrophils, eosiniphils), monocytes and macrophages, thus speeding the resolution of inflammation and elimination of the extracellular microbes from the body. Tissue macrophages are widely distributed and strategically situated at the interface of a given organ with the blood or cavitary boundary, such as: alveolar macrophages in the lungs, Kupffer cells in the liver sinusoids, macrophages in the spleen, synovial cells in the joint cavities, perivascular microglial cells in the lining of CNS, mesangial phagocytes in kidneys. Enhanced phagocytosis by tissue macrophages, which is of great importance, helps to locally resolve the inflammatory and infectious processes in various tissues and organs, and protects the body from the dissemination of infection.
The POAs also stimulate functional activities of macrophages as the key “communication centers” of the immune system, balancing the production of various cytokines and regulating multiple feed-back mechanisms of both the innate and adaptive immunities.
The POAs modify the specific (adaptive) immunity by regulating the rate of proliferation of T- and B- lymphocytes, accelerating the production of specific antibodies by the B cells and modulating the cytokine production by the T cells, thus balancing the adaptive immune response and its interrelationship with the adaptive immune response. They specifically enhance proliferation of normal resting or weakly activated T- and B- lymphocytes thus balancing the immune response and keeping it under control. On the other hand, the POAs down-regulate the proliferation of highly activated immune cells (typical for autoimmune disorders) and transformed lymphoblasts (typical for some cancer diseases), without exerting cytotoxic effects. This down-regulating mechanism may involve specific inhibition of DNA polymerase activity via cytokine-regulated gene expression.
One of the ways how the use of Samento may down-regulate the pro-inflammatory and auto-immune responses can be demonstrated with autoimmune conditions. The current prominent theory suggests a central role for the infectious microorganisms in the etiology of the autoimmune disorders, when the body’s own substances (especially various cell membranes) become immunogenic (looking like “non-self” for the immune system) due to the direct chemical and/or physical alterations by microbes, and elicit the immune response to themselves. This autoimmune response triggers the cascade of imbalanced production of various cytokines and disturbances in the cell communication network, resulting in impaired functioning of many components of both the innate and adaptive immunities. The microbial antigens may also mimic normal “self” substances or cross react with them (well known phenomenon of molecular mimicry), inducing autoimmune or cross-reacting immune responses with subsequent damage to the tissues. With the use of Samento, the enhanced and balanced immune system is able to kill the microbes and eliminate them from the cell membranes, restoring the normal structure and functional integrity of these membranes, making them look like “self” again. The result of these events is that the inflammatory and autoimmune reactions subside, and the auto-immune response becomes down-regulated, manifesting in clinical improvement.
Another way of action of Samento can be attributable to its detoxifying effect (toxins-neutralizing effect). The strongest evidence for that we have with the Parkinson’s disease. When patients who clinically improved on Samento therapy make a few-week break in the use of Samento, their clinical symptoms reappear, and then diminish or disappear again upon the continuous use of Samento.
All of the abovementioned effects demonstrate that Samento acts as the immune system “adaptogen”, not always up-regulating or down-regulating, but does what exactly is needed by the body at the current moment to ensure the enhanced and balanced immune response to any harmful external stimulus.
The proof of this statement is in multiple clinical data showing that Samento is beneficial for the patients with:
- Non-specific immunodeficiency states;
- Autoimmune conditions and allergic disorders;
- Bacterial, fungal, and viral infections (including the HIV, EBV, HSV types1 and 2);
- Inflammatory diseases of the GI tract;