The present article is related to the observation made by the author in his two and half decades of clinical practice on the cure of the divergent inflammatory diseases such as Asthma, Arthritis, Tuberculosis, etc. by administering a single molecule/ medicine. Extensive literature and patent search could not present any scientific explanation for the phenomenon observed and reported. Preliminary research at the author’s clinic and lab has enabled the postulation and confirmation of a novel theory and immune pathway involving Histamine haemostasis referred to as the Rao’s Vicious Cycle. In this study the medicine used belongs to the category of allergies, a new mechanism is proposed for the action of mediators during the inflammation. It has been postulated that the histamine liberated from the mast cells is the key link among the divergent diseases. During inflammation, histamine is released at the inflammatory sites as predicted by Rao’s vicious cycle. The later refers to the proliferation of TH2 type of reaction and its dominance over TH1 reaction. In this method of cure known as Appa Hista, antihistamine antibodies, combat the histamine at the inflammatory sites and also block TH2 type of reaction, thus indirectly helping the TH1 type of reaction. The dual effect of Appa hista antibodies has been visualized in 1) Killing the intracellular organisms through TH1 type of reaction and; 2) Neutralizing the histamine at inflammation site at the same time blocking the excess TH2 type of reaction. Since Appa Hista directly attacks histamine where ever it is present, it may cure all inflammatory diseases.
The present investigation deals with the cure of some of the most stubborn problems such as paralytic stroke, arthritis, tuberculosis etc., by using histamine conjugated normal human immunoglobulin. Histamine is a chemical mediator and also the prime mediator of inflammation. It is a vasoactive amine, found long back and established as a chemical mediator of inflammation. This compound is essential for vascular permeability and allows the vessels to leak the protein rich exudate and cells to the site of inflammation. The latter is divided into two groups: 1) Acute inflammation and 2) Chronic inflammation. While chronic inflammation may originate as chronic itself, an acute inflammation, may, over a period of time become chronic. The inflammatory response is closely coupled with the process of healing or repair. A foreign body (agent) always wants to destroy the host tissue for its settlement, while, the host always tries to get rid of the agent as it is foreign. Thus, inflammation can be considered as a protective response of the host and serves to destroy, dilute or wall off the injurious agents, and, also as far as possible heal and reconstitute the tissues.
Normally, inflammation is an immunological (protective) phenomenon and, pain is a protective signal to get rid of the stimuli (causes). At times they become pathological and produce disease.1 Repair begins during the early phases of inflammation but reaches completion usually after the injurious influence has been neutralized. During repair the injured tissue is replaced by parenchymal (functional) cells or by filling of the defect with fibroblastic tissue (scarring) or most commonly by a combination of these two processes. The defense mechanism is such that the system tries itself best to give protection by innate immunity. Alternately, if the agent is a stronger one, then only the acquired immunity is triggered either by humoral immunity (present in body fluids) or by cell mediated immunity or by both. The humoral/cell mediated immunity is offered by several preformed or existing proteins like compliment and antibodies, or, by cells like macrophages, lymphocytes and neutrophils. When an agent initiates an injury, the defense mechanism is triggered by release of mediators. Rather than too few, there are a large number of mediators in the defense system.
Cells of the immune system:
The cells that are developed in the bone narrow mature and liberate into the blood stream. A few cells settle in the tissues and lympho reticular system to perform their immunological function. The cells in the blood are red blood cells (RBC) white blood cells (WBC) and platelets. Red cells supply oxygen to all the systems. White blood cells defend body from foreign stimuli and platelets help in clotting.
The WBC is further divided into Granulocytes, lymphocytes and monocytes. It is well known that granulocytes are further divided into polymorpho nuclear leucocytes, Eosinophils and Basophiles. Lymphocytes are divided into T cells, B cells and NK cells. Monocytes are referred to as monocytes in the blood and as macrophages and mast cells in the tissues.
Mediators are found in cells as well as in plasma. Mediators are classified into preformed mediators and newly synthesized mediators. Preformed mediators always exist even in the absence of the inflammatory stimuli. These are histamine, serotonin, lysosomal enzymes which are generated by the cellular sources mast cells, platelets, neutrophils, macrophages etc. The newly synthesized mediators, on the other hand, are formed in the presence of an inflammatory stimulus. These are prostaglandins, leucoterines, and platelet activating factors, cytokines, and nitric oxide etc., generated from cellular sources such as leucocytes, platelets endothelium and macrophages.
Under the influence of an inflammatory stimulus certain proteins in the plasma like complement under go chain reactions releasing intermediary substances like C3a, C5a and C5b – 9. C3a is an anaphylotoxin attracting histamine to the site, while C5a attracts neutrophils to the site. C5b – 9b, on the other hand, are believed to create MACs (membrane activating complexes) and cause target cells lysis (destruction). A plasma protein known as Hegeman factor, on the other hand, activates, clotting/ kinin cascades resulting in blood clotting and pain.
Immune response (IR):
The response initiated by an antigenic stimulus in the cells and mediators in a host is known as immune response. As is well documented IR can be divided in to two types such as the humoral (antibody mediated immunity (AMI)) and the cellular (cell mediated immunity (CMI)). AMI refers to interaction of antigens with antibodies present in the plasma and in the interstitial fluids (extracellular), resulting in neutralization. CMI refers to the direct killing (lysis) of intracellular bacteria through various cytokines secreted by T lymphocytes.
The current state of understanding regarding immunological reactions can be summarized as follows. Briefly the I Anaphylactic, II Cytolytic and III Immune complex reactions eventually generate TH2 (T Helper cell sub set 2). The latter generate the IL4 IL5 and IL10 (interleukin cytokines) which take part in allergic reactions, basic healing and also provide opposition to the TH1 subset. TH1 subset forms in delayed type of hypersensitivity reaction (type IV) and includes the cytokines IL2, TNF and IFN contributing to intracellular killing.
Two decades of clinical practice in curing various inflammatory diseases and the possible common link between these is summarized in Table 1. The latter clearly points out the administering of the medicine for a primary disease such as Asthma which was found to have a beneficial affect on Arthritis, and so on. Thus, a single medicine normally used in treatment of allergies had resulted in cure of several inflammatory diseases which are hitherto being treated separately. Animal experimentation at All India Institute of Medical Sciences (AIIMS) confirmed the anti inflammatory properties of the medicine.2 This necessitated a re-look in to the fundamentals of cells, mediators and immunological response. Literature and patent search revealed that in 1994 a US patent was granted to Yoshi et al from Japan.3
Subsequently relief by the treatment has been observed in the following inflammatory diseases;
(a) Rheumatic diseases: Rheumatoid arthritis, SLE, Seronegative arthropathies, including reactive arthritis, ankylosing spondylitis, psoriatic arthritis, and various vasculitides.
(b) Nervous system: Paralysis (Cerebro vascular accident due to vasculitis), Encephalitis, Tuberculomas, multiple sclerosis, Epilepsy, peripheral neuritis, migraine, Guillian-Barr’e syndrome.
(c) Respiratory system: Bronchial asthma, TB, Drug resistant tuberculosis, and pulmonary mycotic conditions.
(d) Renal: Glomerulo nephritis, chronic renal failure, nephrotic syndrome.
(e) Genitourinary system: Chronic UTI, Stress incontinence, chronic leucorrhoea, and infertility.
(f) Heart: Hypertension, Rheumatic heart diseases, (also with CCF, Choria) Congestive cardiac failure, Atherosclerosis. Global hypokinesia.
(g) Skin: Chronic venous (Sephanous) ulcers, psoriasis, Lepraneuritis, and Vitiligo (Early Stage).
(h) Eye/ ENT: Iridocyclitis, Uveitis, Retinal detachment, Glucoma, Vasomotorrhnitis, Epistaxis, Allergy, Miners disease.
(i) Gastrointestinal diseases: Peptic ulcer, IBS, Ulcerative colitis.
(j) Psychiatric: Stress related syndromes. Dementias.
(k) Infectious diseases: Cerebral Malaria, Filariasis, Fungal infections and DIC.
(l) Pains: Cancer pains, chronic pains, few cancers arrested.
(m) Endocrine disorders: Thyroid, Diabetes.
COMMON LINK AMONG INFLAMMATORY DISEASES
Reorganization of cells
In the present methodology, the cells are reorganised into cells presenting antigens, cells required in processing antigens and intermediary cells, and, cells found at the site of inflammation. Of particular importance is the role played by intermediaries such as mast cells and basophiles. As will be seen later these are essential for release of histamine, and therefore, key agents for initiating and maintaining the inflammation. It is thus imperative that any control on mast cells should control the inflammatory diseases.
Mast cells4,5 are bone marrow derived tissue resident cells, relatively large in diameter (10-15 mm) and heterogeneous in shape. Under optical microscope the mast cells reveal 50 to 200 densely packed granules in each cell, each granule in turn is bound to membrane. A typical granule of 0.1 to 0.4 mm contains relatively large amounts of histamine, heparin, TNF and other preformed inflammatory mediators. The surface of the each of the cells is coated with high affinity receptors ecoR1, which attracts IgE molecules on the surface of mast cells. Following the attachment of the IgE molecules on the mast cell surfaces, the granules start degranulating. Although mast cells are found in connective tissues through out the body, these are present in large numbers beneath the surface tissues such as skin, lung alveoli, gastrointestinal mucosa and nasal mucus membranes. Thus, mast cells are strategically positioned to interact with inhaled or ingested antigens.
Mechanism of Mediators:6
Histamine at the inflammatory site has a long life (30-60 mts), and, is stable as compared to most mediators derived from phospholipids and nitric oxide. As is well known histamine triggers all the mediators and vice versa. Therefore, in any physical injury such as trauma, cold or heat, the activation of already stored histamine from the mast cells is expected to play a dominant role.
Histamine receptors on lymphocytes:7,8,9
In the proposed protocol it has been postulated that histamine can trigger lymphocytes in releasing other mediators. This is possible only if there is histamine receptors present on the lymphocytes. This assumption has received a recent support from several researchers. Similarly, the action of T cells in the histamine homeostasis10 (self-regulating information feedback) is proposed to take place as illustrated in Fig. 1. An important point to note is that IL6, IL8 and TNF etc., present at the inflammatory site due to tissue injury are also capable of liberating histamine.
IgE B Cells:
The IL4 cytokine is expected to play a dominant role in sensitizing CD4 cells and through it the effector cells i.e. B cells and CD8 cells. Further, in a double pronged manner IL4 can directly sensitize an IgE B cell which in turn releases IgE and acts on mast cells to liberate histamine. The latter in turn goes to the inflammatory site and causes healing through TH2 type of reaction. In case the inflammation is larger, it may turn in to chronic due to liberation of cytokines IL4 IL6 TNF etc.11 These in turn, in a positive feed back cycle, trigger histamine release and aid in maintaining chronic inflammation. This vicious cycle of generation of histamine at the site of injury and its subsequent triggering of IgE B cells ( Histamine pathway II) and CD4 cells ( Histamine pathway I) is termed as Rao’s Vicious cycle. That is strong inflammation can turn into chronic inflammation by the continuous generation of excess histamine in repeated positive feed back cycles. Micro organisms may be exploiting this phenomenon in producing chronic inflammation and autoimmune diseases.
Rao’s Vicious Cycle and it’s interaction with three immunological pathways
As is well known, any immunological reaction operates through three different path ways as shown in Fig.2. The path way 1 is known as IgE / mast cell / mediator path way can be sub divided to reflect physiological and pathological conditions as path 1a and path 1b respectively. It can be noticed that in all the physiological conditions histamine is liberated and together with TH2 affect the cure. The pathological conditions of inflammation on the other hand may turn in to chronic inflammation due to the excessive generation of histamine in a cyclic manner as explained earlier by Rao’s vicious cycle.
Fig. 2 depicts the details of physiological and pathological path ways. The difference between the 3 path ways is in the sources of histamine and also in the intermediaries.
Evidently, the histamine at the inflammatory site together with TH2 cures the inflammation. Thus, histamine physiologically plays a role as type of switch for TH1 or TH2.
IgE/mast cell/mediator path way12 (Fig. 3a) depicts the physiological path way which sets TH2 type of reaction after an allergic inflammation, there by affecting cure. Fig. 3b depicts pathological path way where in the presence of local cytokines IL4, IL6, INF etc., at the inflammatory site trigger the release of excess histamine over and above that required for maintaining histamine homeostasis. This in turn triggers IgE B cells and in a cyclic manner contributes to release of more histamine making the inflammation chronic. This in brief is the Rao’s vicious cycle proposed to be applicable for chronic inflammatory conditions.
The IgG, IgM/Complement/neutrophil pathway as shown in Fig. 4, includes the pathological path 2b. Typically IgG / IgM immune complex interacts with complement, which releases C3a and C5a and bring histamine and neutrophilis into the site. The presence of IL4, IL6, IL8 etc. at the inflammatory site trigger histamine and in turn the Rao’s Vicious Cycle. The TH2 type of reaction, although, helps in healing process in physiological (2a) inflammation through the parenchymal cells, the excess of TH2 found in pathological inflammations can cause over healing, resulting in scaring and stiffening.
In the physiological path way 3a as shown in Fig. 5, theCD8 cells kill the intracellular organisms by TH1 type of reaction, and, the TH2 type of reaction set by histamine heals
through parenchymal cells. Pathological path 3b (T lymphocyte / lymphokine pathway) directly kills the intracellular organisms by TH1 reaction through the cytokines liberated by CD8 cells. However, the TH2 cytokines liberated from IgE B cells and the associated excess histamine through Rao’s Vicious cycle contribute to the chronic nature of inflammation. Thus, in spite of the killing of intracellular organism (TH1 action) the inflammation continues (by TH2 action which opposes TH1). The pain13, stress, and cancer cytokines are also the same as those that cause inflammation and, so can trigger Rao’s Vicious cycle.
Appa Hista refers to the proposed method of curing inflammation using anti- histamine antibodies while exploiting the fundamental phenomena of Rao’s Vicious cycle. It is by now clear that the histamine homeostasis in the body is disturbed during inflammation. Antigen administered in the physiological condition of inflammation reacts with IgE B cells generating the IgE and in turn through TH2 type of reactions affecting the cure. More serious is the pathological condition leading to chronic inflammation. Rao’s vicious cycle plays a major role in generating and maintaining histamine levels above those required for histamine homeostasis. It is interesting to note that the generation of excess histamine is found in acute and chronic inflammation. The cure therefore is to see that antibodies are generated to combat against histamine. In Appa Hista method, histamine conjugated normal human immunoglobulin is intramuscularly injected. It works like a vaccine. This most likely reaches all the lymph nodes and stimulates B cells to produce IgG antihistamine antibodies (also referred to as Appa Hista). The antibodies in turn reach the inflammatory site and neutralize the histamine i.e. it breaks the Rao’s vicious cycle, either directly or enhance the histamine binding ability of the plasma. The histamine binding/ diluting ability is as high as 30 times in normal individuals as compared to that of suffering from allergic inflammation in normal individuals.14
Appa Hista’s main advantage is that it neither interferes in primary histamine release nor causes any immuno suppression. During the past two decades of clinical practice, the author had cured couple of hundreds of patients of both sexes with age groups ranging from 10 to 60 years. The relief from inflammatory diseases found in most cases range from good to excellent (patent application status). The intensity of the disease is found to be reduced on the administration of the medicine along with the gradual increase in the time periods at which the medicine has to be re-administered. This may takes 3 weeks to 3 months depending up on the intensity of symptom. An interesting feature is that the patients felt totally comfortable during in between drug administration periods along with a general feeling of well being, which was not the case with steroids or any other drugs.
There are no side effects observed in the Appa Hista method of cure and applications. It is however found that the method is not very effective in the case of smokers, and alcoholics. From an economic view point the treatment is inexpensive as compared to current day methods used. Also, the drug, which is already bio-assayed and available in the market for last 30 years can be easily procured and administered.
A link is observed among the inflammatory diseases and it is identified as Rao’s vicious cycle. Histamine is present in human body in levels corresponding to that required to maintain histamine homeostasis. During inflammation, histamine is released at the- inflammatory sites as predicted by Rao’s vicious cycle. The later refers to the proliferation of TH2 type of reaction and its dominance over TH1 reaction. In the Appa Hista method of cure, antihistamine antibodies combat the histamine at the inflammatory sites and also block TH2 type of reaction, thus indirectly helping the TH1 type of reaction. The dual effect of Appa hista antibodies can be visualized in:
1) killing the intracellular organisms through TH1 type of reaction, and,
2) neutralizing the histamine at inflammation site at the same time blocking the excess TH2 type of reaction.
Since Appa Hista directly attacks histamine where ever it is present, can cure all inflammatory diseases.
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