Russian methodological letter.pdf

Ministry of Health and Social Development of the Russian Federation Transfer Factors Use in METHODOLOGICAL LETTER

MINISTRY OF HEALTH AND SOCIAL DEVELOPMENT OF THE RUSSIAN FEDERATION Director of Medical Service and the Department of Treatment Developmentfor Health Recovery Resorts (Kurortology) (Signed and Sealed) 30.07.04 No. 14/231 TRANSFER FACTORS USE IN AND SOMATIC DISEASES Methodological Letter Copyright 2005 by Center of MicroNutrientology Published by:Center of MicroNutrientologyMoscow, Russian Federation Printed in the United States of America.
Transfer Factors Using Immunorehabilitation
After Infectious-Inflammatory & Somatic Diseases
This communication presents the results of clinical trials, which were designed to study theeffectiveness of a complex colostrum derived product, Transfer Factor™ (and Transfer FactorPlus™), in various pathological conditions and to study the influence of cellular mediators,which are incorporated in Transfer Factor, on different components of the immune system.
The authors give recommendations concerning the use of Transfer Factor products in medicalpractice.
This methodology letter was considered and approved at the Central Coordination meeting ofthe Methodological Council of Altay State Medical University (protocol No 4, 05.11.2033)and sent to the Ministry of Health and Social Development of the Russian Federation for theirconsideration.
AuthorsAcademician A.A. Vorobiev, Russian Academy of Medical Sciences (RAMS), HonoredRussian Federation (RF) Scientist, Doctor of Immunology.
Professors Iu.V. Telnukh, MD and E.O. Khalturina, MD, Sechenov Medical Academy,Moscow, HM, RF.
Professor M.V. Kisielevsky, MD, Russian Blokhin Cancer Research Center, RAMS.
Doctors N.V. Karbuishea, MD, Professor V.M. Granitov, and Associate Professors A.S.
Khabarov, D.V. Kipriyanov, N.Iu. Raiu, Municipal Hospital #5, Altay State MedicalUniversity, Barnaul.
Candidates of Medical Sciences L.V. Sultanov, E.Iu. Kozhevnikova, S.I. Belyikh, AltayRegional Center for AIDS Prevention and Control.
Professors V.A. Dadli, A.V. Rak, E.S. Stolpnyik, Candidates G.A. Baslovich, L.B.
Gaykovskaya, St Petersburg's Mechnikov State Medical Academy.
Doctors E. Oganova, MD and C.W. McCausland, PhD chemical sciences, 4Life Research,USA.
Associate Professor G.M. Letifov, MD, Rostov State Medical University.
Reviewers:Academician B.A. Tutelian, Director of RAMS Research Institute of Nutrition.
Professor A.V. Karaulov, MD, Clinical Immunology Department, Sechenov MedicalAcademy, Moscow.
Transfer Factors Using Immunorehabilitation
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2. Current Concepts of the Development of Immune Response Mechanisms and the Restoration Principles of Impaired Functions of Immune Cells . 6 3. Colostrum Derived Transfer Factors - A New Generation of Immunomodulating Agents. 9 4. The Use of Transfer Factors in Various Diseases . 12 5. Methods of Transfer Factors Use and Recommended Doses. 18 6. Conclusions . 20 7. References. 21 Transfer Factors Using Immunorehabilitation
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1. Preface
Advances of civilization, scientific and technical progress and achievements in medicine have not helped to reduce the incidence of infectious and non-infectious diseases among thepopulations of the planet. On the contrary, the number of oncological, cardiovascular,respiratory and endocrine diseases and neuropsychiatic disorders is growing.
A new group of so-called emerging inflections, including AIDS, parenteral types of hepatitis and others have appeared. The Earth's population experienced a decrease in generalresistance due to globally unfavorable social (malnutrition), ecological (the atmosphere andthe environment pollution with many from modern technology) and medical (unjustified useof some medicines, narcotics, alcohol, stress and so on) factors that are some of the causes ofthe existing situation. All of these factors are pernicious to the immune system and can causeimmunodeficiency.
The use of immune modulators is one of the principal means in maintaining normal immune system function and in restoring immunity in immunodeficient conditions. Immunemodulators both natural and synthetic substances are capable of stimulating or suppressing theimmune system.
A multitude of immune modulators are used in medical practice but their effectiveness and the other properties defining their safety, simplicity in use and economy factors differ greatly(A.A. Vorobiev, RAMS Bulletin, #4, 2002). Natural, endogenous immune modulators, whichcontain basic substances that take part in the processes of immune regulation, are the mostacceptable and adequate for humans. Being composed of natural peptides obtained from cowcolostrum Transfer Factor™ is considered to be one such immune modulators. The mainfunction of these peptides in the body is to provide immune protection against microbes(bacteria, viruses, fungi, protozoa), cancerous cells, and other antigens capable of disturbingvital processes in the body.
Transfer Factors stimulate the cellular arm of the immune system (killer lymphocytes in particular), activate immunocytokine synthesis, and regulate immune functions. TransferFactor is superior to other, even well known immune modulators being extremely effective inboosting the immune system. It possesses a broad spectrum of action, is safe, is used orally asgelatinous capsules, has no contraindications, causes no adverse reactions and is effectiveboth in adults and children.
Transfer Factor has been successfully used for many years for the treatment and prevention of bacterial, viral, fungal infections, parasitic disease, malignant tumors, autoimmuneconditions, neurasthenic, allergic and endocrine disorders, primary and secondaryimmunodeficiencies and in diseases accompanied by disturbances in immune functions.
Transfer Factor™ and Transfer Factor Plus® products have been extensively studied in Russian clinics and research institutions. This helped to generalize clinical results into theform of methodological recommendations. This methodological letter is meant to acquaintphysicians, medical students, clinical residents and post graduates with current information,concerning the mechanisms of the immune system response to exogenous factors of viral andbacterial origin, with the properties of Transfer Factor products and the results of the studiesaimed at the evaluation of their effectiveness in various pathological conditions.
Academician Anatoly A. VorobievRussian Academy of Medical SciencesRussian Federation Honored ScientistDoctor of Immunology Transfer Factors Using Immunorehabilitation
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2. Current Concepts of the Development of Immune Response
Mechanisms and the Restoration Principles of Impaired Functions
of Immunocompetent Cells
The last decades of the 20th century and the beginning of the 21st century are characterized by a high rate of infectious diseases connected with proliferation of pathogenicmicroorganisms and an increased aggressiveness of opportunistic microflora.
The significance of the problem of infectious diseases prevention has become especially pressing due both to the emergence of formerly unknown diseases (AIDS) and the absence ofthe effective prophylactic treatments for a number of well known infections (acute respiratorydiseases, acute intestinal infections, etc).
The high rate of viral and bacterial infections is caused not only by resistance developed by microorganisms but also by disorders in the host's protective mechanisms resulting fromnumerous external and internal risk factors, and from congenital and acquiredimmunodeficiency.
Despite noticeable advances in the field of specific prophylaxis and antibacterial therapy of infectious diseases, the problem is still very pressing due to the acquired resistance bypathogenic microorganisms to modern methods of treatment. The situation appears to be aneverlasting struggle between pathogenic microorganisms and humanity in the struggle forsurvival. In this situation the only alternative to vaccination or antibacterial therapy may bethe use of immunomodulators that improve specific and nonspecific immunity againstinfections and regulation of immune system function. Immunomodulators may prove to bevery valuable in strengthening specific immunoprophylaxis during emergency stimulationswhen the body's defensive mechanisms meet the challenge of a virulent infection, inconfronting an unknown pathogenic organism, in cases of an increased risk of infection, orconventional treatment failures.
Antigen immunogenicity and recognition play an important role in defining the character of interrelations between a foreign agent and the host and the formation of adequate specificimmunity (35, 48). Phagocytosis of microorganisms followed by intracellular digestion is theinitial phase of an immune reaction. Polymorphonuclear neutrophils and macrophages are themain phagocytic cells. A cascade of enzyme reactions promote activation of the humoralimmunity linked non-specific factors (complement components), thus increasing capillarypermeability, enhancing Polymorphonuclear leukocytes chemotaxis and resulting in theingestion of microorganisms by phagocytes. Numerous intracellular oxygen dependent andoxygen independent bactericidal mechanisms are then employed. The inflow ofPolymorphonuclear leukocytes and increased vascular permeability lead to a powerful acuteinflammatory antimicrobial reaction.
Certain specific antibodies destroy microorganisms that either fail to trigger an alternative pathway of complement activation or prevent phagocytic cell activation. An antibody forms acomplex with an antigen and activates complement in a classical manner followed byenhanced Phagocytosis.
Antibodies are formed by plasma cells, B-lymphocytes being their precursors. Each B- lymphocyte is programmed to synthesize certain specific antibodies consisting of IgA, IgM,IgG, IgE or IgD.
Another lymphocyte population, namely T-lymphocytes, controls other types of disease agents including intracellular infections. Like B-lymphocytes, each T-lymphocyte is providedwith a specific receptor, which recognizes an antigen. Later T0-cells are differentiated intosubpopulations forming T-helpers (Th), which participate in the formation of cytotoxic T- Transfer Factors Using Immunorehabilitation
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lymphocytes and T-suppressors (Ts), which monitor the strength of immune response andnatural killer (NK) cell response.
The two-stage system of specific immune response development which has been confirmed both experimentally and clinically, is a vivid illustration of an antigen's highlyimmunogenic influence (49). According to this concept it is the directive activity of cellularmediators (cytokine) that causes macrophage activation, Phagocytosis of microbes (viruses)and presentation of the most immunogenic antigens to T-lymphocytes with ensuingdifferentiation. It is established that during the first stage of immune response a macrophage isactivated both by its own cytokines (IL-1) and by cytokines (macrophage activating factor,IL-2 & 4, INF-a, INF-g) produced by the Th0 lymphocytes. This complex of cytokines isunderstood to induce activity of the 2nd class of antigens of the Major HistocompatibilityComplex (MHC), which are on the membranes of antigen presenting cells (49, 51, 56).
Macrophages and other antigen presenting cells present the antigens to T0-lymphocytes totrigger the specific cellular response phase of immune response.
It should be pointed out that both production and activation of cellular reaction mediators (cytokines) under physiological conditions occur simultaneously with the cytokinesfunctioning as a unified harmonious system. An impact on any one component of the immunesystem inevitably affects the function of its other components (50). This forms the basis of themodern theory of the immune system network regulation (24, 50), which postulates that eachsingle element of immune cytokine regulation is functionally related to many other elements.
Thus, the entire cytokine system is a network structure undergoing constant interaction among its different components and this is why an imbalance of the cytokine networkfunction lies at the basis of pathological manifestations in many diseases (41). Both the typeof immune response and the processes of cellular proliferation and differentiation in thehemopoietic and immune systems depend on cell mediator balance.
Previously, R.M. Khaitov and B.V. Pinegin (49) presented a scheme describing the staged development of a specific immune response to a highly immunogenic antigen of bacterial orviral origin. According to the scheme, infectious antigens first activate non-specificpreimmune resistance mechanisms including: • Factors of natural resistance that are more active during the first 4 hours; • Factors of an early inducible response that last for 96 hours.
In light of modern findings the interrelations and the roles of populations and subpopulations of lymphocytes and cytokines, the mechanisms of interaction of allcomponent factors of non-specific monocytic-macrophagal origin, and the importance of theactivity of class 1 and class 2 antigens of the MHC for the development of a specific phase ofthe immune response, are defined and stressed at all stages of development of immuneresponse.
The effect of antigens with low immunogenic response differs strongly from that of antigens with high immunogenic response. Low responders are not capable of reacting withantigen presenting cells, of causing activation of the immune system macrophagal responsewith the production of the first phase cytokines, or of increasing the number of the class 2antigens of the MHC (1, 2). In chronic infectious-inflammatory diseases caused byopportunistic flora, the monocytic-macrophagal phase is not activated and the presentation ofthe complex (antigen plus class 2 MHC determinant) to Th0-lymphocytes followed by thedevelopment of the specific phase of the immune response does not take place.
The formation of an adequate and stable immunity resulting from vaccinations of children depends not only on the immunogenic properties of the antigens of the immune response, but Transfer Factors Using Immunorehabilitation
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on the strength as well as the decisiveness of the immune response. Weak immune or atopictype immune responses do not mount a strong initial and collective resistance to infection.
The preferential production and activation of certain cytokines may be a market of a given pathological condition. Thus, children suffering from upper respiratory tract inflammatorydiseases with frequent exacerbations that respond poorly to traditional therapy, exhibitincreased production of proinflammatory cytokines (47). Long term immune function underconditions of chronic recurrent infection probably leads to a shift in cytokine balance to analtered quantitative and qualitative scale accompanied with a constant stimulus for theirexpression, thus supporting the inflammatory process. In this situation immunomodulatingtherapy may contribute to renewed response and initially to the production ofproinflammatory cytokines activating an otherwise quiescent process against the infection. Awell known approach to the treatment of persistent dormant infections is based on thisprinciple. It is aimed at their provocation followed by effective complex treatment. There areconvincing clinical and experimental data on the use of certain stimulatingimmunomodulators being used to activate the monocytic-macrophagal link of the immunesystem (15, 3). Sodium nucleinate myelopid, likopid, polyoxidony, echinacea and others areamong such immunomodulators (14, 17, 23).
The main treatment for non-specific immunotherapy activation is the use of interferon (IFN) products (amyxin, cycloferon, neovir), macrophages, B- and T-lymphocytes asstimulators (thymus products, pirogenal, prodigiosan, etc), natural and recombinant IFN withantiviral and immunomodulating effects as well as interleukins and other cytokines. In somepatients IFN therapy produces side effects and induces autoimmune processes. Thus, evensuch popular agents as IFN can not be regarded as a panacea and their effectiveness in certainviral infections does not exceed 30-50%.
Cytokines are known to regulate the function of antigen presenting cells, thus markedly shortening the period of specific antibody production and enhancing the presentation ofantigens to immunocompetent cells.
Chronic inflammation is a condition of unstable equilibrium between clinically mild protracted inflammatory processes and the response of immunocompetent cells. Disturbanceof this equilibrium may be induced by an additional infection or by immunosuppressiveagents, which suppress the effect or functions of the immune system. Each exacerbation of achronic inflammatory process activates the immune system and restores equilibrium atanother, lower level of defense. Immunocorrecting therapy should be carried out duringremission of these chronic infectious-inflammatory diseases. It may be a three-stage regiment: 1stt period: intensive immunostimulation (20-30 days) 2nd period: maintenance therapy 3rd period: immunorehabilitation Immunorehabilitation measures are a central issue of current human biology. At this stage of the regime natural immunomodulators such as photochemical agents, adaptogens, transferfactors, restorative health resorts and other means should be used more extensively.
Transfer Factors Using Immunorehabilitation
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3. Colostrum Derived Transfer Factors – A New Generation of
Immunomodulating Agents
The discovery of transfer factors by H.S. Lawrence in 1949 marked the beginning of a new era in the development of immunology (32, 33, 54). He established that immunity can betransferred from one person to another by injecting a leukocyte extract containing moleculesnamed transfer factors. The superb properties of these immunoactive signal molecules calledtransfer factors are capable of revolutionizing medicine.
According to Kirkpatrick, et al (46) transfer factors are peptides consisting of 44 amino acids. Unlike antibodies, which have large molecular masses, transfer factor molecules areonly a small faction of antibody size and have molecular weights of less than 10,000 daltons.
According to some authors the boundaries are between 3,500 to 5,000 daltons.
It was later found that transfer factors are not species specific but possess a versatile effectiveness irrespective of the biological species of donor or recipient. Therefore, they maybe sourced from different mammals, i.e. they can transfer immunity to people even if they arederived from a different mammal species. According to literature data transfer factors exertmultitudinous impacts on the immune system, regulating functions of T-suppressors, T-killersand macrophages (31).
Transfer Factor™ (TF) (produced by 4Life Research, USA) is a hypoallergenic product, free of casein, lactoglobulins and other large proteins, but it does contain intact cytokinefractions identical to leukocytic cytokines. Academician A.A. Vorobiev of the RussianAcademy of Medical Sciences points out that unlike other immunomodulators Transfer Factorhas a wide spectrum of activity, is safe, is administered orally, has no contraindications orside effects, and is effective both in adults and children.
Being versatile immunocorrectors transfer factors induces, moderates and/or normalizes immune response. Depending on the type of disturbance it either stimulates weak immunity,or normalizes or enhances protracted immune reactions, thus preventing the onset ofpathological processes. These effects are due to the fact that TF has three main fractions witheach named according to its main effect on the immune system: inducer, antigen specific andsuppressor transfer factors. Inducers provide general readiness of the immune system to wardoff aggressors. Antigen specific transfer factors are a set of certain antigens and cytokineswhich help the immune system to recognize many microorganisms and antigens in advance.
Suppressors prevent the immune system from concentrating all its strength on a defeatedinfection while ignoring other threats. Suppressors also regulate the immune responseintensity, thus preventing autoimmune reactions. Cytokines, a part of the composition of TF,regulate suppressor cells functions, help maintain adequate immune reaction and the degree ofprocess activation, i.e. body reactions may become predictable and manageable.
The antigen presenting TF components were found to shorten the period prior to antibody production by augmenting the process of antigen presentation to immunocompetent cells.
As a rule, persistence of chronic infection is known to be due to inadequate phagocytic and digestive functions f macrophages; this protracts the period of foreign antigens presentation toT-lymphocytes, and ensuring antibodies production.
Transfer Factor' variety mechanisms and actions, their natural origin and lack of contraindications broaden the sphere of their application. The antigen specific components ofTF influence the activity of macrophages and cytotoxic T-lymphocytes, thus helping theimmune system to recognize certain microorganisms and antigens. And, because of the stagesof antigen recognition and presentation to antibody producing cells are skipped; it also Transfer Factors Using Immunorehabilitation
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markedly enhances the production of specific antibodies by bringing about antibody synthesiswith a ready "matrix" of an antigen specific factor.
A very important aspect of the effects of transfer factors is the non-specific activation of macrophagal reactions that contribute to complete Phagocytosis, recognition of any antigensby macrophages, and their presentation to other immunocompetent cells. A similar process isroutinely accomplished by macrophages located in Peyer patches in the intestines. In this waya stable level of natural defensive antibodies and the rate of the production of specificantibodies against certain pathogenic microorganisms entering the body via the gastro-intestinal tract are regulated.
Nature has devised the most effective and prompt means of protecting infants by transmitting transfer factors from mother to child. During the first hours and days of lifeinformation mediators and ready immunoglobulin antibodies entering the body of a newbornvia colostrum providing protection not only as a first aid measure upon the encounter ofinfectious pathogens, but also to "teach" intestinal macrophages and Peyer patch lymphocytesto quickly recognize foreign antigens and trigger protective immune mechanisms.
Scientific interest in transfer factors is accented by the fact that since the time of their discovery more than 40 million US dollars have been spent on their research, more than 3000scientific papers have been published and eleven international conferences have been held.
Despite these facts, the study of structural aspects and the mechanisms of transfer factorseffect are still challenging problems for involved scientists (46).
I8 defense factors participate to a certain degree in the development of almost every pathological condition. Effective treatment of many infectious, autoimmune and allergicdiseases depends on timely use of immunocorrecting drugs. The way a particular immunesystem responds to detrimental factors and the environment in which a pathological processarises and develops are of great importance. It should be pointed out that since the discoveryof transfer factors more than 50 years ago they have become one of the most effective meansto strengthening body resistance to various detrimental factors. Their demonstratedimmunocorrecting effects in many infectious and somatic diseases have been studied andreported by scientists of different countries.
Transfer factors' wide spectrum of clinical effects, which were reported at the 11th International symposium (dedicated to transfer factors), encouraged doctors to recommendthem to patients of different ages from infants to elderly people being treated in intensive careunits. The effectiveness of oral use of transfer factors preparations was also reported.
Due to its great effectiveness TF can be used in combination with other immunomodulators and adaptogens. The use of TF in conjunction with such adaptogens asimmunal, tactivin, thymogen, myelopid and others will help to direct their immunomodulatingeffect along the paths of cytokines and antibody production.
Comparative scientific data obtained from laboratory investigations confirm the stimulating effect on Natural Killer (NK) cells by TF and Transfer Factor Plus®. It has beenestablished that TF is significantly more active than other well know immunomodulators,since TF increased NK activity by 103% and adaptogens fortified TF PLUS by 248% (32,46).
In-vitro studies carried out by M.V. Kisielevsky and E.O. Khalturina (28) at Russian Cancer Research Center demonstrate mononuclear blood cells from health donors. Thegreatest effect was recorded 48 hours following mononuclear cell incubation with theproducts at different concentrations. The level of effective concentrations ranged from 0.1 to0.0001 mg/ml. These products, which contain mixtures of transfer factors derived from twosources, colostrum and egg yolk, were most effective in proportions 70:30 and 50:50(bovine:egg). Incubation of these products with mononuclear cell resulted in an average Transfer Factors Using Immunorehabilitation
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increase of mononuclear cell cytotoxicity from a low of 18% to 80-99% with and somesamples exceeding the cytotoxic stimulating effects of interleukin-2.
Transfer Factor™, a product of 4Life Research, is a proprietary concentrate of transfer factors (Transfer Factor XF™) derived from bovine colostrum by means of an exclusive andpatented process. Pharmaceutical form: gelatin capsules, containing Transfer Factor powder(bovine colostrum concentrate) and maltodextrin.
Transfer Factor Plus® is a proprietary product of 4Life Research containing: • Transfer Factor XF powder (bovine colostrum concentrate) • Zinc monomethoinine 20% (3.3 mg of zinc) • Proprietary Cordyvants' mixture • Inositol hexaphosphate • Soy beans extract (phytosterols) • Cordyceps sinensis, powder • Baker's yeast (D-b-glucan) extract • Lemon, peel powder • Agaricus blazeii Mushroom extract • Aloe gel powder (Aloe vera leaf) • Oats extract, avena sativa (b-glucan) • Olive tree (Olea europaea) leaf powder extract • Maitake Mushroom (Grifolea frondsa) powder extract • Shitake Mushroom (Lentinus edodes) powder extract.
Transfer Factors Using Immunorehabilitation
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4. The Use of Transfer Factors in Various Diseases
With the diversity of exiting immunomodulators capable of producing either stimulating or suppressing effect on the immune system, we chose to scientifically investigate the use oftransfer factor products in pathological conditions necessitating immunocorrection.
Studies demonstrating the clinical and immunological effectiveness of Transfer Factor™ and Transfer Factor Plus® in the treatment of patients with HIV infection, hepatitis B and C,herpes, urogenital chlamydiosis, severe bacterial infections (osteomyelitis), helminthicinvasions (opisthorchiasis), as well as malignant tumors (gastric cancer), dermatoses(psoriasis, atopic dermatitis) and duodenal ulcer were carried out in different clinics ofRussian Federation from 2000 through 2003.
The results of the clinical studies, included in this paper, helped to evaluate the effectiveness and safety, the duration of treatments, the doses of Transfer Factor products, andprospects of their use not only in the above mentioned diseases, but in the complex treatmentof various pathological conditions.
The Effectiveness of TF Use in Viral Hepatitis
Destabilized immune mechanisms play a leading role in the pathogenesis of parenteral hepatitis (viral hepatitis B and C) as well as in the course and outcomes of the diseases (42,43). Despite considerable experience in viral hepatitis treatment, including chronic ones, anumber of issues concerning an optimal regimen are still being discussed with doses and thetreatment with interferons (INF) as the current drugs of choice. The fact that treatment withINF of one patient with the chronic form of hepatitis C costs $10,000-$15,000 prompts thenecessity of solving this issue. In addition, this antiviral therapy prescription has a list of otherindications, but interferons are sometimes poorly tolerated by patients and the host producesantibodies against recombinant interferons. For these reasons the search for agents withproven therapeutic effect in the patients with viral hepatitis is quite justified.
The first results obtained from adult patients receiving TF along with the conventional therapy attests to a high effectiveness of cellular cytokines use in this kind of pathology (9).
Along with the normalization of biochemical values and the decrease of viral load (62% inmost cases), all patients registered a marked improvement of the generate state, were moreefficient and did not experience excessive fatigue, and there was no discomfort in the righthypochondrium. Further studies with the patients with acute and chronic forms of viralhepatitis B and C, wherein patients were followed up for 6 months after the treatment, werecarried out by the same authors (19, 21). Fifty (50) patients with chronic viral hepatitis B andC and 15 patients with acute viral hepatitis B received TF, one capsule 3 times daily for 14days. The resulting data were comparable to those obtained in patients receiving conventionaltreatment with interferons.
Twenty four (24) patients with acute hepatitis B and 34 patients with chronic hepatitis C (CVHC) received TF PLUS, 1 capsule 3 time daily for 14 days. The control group, 15 CVHCpatients, received 3,000,000 IU of reaferon (an antiviral IFN) intramuscularly 3 times a week.
The remaining patients received basic therapy aimed at improving bile secretion (holoasa orhophitol) and liver function (riboxin per os). Identical immunocorrecting effects wereregistered in the patient group receiving TF PLUS for 2 weeks and in the patients, receivingIFN therapy for 3 months. In the patients receiving TF PLUS there were earlier symptomsdynamics that were positive. TF PLUS was well tolerated and there were no side effects ascompared with fever, joint pain and asthenia during interferon therapy. It is worth pointingout that the incidence of viral remission in the groups receiving reaferon and TF Plus was the Transfer Factors Using Immunorehabilitation
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same, i.e. 65%. At the same time the level of g-interferons production was significantly higherin the patients receiving TF Plus.
The effectiveness of TF and TF PLUS in the treatment of viral hepatitis B and C may be of great help in considering the use of the TF products as the alternative treatment inrecombinant interferons or as an addition to the conventional therapies for viral hepatitis.
The data obtained indicates further studies of the effectiveness of TF products should be conducted to additional patients in order to develop the most effective schemes of complextreatment, pharmacologically effectiveness, the dose courses and the economics.
The Use of TF in Chlamydial Infections
In recent years chlamydial infection has become a serious health care problem. The majority of reports of domestic as well as foreign authors are dedicated to urogenitalchlamydiosis (40, 52). The use of modern antibiotics leads to the development of such sideeffects as dysbacteriosis, toxic liver lesions, and secondary immunodeficiencies. Whendeveloping therapeutic measures one must bear in mind the cycle of chlamydia development,the possibility of L-forms formation (lacking a cell wall), and its perseverance in the body thatnecessitate not only the correct choice of antibiotics but the search for effectiveimmunocorrecting agents (6). The use of TF and TF PLUS in the treatment of urogenitalchlamydiosis in adult patients is of great interest (22, 26).
Twenty-four (24) male patients with urogenital chlamydiosis received antibacterial therapy according to the traditional scheme for a month (10 days each of clarythromycin, doxicyclinand ofloxacin). The second group (26 patients) received one 10 day course of clarythromycinand in addition TF PLUS, 1 capsule 3 times daily for the 10 days. The third group (23patients) received clarythromycin and TF according to the same scheme. The examination ofurethral smear and prostate secretion using the Polymerase Chain Reaction (PCR) DNAmethod two months after the end of the treatment registered 100% chlamydia eradication inall three groups.
Seventy-two percent (72%) of patients that received traditional antibacterial treatment complained of discomfort in the epigastric area and one third (32%) complained of nausea.
There were cases of vomiting (12%) and dyspepsia (12%). Intestinal dysbacteriosis with theprevalence of fungal lesion and genital candidosis were registered in 88% of the cases. Fromantibacterial therapy there were hepatotoxic effects such as jaundice syndrome (8%), liverenlargement (17%) and increased activity of hepatic enzymes (54%). All these manifestationsnecessitated additional therapies such as the use of enzymes and other bioagents, additionalagents for improving hepatic function, and the use of fungicides, thus prolonging the courseof the treatment and increasing costs.
The first phase of specific immune defensive response is know to start with the activation of the entire cytokines complex (interleukins, interferons, adhesion molecules and etc.), i.e.
monocytic-macrophagal phase activation (48, 49). The levels of IL-1b, IL-2 and IFN-gconcentrations were defined before and after the treatment in 45 urogenital chlamydiosispatients. The imbalances in the cytokines studied are shown in the data. There is a statisticallysignificant different between the concentration of the main proinflammatory IL-1b and itsnormal value.
IL-2 is a classic interleukin, which not only participates in the induction of cellular immunity, but also performs its main function, namely, destruction of cells altered byexogens. It also activates T-cells, NK cells as well as all cellular entities (macrophages,neutrophiles and others) that are capable of destroying diseased cells and microbes. In ourstudies IL-2 titers were found to be high during the first days of development of theinflammatory process. IL-2 concentrations were significantly different from its normal Transfer Factors Using Immunorehabilitation
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concentration; while at the same time INF-g concentrations in urogenital chlamydiosispatients revealed a statistically significant decrease as compared with that of the controlgroup.
There was no significant difference in the effects of TF or TF PLUS in either the dynamics of clinical manifestations or in the immunological shifts. This is yet another confirming factthat cytokines in these products are the major active principle and other componentspotentiate their effect.
Urologists may prefer TF PLUS, which would be quite understandable since it contains sins, which produces beneficial effect on sexual function. Zinc helps prevent the formation ofhypertrophic prostatic processes thus promoting a purposeful prevention of its benignenlargement.
It should be pointed out that combining interferon drugs and antibiotics in the patients with chlamydiosis (41) and leikinferon and antibiotics in children with chronic pyelonephritis (28)protects them from adverse effect of antibacterial drugs and minimizes the development ofintestinal dysbacteriosis.
The combined use of interferon agents, cytokines and antibacterial therapy brings a marked therapeutic effect with lower doses of each component. The potentiating effect of cytokinesallowed for both significantly decreasing the effective dose of antibiotics and minimizingtheir negative effect. It may be a useful strategy to use oral doses of cytokines to help patientssuffering from intestinal infections and intestinal dysbiosis caused by persistent intracellularinfections. TF potentiates the effect of eubiotics, enzymatic products and adaptogens.
The Effectiveness of TF Use in Osteomyelitis
Studies of the effectiveness of TF in osteomyelitis patients carried out at St Petersburg State Medical Academy (12, 13, 38, 39) revealed a diversity of its mechanistic effects.
Chronic osteomyelitis is a protracted severe infection. Free radicals and lipid peroxidation reactions play a major role in the pathogenic mechanisms of the disease and in inducingimmune deficiency in patients (36, 37).
Third-three (33) patients, ages 25 to 64, with different forms of osteomyelitis were included in the study. The patients were divided into two groups. The protocol consisted ofsurgical removal of the purulent infection, performed a week after the beginning of TF use,and a wide spectrum antibacterial therapy (gentamycin, ampiox and others) in post operativeperiod.
The main group patients (20 people) were receiving TF, 2 capsules 3 times daily, along with the standard antibacterial therapy. Thirteen (13) nosology, sex and age matched peoplecomprised the control group and received standard treatment.
It was shown that in addition to its immunomodulating effect, TF influenced the biochemical non-specific resistance mechanisms, including free radicals oxidation, increasedcellular membranes stability and the antioxidant defense activity. The nature of the changes inbiochemical values showed that in addition to being immunotropic, TF may also produceadaptogenic effects.
There were significant changes in humoral immunity, characterized by increased IgA production, stimulation of phagocytic immunity, as well as in the dynamics of certain T-cellspopulations and without a noticeable increase in circulating immune complex (CIC) level.
Patients experienced clinical improvements in their condition and post-operative rehabilitationperiods were shortened.
Transfer Factors Using Immunorehabilitation
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Due to its membrane stabilizing and its antioxidant effects TF can be extensively used at the beginning of a microbial-inflammatory processes (before the development of immunereactions) when adhesive processes are of consequence.
The use of TF in the patients with hematogenic osteomyelitis prompted the following method of its use both in the active phase and for immune disturbances during rehabilitation:2 capsules 3 times daily for 2 weeks prior to surgery along with the basic therapy and for 2months following surgery. TF is then replaced with two months of vitamin-mineralsupplementation. Subsequently, after checking patient immune status and in cases ofimmunodeficiency TF, 1 capsule 3 times daily, should be given for 2 months and the abovementioned treatment should be repeated.
In case of immunodeficiency in other non-hematogenic forms of osteomyelitis TF, 1 capsule 3 times daily, should be taken for 2 weeks before and for two months followingsurgery. Following a 4-5 month break in therapy, in cases where immunodeficiency hasreoccurred TF should be administered for another two months.
If remission is interrupted with an exacerbation of osteomyelitis TF, 2 capsules 3 times daily, should be taken for one week before and for one month after surgery.
The User of TF in Immunorehabilitation Therapy of HIV Infection
Acquired Immunodeficiency Syndrome (AIDS) is one of the most serious problems confronting modern medicine. For HIV patients immune modulation therapy (i.e. therestoration of normal immune function) is aimed altered immune mechanisms and at thepathogenic agent(s). The results of studies conducted (10, 11) showed that TF PLUStreatment significantly improved the immune status of HIV patients. The product also proveduseful in other aspects of therapy as for example the level of circulating immune complexes(CIC) decreased to normal values in 50% of patients receiving TF PLUS.
Because the CD4 T-helper marker is a HIV receptor, whereas HIV is tropic to T- lymphocytes and other immunocompetent cells it infects mainly T-helpers while sparingcytotoxic cells. A significant increase in T-helper (CD4+) levels in patients receiving TFPLUS is an important aspect in helping to attain the main goal of such patient treatment,namely, maximum life extension and preservation of its quality.
In HIV therapy patients received TF PLUS, 1 capsule 3 times daily for two weeks.
Repeated courses of TF PLUS are prescribed during the process of out-patient follow-up asbased upon the investigative results of a patient's immune status.
The User of TF in the Complex Treatment of Atopic Conditions
Allergic diseases are one of the many challenges for modern medicine. Statistics from all over the world show this pathology to by skyrocketing (up to 20% of the population). Nowdays, one person in five on the Earth is suffering from some form of atopic pathology.
According to the World Health Organization's (WHO) prognosis, atopic conditions will holdthe first place in general morbidity in the 21st century. At the same time the availabletraditional antihistamine agents are not effective enough; their effects are limited to partialhistamine receptor blockage and are often accompanied by adverse reactions. Pathogenicmechanisms of allergy development are known to be connected with a disturbance I thecourse of T-lymphocyte differentiation, decreased activity of the T-suppressor cells andexcessive IgE production. The final link of this chain is mast cell activation anddegranulation. It is necessary to find the means of influencing the various links of these atopicreactions. In our view cellular cytokines that regulate suppressor cell activity are suited best ofall for this purpose.
Transfer Factors Using Immunorehabilitation
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Transfer factors used as a biologically active substance will help to module local (i.e.
within the limits of gastro-intestinal tract0 and general immune reactions of dietary allergiesas well as atopic skin reactions in the diseases characterized by atopic reactions, after 20 daysof the product administration all patients had remission.
Promising results were obtained from TF use in dermatovenerology (29, 30), namely, in psoriasis and atopic dermatitis patients where autoimmune and allergic reactions playimportant roles in the pathogenesis of these diseases (8). After 7-10 days of TF administrationalong with traditional drugs, patients reported less intensive itching, scaling and skin eruption.
Immunomodulating Effect of TF Use in Opisthorchiasis
The use of TF PLUS, 2 capsules 3 times daily for 7 days, in opisthorchiasis patients brought about clinical and immunological effects 920). Unlike the control group patients whoreceived only anthelminthic treatment, patients treated with TF PLUS demonstrated acomplete remission and in all patients there was a disappearance of vasculitis and arthralgiathat occurred within 6 months following treatment.
Immune system indices in the patients who received TF PLUS different significantly from those of the control group patients. Two weeks after treatment there was an increase of IgGlevel and more active CIC formation in the patients of TF PLUS group. Also, in the patientswho received TF PLUS their concentrations of IFN-g, which plays an extremely importantrole in the development of a specific immune response, increased more than twofold ascompared with the values before the treatment and with those of the control group (27, 34,44). Conventional anthelminthic treatment alone did not bring about any tangible changes inthe indices of the immune system humoral components studied, thus reflecting a certainunresponsive characteristic of the process.
The results of this study have convincingly shown the clinical and immunological effectiveness of TF PLUS in the complex treatment of opisthorchiasis patients. The productsignificantly contributed to clinical recovery of the patients during a six-month period.
TF PLUS used for immunorehabilitation, when carried out after bilthricide treatment, is of practical value in the process of forming defensive immunity. It also prompts quickelimination of Op. felineus antigens, arrests the development of immunopathologicalprocesses and brings about more complete and easier recovery.
The Role of TF in Immunorehabilitation of Oncology Patients
Gastric cancer is an oncological disease characterized by the development of persistently stable immunodeficiencies, which are also a consequence of the peculiarities associated withthe surgical treatment of the disease.
Numerous immune condition studies of gastric cancer patients have shown that development of secondary immunodeficiency adversely affects both the adequacy and theeffectiveness of immune response and shortens the duration of remission periods. Thesefactors necessitate a complex approach to gastric cancer immunotherapy after maximumreduction of the diseased cells (25).
Twenty-five (25) patients (the treatment or main group) with second or third clinical stage of gastric cancer participated in clinical studies of TF PLUS. The studies were conducted inRAMS Cancer Research Center. Twenty-five (25) patients of sex, age, nosology, and matcheddisease stage comprised the control group (25). All of the gastric cancer patients in bothgroups underwent surgical treatment and during the post-operative period the standardprocedure of immunotherapeutic treatment. To stimulate non-specific immunity, patients inthe treatment group received TF PLUS, 1 capsule 3 times daily for 30 days, along with the Transfer Factors Using Immunorehabilitation
After Infectious-Inflammatory & Somatic Diseases
standard treatment. It should be pointed out that initially the majority of patients sufferedfrom immunodeficiency of varying severity and immunodeficiency was provoked by surgery.
After the end of the course of complex treatment the study was continued with TF PLUS administration and it demonstrated that the continued treatment was beneficial to immune,interferon and cytokine status, as well as for the clinical improvement of the patients. Therewas an increase of CD3+, CD4+ and CD8+ content in bloody lymphocyte populations and thenumber of NK cells in blood samples markedly increased both showing activation of the cellmediated immunity. Concerning humoral immunity, positive charges towards normal levelsof TNF-a and IL-1b production were registered.
Other positive changes characterized by decreased severity in intoxication syndrome, improved general state of being better appetite and disappearance of weakness and fatigue inthe clinical course of the disease were observed. The post-operative period was uneventful.
There were no reoccurrence of the disease during the course of the complex immunotherapythat was fortified by TF PLUS.
TF PLUS is well tolerated by patients and is effective as a part of a complex immunotherapy for oncology diseases and can be successfully used in clinical practice.
The Effectiveness of TF PLUS in the Complex Treatment of Duodenal Ulcer
Convincing results supporting the use of TF PLUS in a multi-faceted treatment of Helicobacter pylori (Hp) associated duodenal ulcer were obtained by Iu.V. Telnyikh atMoscow's Sechenov Medical Academy.
Thirty-five (35) patients with duodenal ulcer associated with Hp took part in the clinical studies. They were divided into two groups. The control group (15 patients) received Omez,Amoxycillin, and Clarythromycin according to traditional treatment in order to eradicate Hp.
The main group (20 patients) received TF PLUS, 2 capsules 3 times daily for the first 10days, then 1 capsule 3 times daily for the following 20 days along with the eradicationtherapy.
Laboratory results measuring humoral and cellular immunity showed that there was a pronounced immune imbalance in patients with duodenal ulcer with associated Hp diseasethat had persisted for more than 10 years and who had a pathological condition of the hepato-biliary system. Blood samples from these individuals showed a marked decrease in bothpercent and absolute number of natural killers (NK) with decreased activity, a decrease of T-helpers, and an increase of T-suppressors number which results in a decrease in theimmunoregulatory index. Other authors have obtained analogous data (4, 5, 53, 55). The 10-day eradication therapy with Omez, Amoxycillin and Clarythromycin aggravated the immuneimbalance leading to the development of secondary immunodeficiency due to the antibiotic'sactivity and its aggravation of intestinal dysbiosis.
The combination of Hp eradication therapy along with the natural immunomodulators TF PLUS brought about a marked and statistically significant improvement of both humoral andcellular immunity, which resulted in normalization of the immunoregulatory index andimproved neutrophils and natural killer cell activity. The elimination of the secondaryimmunodeficiency by TF PLUS activity resulted in the improvement of the condition ofpatients with duodenal ulcers. In particular, the effectiveness of eradication therapy wasincreased by 21.7%, pain and dyspeptic syndromes, respectively, were arrested 4 and 4.5 daysearlier and mucosal ulcer scarring occurred 8 days earlier in the TF PLUS treatment group ascompared with the control group. Eradication of Hp was 73.3% successful in the controlgroup. Eradication of Hp in the group receiving TF PLUS was 95%.
The clinical data obtained and the data from other authors show the usefulness of TF and TF PLUS in various infectious and somatic pathologies.
Transfer Factors Using Immunorehabilitation
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5. Methods of Transfer Factors Use and Recommended Doses
The developments of rational and effective regiments for the use of TF in various pathological conditions have been demonstrated. Both literature data and the results of clinicalstudies presented in this paper give justification for recommending regimes for TF and TFPLUS use in initial and anti-relapses of somatic and in infectious diseases (table 1).
The conventional scheme of TF use is: For the prevention of seasonal diseases (spring, autumn) connected with the weakeningof the immune system – 1 capsule 3 times daily for 30 days; In acute infections at the beginning of a disease - 2 capsules 3 times daily for not lessthan 7 days.
Transfer Factors Using Immunorehabilitation
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Table 1. Schemes of the use and average course doses of TF and TF Plus (TF+) in various diseases in adult patients.
Duration of a
1 capsule 3 times daily 14 days repeated courses with immunogram monitoring Acute Viral Hepatitis B 1 capsule 3 times daily 14 days individual repeated courses (sluggish or protracted course) during follow-up study Chronic viral hepatitis B and C 1 capsule 3 times daily For 14 days each month for the first thee months. Repeatedcourses for 14 days, 1 capsule 3 times daily, monitored bybiochemical analyses, liver ultrasound investigation once every2-3 months.
Hematogenic Osteomyelitis & 2 capsules 3 times daily 14 days before surgery and 2 months after surgery immunodeficiency – 1st Type antibacterial therapy In case of immunodeficiency persistence 1 capsule 3 times daily after a 2 month treatment Chronic Osteomyelitis aggravation TF and basic treatment 2 capsules 3 times daily 1 week before surgery and 1 month after surgery 1-2 capsules 3 times daily 7 days repeated courses in case of persistence of After anthelminthic treatment immunopathological processes manifestations (arthralgia, vasculitis) Acute Urogenital Chlamydiosis TF+ and antibiotic 1 capsule 3 times daily Chronic Urogenital Chlamydiosis TF or TF+ and antibiotic 2 capsules 3 times daily/ (complaints & clinical manifestations 1 capsule 3 times daily 10 days and for 2 months after the end of the basic treatment lasting for more than 2 months) (antibacterial therapy aimed at prevention of complications) The involvement of internal reproductive TF+ complex treatment along 2 capsules 3 times daily 10 days during a process aggravation organs (as complications of chronic with various groups of drugs, 1 capsule 3 times daily 10 days as a preventative measure the frequency of TF use urogenital chlamydiosis) as well as physio and depends on the extension and severity of the process, as well restoration treatments as the presence of a secondary immunodeficiency and as apreventive measure and varies from 2 to 4 times a year Psoriasis, Atopic Dermatitis 1 capsule 3 times daily 14-21 days; repeated courses and during unfavorable seasonsof the year Gastric Cancer after Surgery 1 capsule 2 times daily 30 days minimal frequency of repeated courses: 2 months - during eradication 2 capsules 3 times daily - after eradication 1 capsule 3 times daily until the end of a month (20-23 days) - anti-relapses treatment 1 capsule 2 times daily for 1 month early in spring and late autumn Transfer Factors Using Immunorehabilitation
After Infectious-Inflammatory & Somatic Diseases
Immunorehabilitation for many infectious and somatic diseases is becoming one of the most important components of successful therapies. The adaptability and frequentintracellular persistence of infectious agents, as well as the absence of an active immunereaction on the part of the individual with such diseases dictate the necessity of consideringthis approach. In addition, a large portion of population suffers from secondary immune-deficiencies caused by the unfavorable effects of social, ecological and other factors.
Mixed infections hold a special rank among so-called "new" infections. It is the condition when, due either to simultaneous or sequential infection by different agents, the clinicalmanifestations of a disease undergo significant changes. Their frequent occurrence isexplained by various immunopathological conditions.
Faced with a steady increase in atopic reactions, which aggravate the course of many diseases, hamper the administration of an effective treatment, and autoimmune processes,which trigger progressive pathological conditions, physicians must not only know the basicprinciples of immunology but should actively seek new immunomodulating approaches fortreating such conditions.
At present, the main courses of active non-specific immunotherapy are the use of interferon inductors, stimulators of macrophagal activity B and T-lymphocytes, natural andrecombinant interferons with antiviral and immunomodulating effects, as well endogenousregulators of immune reactions such as interleukins and other cytokines. The use of naturalendogenous non-specific immunomodulators opens up new prospects ofimmunorehabilitation in various infectious and somatic diseases. Generally, parenteraladministration of cytokines result in pronounced proinflammatory effects leading tointensification of already hyper inflammatory reactions. In our view the use of TransferFactor, a unique and new generation immunomodulators derived from bovine colostrum, isvery promising in countering this problem.
Experimental data and the results of studies carried out in different clinics of this country have demonstrated the immunomodulating effects of oral forms of transfer factors in variousinfectious, parasitic and somatic diseases. According to the results of these studies, TFproduced practically the same immunomodulating effect as did the most often usedinterferons, cytokines and other immunomodulators. In addition, oral use of TF minimizesadverse reactions, gives optimal pharmaeconomic effects and helps to shorten the course ofimmunorehabilitation therapy.
TF and TF PLUS have marked immunocorrecting effects and are useful for their therapeutic and prophylactic effectiveness in various forms of infectious and somaticpathologies, which are accompanied by disease induced disturbances in immune status.
Transfer Factors Using Immunorehabilitation
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