14 Lectin-Standardized Mistletoe Extracts
Origin of the Mistletoe Extract Therapy
Mistletoe (Viscum album L.) has been prescribed as a natural remedy by Hippocrates, by the Druids, and by Arabian physicians long before Rudolf Steiner in the 1920s promoted aqueous extracts from mistletoe for treating tumors according to so-called anthroposophical considerations.
Aqueous mistletoe extracts have a complex composition. Since the early 1950s, various mistletoe constituents have been isolated, e.g., low molecular weight substances (phenolic vegetable acids, flavonoids) and high molecular weight compounds (viscotoxins, polysaccharides, glycoproteins/lectins).
It was only through further development of analytical test procedures at the beginning of the 1980s that it became possible to isolate active plant substances in larger quantities, characterize them, and evaluate at least some of their pharmacological activity.
In the context of these studies, it became clear that the immunological effect of mistletoe extracts partly depended on their lectin content. Qualitatively, mistletoe lectins are divided into two groups according to their sugar specificity: galactoside-specific (Gal) lectin and N-acetylgalactos-amine-specific (GalNAc) lectin.
The Gal lectin (mistletoe lectin 1, ML-1) predominates in mistletoes from deciduous trees, while the GalNAc lectin is found primarily in mistletoes of coniferous trees.
At present, several mistletoe preparations are available on the German market that are manufactured according to different processes. Mistletoes from different host trees are harvested and processed at different times of the year. Defined anthroposophical manufacturing procedures subject the mistletoe extract to fermentation by Lactobacillus species, a process that partly degrades the ML-1 lectin.
So far, aqueous mistletoe extracts have been classified by evidence-based medicine as falling into the group of therapeutics that have a supposed, but not yet sufficiently proved, clinical efficacy. In order to allow for their responsible application according to scientific criteria, mistletoe preparations were tested for their biological activity. It is primarily due to the identification of an immunoactive component (ML-1) and the evaluation of its properties that the clinical administration of mistletoe extracts was standardized and thus became relevant for scientifically oriented medicine (1).
Mechanism of Action and the Application of Mistletoe Extracts in Medicine
The following mechanisms of action are currently postulated for mistletoe extracts:
– cytotoxicity
– modulation of the immune response
– stimulation of the immune response
– induction of apoptosis
– stabilization of DNA.
The cytotoxic effect of mistletoe extracts is dose dependent and can be demonstrated in vitro. Apart from mistletoe lectins, there are obviously other components responsible for the cytotoxic effect, but their detailed analysis is still pending.
It has been demonstrated for ML-1, as well as other mistletoe lectins, that their in-vitro cytotoxicity is nonspecific. Depending on the mode of application (intratumoral, intravenous, intracavitary), this property could possibly be used for treatment in oncology.
The immunomodulator activity of mistletoe extracts seems promising, for example, in the treatment of rheumatoid diseases, which are usually characterized by immunological dysregulation of T lymphocyte subpopulations (helper/inducer T cells, CD4; suppressor/cytotoxic T cells, CD8). The CD4/CD8 cell ratio is characteristically altered in rheumatoid diseases and manifests itself especially through an increase in CD4 cells, resulting finally in an increased ratio. The starting point for immunomodulation in rheumatoid diseases seems to be the regulation of both CD4/CD8 ratio and Th1/Th2 ratio, and this is usually followed by the suspension of symptoms. It is currently not completely established which of the components of mistletoe extracts are in the end responsible for immunomodulation. Although ML-1 is a potent immunomodulating component, it is the efficacy of homeopathic and ML-1-deficient mistletoe extracts that seems to indicate that other components must be involved in the immunomodulating activity (9).
There are diverse application schemes for inducing optimal effects by mistletoe extracts. For immunomodulation, mistletoe extracts are taken orally and by inhalation or are administered by intracutaneous, subcutaneous, intravenous, and sometimes intracavitary injections. When using mistletoe extracts as an immunomodulating substance, it should be noted that ML-1 especially must be administered in the optimal dose, because otherwise the immunomodulation achieved might be less than optimal. This measure is valid for all forms of application.
If the cytotoxicity of mistletoe lectins is to be used therapeutically, higher dosages are usually required than in the case of immunoactivation or immunomodulation. Such high-dose therapies can be administered by intravenous, intratumoral, or intracavitary injection, but they have not been evaluated scientifically. The mistletoe extracts would be assessed in this case like cytostatic agents, no matter which of its components is responsible for the effect.
Considering the multiple mechanisms of action and forms of application of mistletoe extracts, with special reference to the introduction of mistletoe preparations by R. Steiner to anthroposophical cancer therapy, it is no wonder that in various medical fields (such as anthroposophy, naturopathy, homeopathy) mistletoe therapy has been practiced for a long time in oncology patients, while evidence-based medicine has so far rejected this type of treatment because of insufficient evaluation.
From the scientific point of view, anthroposophical as well as homeopathic preparations of mistletoe extract are prepared according to their respective doctrines. Manufacturers declare procedures for the standardization of manufacturing (such as procedure standardization, biological standardization, dilution according to the regulations of the German Homeopathic Pharmacopeia, HAB 1). The scientific relevance of these standardization procedures remains in dispute (4).
Experimental Studies
Under the impression that the lectin-carbohydrate interaction plays a role in immunoregulation and that obvious successes of mistletoe therapy can be traced back to the presence of defined components in the extract, various experimental studies focused on proving the efficacy of ML-1. Initial in-vitro studies (Table 14.1) confirmed the immunomodulating activity of ML-1:
• significantly increased expression of activation markers on human/murine mononuclear immunocytes following incubation with ML-1 [e.g., interleukin-2 (IL-2) receptors on T lymphocytes; HLA-DQ antigens on B lymphocytes]
• significantly increased cytokine secretion by human/murine mononuclear immunocytes [e.g., IL-1, IL-2, interferon-γ (IFN-γ), and TNF-α following incubation with ML-1]
• no increased proliferation of tumor cells by ML-1 incubation
• cytotoxic effect on tumor cells (with higher ML-1 doses)
• significantly increased phagocytic activity (chemiluminescence test) of human polymorphonuclear leukocytes (granulocytes) following incubation with ML-1 (1, 4, 8).
Initial designs of in-vivo experiments (Table 14.1) yielded results suggesting an involvement of cytokines in the ML-1-induced immunomodulation. In mouse and rabbit models, administration of the optimal ML-1 dose was followed by increased body temperature, increased activity of defined immunocytes, and also by a significant thymus-activating effect, suggesting that ML-1 strengthens the body’s defense mechanism.
Experiments on the immunoactive effect of the GalNAc lectin in the corresponding murine model did not show comparable effects on the number and activity of immunocytes or on the proliferation, maturation, and emigration of thymocytes.
Because it was feared that ML-1 injections might cause an increase in connective tissue or shift of fluid into the thymus, both of which would imitate thymus-cell proliferation, the number of thymocytes per mg organ weight was determined. Quantitative analysis of the number of thymocytes confirmed the effect of ML-1 on thymocyte proliferation. Statistically, the number of thymocytes was significantly higher after administration of ML-1 than in control animals. This experimental design demonstrates that subcutaneous administration of the optimal immunoactive ML-1 dose obviously induces vigorous proliferation of thymocytes and acts as a stimulus for the maturation of lymphatic cells of both helper/inducer CD4+ phenotype and suppressor/cytotoxic CD8+ phenotype, as demonstrated by means of flow cytometry using monoclonal antibodies. It is interesting to note that the number of double-labeled (CD4+/ CD8+
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
