(Immune system support)
Trial 1: Hay fever
The trial had been performed together with 17 physicians and health practitioners, starting December 2006. Due to an extremely warm winter hazel, alder, birch and willow flowered at the end of February. Assessment was 28.02. In some unclear cases the patients had been contacted by phone. No reaction of a patient with known allergy was taken as positive.
24 patients were assessed at the end of April again. 11 patients finished the trial, 10 of them because they were free of symptoms.
From 35 cases 6 were free of symptoms, 15 were significantly improved and 8 slightly. A verification after pollen count of birch showed an improvement of even 84% (55% significantly better and 32% free of symptoms). In 4 cases out of 5 cases of chronic allergic asthma (3-27 years duration) an improvement could be seen (2 cases free of symptoms (1 case of them chronic since 11 years)).
Trial 2: Hay fever:
imoduSAN was administered for six weeks to 14 patients suffering from hay fever using a dose of three tablets (450 mg each) a day.
|Patient||Age||male/female||Symptoms Improved first days||Symptoms improved after 6 Weeks|
much worse (—); significantly worse (–); worse (-); equal (+/-); better (+);significantly better (++); without symptoms (+++)
In 79% of all cases hay fever symptoms improved. 57% were significantly better or without symptoms.
Trail 3: AIDS
We started with so-called patients beyond treatment in East Africa (Gradl 2011) using imoduSAN.
40 patients (women and men aged between 19 and 48 years) in Kampala (Uganda), suffering from full blown AIDS received orally imoduSAN daily for 90 days. On days 0, 45 and 90 bodyweight, CD4+-counts, virus load, general health status and additional diseases had been recorded.
|Figure 1 Shift of immune response in full blown AIDS Trial 1 Virus copies and CD4+ Cells|
2 patients succumbed to the AIDS virus and two dropped out (could not be examined again) for unknown reasons. On day 90, 28 (74% of 38) patients could be found to be below the limits of full blown AIDS due to CD4+-counts and virus load. Diarrhoea stopped in all of these cases and body weight became normal. In the remaining 10 cases in 8 people health status as well as CD4+-counts and virus load improved significantly. 6 months after the start of the trial 19 patients were able to go to work regularly again.
Trial 4: AIDS
21 patients in Nairobi, Kenya, suffering from HIV/AIDS were given imoduSAN daily for 3 months. One of them succumbed to the AIDS virus after two weeks. One patient left Nairobi and could not be contacted again. 19 patients could be evaluated (4 male and 15 female patients).
|Figure 2 Shift of immune response in full blown AIDS Trial 2 CD4+ cells and body weight|
Age: The age was between 29 and 58 years (an average of 40.7 years). They were tested HIV-positive between 3 month and 8 years (an average of 5.6 years).
- CD4+-count: At the start of the trial CD4+-count was between 52/µl and 453/µl (an average of 209/µl) and 265/µl to 920/µl (an average of 565/µl) three month later. CD4+-counts increased in all cases, in one case even from 52/µl to 532/µl and in another from 58/µl to 485/µl.
- Tuberculosis: 5 patients suffered from tuberculosis, which improved in all cases. After three months three of them were free of tuberculosis, starting from a very severe state. In two cases the health of tuberculosis patients had improved significantly.
- Body weight: In all cases body weight increased, starting with 35 to 85 kg (an average of 52.2 kg) to 46 to 100 kg (an average of 65.0 kg). In one case body weight increased from 37 kg to 60 kg.
Symptoms were recorded only for some patients. It can be assumed that the others did not show these symptoms.
- Night sweats: Disappeared in all but one case. In the remaining case it decreased significantly.
- Fever: disappeared in 2 out of 2 cases.
- Diarrhea: disappeared in 6 out of 6 cases.
- Headache: disappeared in 11 out of 11 cases.
- Pneumonia: disappeared in 4 out of 4 cases.
- General weakness: in 10 out of 11 cases patients recovered completely. In the remaining case health improved significantly.
- Skin thrash: disappeared in 3 out of 3 cases.
- Mental status: improved to normal in 4 out of 5 cases and significantly in the remaining case.
- Respiratory problems: disappeared in 2 out of 2 cases.
- Lipodystrophy, abscess, swelling of the ankles, paralysis, joint pain, herpes, white coated tongue and very dry skin became significantly better or disappeared in single individual cases.
These trials in Africa showed that in full blown AIDS cellular immunity may be restored by imudoSAN. Since health even in terminal cases could be restored it can be inferred that there was a cellular immune deficiency based on which the virus could develop. Due to the questionable virus determination it makes no sense to speculate whether in Africa there are other subtypes of the virus that can be treated more easily.
In Vitro Trials:
Human leucocytes (buffy coat) were washed twice in TC 199 and made up in TC 199 to 4 x 106 cells/ml.
10 concentrations of EGAA-2 in TC 199 in 8 replicates were added in microliter plates (50 µl to 150 µl cell suspension). 2x 8 rows served as controls. After incubation of 48 hours (36°C) INF-γ, IL-2, IL-4, and IL-10 were determined by enzyme-linked immunosorbent assay (ELISA) in the supernatants. Mean changes in percent in comparison to the controls are used as results.
For human dose a body weight of 70 kg and a blood volume of 6 l were assumed.
|mg / 70kg
Mode of action:
The aim of the immune system is to differentiate between self and non-self to eliminate foreign substances like bacteria, virus or other intruders.
Innate immunity: In most cases the intruder is processed in an unspecific way by macrophages being eliminated by natural killer cells (NK-cells) a sort of lymphocytes.
Three reactions are specific to a specific antigen (normally molecules on the surface of bacteria and virus or foreign protein etc.). After being presented to T-helper cells (TH, a sort of lymphocytes) they activate three different ways of immune response:
- Humoral response (TH2 mediated): TH2-cells process the antigen and present it to B-lymphocytes, which transform into plasma cells, producing antibodies specific to the specific antigen. Reacting with the antigen, an antigen-antibody-complex is formed that can be eliminated by macrophages or attach to mast cells starting an inflammatory reaction. Antibodies are effective against most bacteria and intestinal parasites.
- Cellular response (TH1 mediated): TH1-cells present the antigen to specific T-killer cells that can eliminate the intruder mainly via nitric oxide (NO).This response is effective against virus, mycobacteria but also in eliminating the body’s own cancer cells.
- Immunosuppression by Treg cells: Not in all cases is an immune response positive. During pregnancy e.g. a cellular immune response to the (semi-foreign) embryo may result in abortion. Like most reactions, immune reactions tend to overreact and have to be regulated down. This is performed by so-called Treg cells. It would be helpful to find a way to stimulate Treg cells specifically to regulate down autoimmune diseases.
Differentiation of TH1- and TH2-cells: The balance of TH1- and TH2-cells is critical sometimes. Allergies of an immediate type are an overreaction of humoral response (TH2 mediated). In some cases (PMWS in piglets; full blown AIDS in human), TH1-mediated response lacks completely (Maurer, Gradl 2002). Both cases are over-compensated by high antibody titers.
After the decision to start a TH1 mediated immune response (or vice versa) the other type is suppressed by cytokines (IL-10, IL-4, IL-5 or INF-γ, Fig. 9).The suppression of TH2 may increase TH1-mediated response.
TH2 cells are promoted by prostaglandin-2, which is formed from arachidonic acid from cell walls by cyclo-oxygenase-2 (COX2). This enzyme can effectively be inhibited by humulone, the bitter of hops. If applied orally, the necessary quantity however is much too bitter. By using quantum dot-technology the same effect can be obtained by only 3.6 mg per day. This means that using this small amount, a mainly humoral immune response can be turned into a cellular response. The effect can even be enhanced by procyanidines (as quantum dots) acting on T-killer cells (Fig. 10) (Appelton, Tomlinson, Wikoughby 1996).
For allergies of an immediate type, a sufficient number of T-helper cells type 2 (TH2) is necessary. Some specific factors have an impact on differentiation to TH1 and TH2. Prostaglandins cause a shift to TH2.Humulone (hops-acid) inhibits cyclooxygenase 2 being responsible for the formation of prostaglandins.TH1 activates intracellular killing with NO, which plays a pivotal role. NO is cleaved from arginine bythe enzyme NO-synthase. NO-synthase is promoted by procyanidin (from cocoa).
A combination of hops extract and cocoa in a specific preparation together with brown algae used as food supplement caused an improve in hay fever in 79% of all cases. In 57% of them the improvement was scaled significantly better or symptom-free.
- Mechanism of allergies of immediate type (Hypersenitivity Tyoe1)
IgE-antibodies are induced by an allergen. They bind by their Fc-end to mast cells. After a new exposition to the antigen (allergen) the mast cell releases histamine (kininogens), which causes vasodilatation, formation of mucus, spasms of smooth muscles, edema and pustules on the skin.
Whether this reaction occurs depends to which subpopulation T-helper cells (TH) differentiate, to TH1 or TH2. This is mainly controlled by cytokine pattern. The macrophages play the pivotal role by secreting IL-12. IL-12 inhibits the formation of IL-4 and IL-5 (both typical for the development to TH2).
To activate an IgE-producing plasma-cell, a coupling via the CD40/CD40-ligand system to a TH2-cell is necessary. IL-4 controls differentiation from a cell, which produces IgG to a cell producing IgE, while IL-13 induces the production of antibodies.
Many parameters are known to control the decision to TH1 or TH2. Besides cortisol, antibiotics, progesterone and chemotherapeutics a lack of proteins, chronic tuberculosis, pregnancy and aging cause the switch to TH2. (Betz et al 1991; Gold et al 1994; Hilkens et al 1995; Kasakura 1998; Katamura et al 1995; Kremer 2002; Lucey et al 1996; Mosmann et al 1996). The same is true for a lack of folic acid (Beisel 1996) and a lack of DHEAS (Biglieri 1988; Hilton et al 1988; Raffi et al 1991; Christeff et al 1996; Ferrando et al 1999).
To find a treatment for allergies, scientific research has focused on inhibiting IL-4 and partially IL-13 but also IL-5 and IL-12 to avoid differentiation to plasma cells producing IgE (Borish et al 1999; Borish et al 2001; Cieslewitz et al 1999; Grunig et al 1998; Hasko et al 1998; Horejs-Höck et al 2003; Mueller et al 2002; Reinemer et al 2000; Stolzenberger et al 2001; Wills-Karp et al 1998).
It is possible to control differentiation of helper T-cells to TH1 by using some natural substances One example is cimetidine (Ishikura et al 1993) being an activator for IL-12 but also humulone from hops extracts (Honma et al 1998; Shimamura et al 2001). Humulone inhibits cyclo-oxygenase-2 whereby fewer prostaglandins are released from arachidonic acid. Prostaglandins switch the differentiation to TH2. Ca++-dependent induced NO-synthase can be promoted by procyanidine (e.g. from cocoa) (Malina et al 2000).
An important effector in cellular immunity is NO, being cleaved from arginine by NO-synthase. The same parameters, which activate cyclo-oxygenase-2 in general, activate induced NO-synthase. In both cases the substances interact with a series of receptors triggering a cascade of transmitter signals, which activate transcription factors and promote genetic expression for biosynthesis of cyclooxygenase- 2 (Appelton et al 1996; Cishek et al 1997; Goppelt-Struebe 1995; Herschman 1996; Minghetti et al 1998).
- Therapy of allergy of immediate type
Allergies are a widespread, growing disease. In Germany 12 million patients are suffering from allergic rhino-conjunctivitis, 6 million from cross-reacting nutritional allergies and 4 million from asthma bronchial.
In many cases avoiding of contact may be the choice. In house dust, pollen and often in nutritional allergies this is nearly not practicable however. The only specific therapy against allergies of an immediate type is the so-called specific immunotherapy (hyposensibilization) For a period of 3-5 years the allergen is administered in growing doses. In many cases IgG-antibodies instead of IgE-antibodies are produced. In cases of insect sting allergies 95% of all cases can be treated successfully, and in cases of house dust allergies 70% of all cases can be treated successfully.
For prophylaxis and (symptomatic) treatment, mainly antihistaminics and mast cell stabilizers are used. They inhibit the release of the mediator histamine. Mucous membranes shrink after oral or local (eye or nose) administration. Contrary to first generation antihistaminics, these drugs now no longer cause fatigue. The most important active substances are chromoglycidic acid stabilizing mast cells and cortisol, which soothes inflammation. In the beginning, high dosed calcium may be helpful. Complementary medicine is used frequently since allergies are a widespread disease and antihistaminics are more or less only symptomatic. In many of these therapies like autoblood treatment, a TH1/TH2-switch may be the mechanism. It also is well known that psychic factors play a role. Suggestion therapy can sometimes be chosen. This leads to inhibition of neurotrophins occurring excessively in allergies and remaining for days and weeks. We now know more about these neurotransmitters produced as well by nerve and immuno competent cells. At the moment the use of cytokine blockers is limited to trials.
The reason of AIDS is still unknown. After a quarter of a century, we know AIDS is a cellular (TH1-modulated) immune deficiency or even a complete lack of it. As a consequence, there is no protection against viral diseases (and infections with mycobacteria, like tuberculosis and leprosy) and cancer cells. This may end in death. From the beginning it was guessed, it could be a viral infection of the immune system. The virus however (a retro virus is assumed) is not identified according to classical microbiological criteria. On the other hand, just as little, it is not proved that the virus does not exist.
Just as well, virus identification by PCR only, has to be distrusted. A PCR gives me a very good fingerprint, but, “there is no use of a fingerprint for the detective if he has no suspect” (freely quoted from Karin Mullis who invented PCR).
A cell count of T-helper cells (with CD4+-marker) in peripheral blood is as questionable. It does not differentiate between TH1 and TH2 and there are other cells bearing the same marker. We well know that a lack of one type of immune response is often compensated by a high activity of the other type. Therefore an increasing CD4+-cell count does not indicate an increase in cellular immune response. From trials in pigs suffering from PMWS, we know that TH-cell count in peripheral blood does not correlate with cell counts in lymph nodes. In one of the biggest studies on antiviral medication of AIDS (Lederberg et al. 2006) over 10 years with 22000 patients from 811 physicians and 22 countries only a mean increase of CD4+-cell counts from 170 to 200/µl by antiretroviral treatment resulted (standard value 400-1500/µl). In the summary this small increase was related to mortalities: “Virological response after starting HAART improved over calendar years, but such improvement has not translated into a decrease in mortality”. More clearly: the treatment improved laboratory parameters but not health.
Despite these analytical doubts virus load and CD4+-cell counts had been used in the following trials. They are parameters therapists are familiar with. If a new disease appears, accompanied by a virus (like AIDS 25 years ago) two hypotheses result:
- The virus can develop, because there is a lack of cellular immune response
- The virus (in TH1-cells as hosts) causes the lack of cellular immune response
Depending on which of these hypotheses is right, two diametrically opposed treatments result. In the first case cellular immune response should be restored, and by promoting TH1-cells the virus should be eliminated.
In the second case the virus has to be attacked. It is not possible to kill a virus (in physiological conditions) for the simple reason that it is without its own metabolism and is not really living. It is necessary therefore to kill the host cell. This is performed by substances causing a termination of DNA like NRTI and NNRTI, while the third part of a triple therapy, a proteinase inhibitor, unfortunately kills mitochondria if used in the usual concentrations.
For another cellular immune deficiency, occurring together with a (identified) circo virus in piglets, PMWS (Post Weaning Multisystemic Wasting), we developed a method (Gradl 2004) to switch the balance between TH1 and TH2 in favor of TH1. By humulone, the bitter of hops as quantum dot (Gradl 2008), prostaglandin formation is inhibited and TH2 is reduced. In this way TH1-cells are promoted. Using procyanidines as quantum dots effector cells of cellular immunity are improved. In addition we used a guluronan complex from alginic acid, improving oxygen transfer to cells significantly (Gradl, Maurer 2000). This mixture had been completed by extracts from cloves and nutmeg (both inhibit prostaglandin formation), lemon skin (anti-oxidant) and thyme (adaptogen). Used in feed, in piglets suffering from PMWS, it was possible to increase daily weight gain by 13.8%, feed conversion by 16% and to reduce losses significantly. These are nearly values that can be expected in piglets without PMWS. In this case the second hypothesis proved to be right. After restoring cellular immunity the animals could cope with the virus. TH1-cells i