Review - Transfer Factor A brief review of the immune system is presented here for a better understanding of the section that follows. Additional information appears in the links section. THE IMMUNE SYSTEM
The immune system is composed of a global and dynamic collection of highly specialized cells and tissues dispersed through out the body. Within this system is the bone marrow, the white blood cells, the lymph nodes, the spleen, Peyer,s patches the thymus and the mucosal and the gut associated lymphoid tissues. There are two functional divisions within the immune system, innate and acquired. A schematic diagram of these two systems is depicted in the following figure.
Innate (natural) immunity derives from all those elements with which an individual is born and are always present and available at very short notice to protect the individual from challenges by foreign material These elements include the skin, the mucous membranes and cough reflex as physical barriers to environmental agents. Chemical influences such as pH, secreted fatty acids and the enzyme lysozyme constitute effective barriers against invasion by many microorganisms. Numerous internal elements are also features of innate immunity, fever, interferons interleukins, complement, lysozyme in the tears and saliva, acute â€“ phase proteins, beta lysine, polyamines and the kinins. Other internal elements of innate immunity include natural killer cells, granulocytes, macrophages, microglial cells of the central nervous
system and the cytotrophoblasts of placental villi. These cells all participate in the destruction and elimination of foreign material that has succeeded in penetrating the physical and chemical barriers of the innate immune system. ACQUIRED IMMUNITY
In contrast to innate immunity, which is an attribute of every living organism, acquired immunity is a more specialized form. It has developed late in evolution and is found only in vertebrates. The various elements that participate in innate immunity do not exhibit specificity against the foreign agent that they encounter, while acquired immunity always exhibits such specificity. Upon contact with an offending foreign agent that has penetrated the body or after immunization or vaccination, a chain of events leads to the activation of a category of cells called lymphocytes. Upon lymphocyte activation, a second cascade of highly complex events leads to two major types of immune response. Humoral, antibody or B lymphocyte mediated immunity that generally kill and eliminate extra cellular pyogenic (puss producing) microorganisms and neutralize toxins. Cellular or cell mediated or T lymphocyte mediated immunity against intracellular pathogens, such as yeast cells, certain bacteria viruses, some protozoans and tumor cells. It should be mentioned however, that T and B lymphocytes are totally interactive and for the most part cooperate in prompting the immune response. There are two types of T lymphocytes: T helper-inducer, also known as CD 3 cells. T suppressor-cytotoxic, also known as CD 8 cells. Within each T lymphocyte population, there are a number of sub populations each of which may perform a different function. It is important to realize that T cells do not synthesize or secrete antibodies, however, T cells do cooperate with B cells to induce production of antibodies by B cells. During cellular immune activation, certain T cell populations secrete regulatory peptides or hormone like products know as cytokines. The various cell populations and the cytokines orchestrate the immune system to a crescendo that culminates in an immediate or long term, perhaps life long immunity. Variations in the numbers and functions of these cell populations and cytokines involved compared to normal values may be indicative of various diseases, however, diagnosis of any immunologic disorder, requires comprehensive laboratory tests and evaluation. TRANSFER FACTORS
Transfer factors (T.F.) are low molecular weight peptides or immune messengers that transfer the ability to express cell mediated immunity (or delayed type hypersensitivity) from immune donors to non-immune recipients. H. Sherwood Lawrence demonstrated this passive transfer of immunity (1,2) in 1949. He collected leukocytes from immune donors who demonstrated a positive skin reaction to a specific antigen and prepared extracts from them. He injected the extracts to skin test negative or immune compromised subjects. Subsequently the recipients reverted to skin positive reactions to the same antigens. These experiments thus provided direct and dramatic evidence for transfer of systemic and
specific immunity between individuals. Subsequent repetition of these experiments with other antigens and indeed therapeutic trials of transfer of cellular immunity conducted by many investigators have confirmed and extended Lawrence's original observations. The results of these studies appear in thousands of publications a mini review of which appears later (see clinical and therapeutic uses of T.F.). It should be emphasized that transfer factors do not act as drugs for specific disease conditions, however, apparently, they endow the recipient with de novo immune capacity to resist and repel infections. Transfer factors are small peptides composed of number of amino acid residues (66, 67). Multiple combinatorial patterns between these amino acids create a vast number of different T.F. molecules. Such a large number of molecules would then satisfy the notion that a specific T.F. molecule is necessary to transfer immunity to each and every specific antigenic determinant (68). Another words, T.F. transfers immune power to a recipient who will subsequently gain specific immunity. MECHANISM OF T.F. ACTION
Clinical trials have demonstrated that antigen specific T.F. therapy, results in induction of cell mediated immunity and successful response to the corresponding antigen or hostile invaders (38,69,70). The T.F. recipient apparently becomes educated or armed to recognize and repel viral, bacterial, fungal, protozoan and possibly even neoplastic invader. Recent experiments in murine (mice) recipients have shown that in vivo administration of transfer factors endows the recipients' spleen cells with the property of responding to the corresponding antigen in vitro by secreting gamma interferon (71), a product of T helper 1 cells. These experiments demonstrate induction of cell-mediated immunity in the recipient mice, however, the nature of structure of the target molecules or receptors for TF are not known. An intriguing facet of T.F. is that two opposing antigen specific activities can be detected within the same preparation (72,73). One activity is possessed of helper function (inducer factor), while the opposing activity is possessed of suppressor function (suppressor factor). Since the immune response may be both under active as in various types of immune deficiencies or over active as in allergy or autoimmunity, the inducer/suppressor factors help to maintain an immune regulatory network that keeps the immune system balanced and healthy. SOURCES OF TRANSFER FACTOR
There are many sources of T.F. mammalian, chicken cells or even cells from primitive species. Early researchers prepared T.F. from leukocyte extracts of donors. Specific T.F. for a particular antigen or pathogen can be prepared from immune or vaccinated donor cells. More recently, colostrum extracts have become the preferred source of T. F. Colostrums are rich in T.F. and readily available from commercial sources. Colostrums are the pre milk and the first food given by a mother to the newborn. During the first few days of life, colostrum and later the mother's milk protects the baby from infections while it's own immune system matures. ORAL TRANSFER FACTORS
Most of the original clinical trials with transfer factors (14,38,47,48,49) used parenteral injections to administer T.F. Obviously the oral route would be preferable, however, it was originally assumed that the acidic and enzymatic environment of the gastrointestinal tract would destroy the factors. Experimental (38) and human trials (10,15,32,33,53, also see
Biotherapy vol. 9, 1996) have amply demonstrated there is little if any loss of transfer factor activity taken orally. SPECIES SPECIFICITY AND TRANSFER FACTOR THERAPY
Transfer factors made form animal or human sources can transfer immunity to each other. That is, there are no species barriers fro T.F. therapy. Even primitive species have cells from which one can prepare T.F. Therefore larger animal sources provide adequate quantities of T.F. for human use. RATIONAL FOR TRANSFER FACTOR THERAPY
Transfer factor is an immunoregulatory, immunosupportive agent with normalizing effect on aberrant immune response. As such it does not act in the same way as an antibiotic or a chemotherapeutic agent but rather, it may up regulate or down regulate immune responsiveness through its helper/suppressor activities to achieve normalcy. T.F. is an effective and safe product that acts as an adaptogen with broad based immune activity. CLINICAL AND THERAPEUTIC USES OF TRANSFER FACTOR
The Food and Drug Administration have not evaluated the following information. It is not claimed that any product mentioned here can prevent treat or cure any disease. It is not suggested that anyone should replace traditional medical treatment for any product mentioned here. On this website you will read testimonies about nutritional supplements. Please use common sense, information and good judgment to evaluate these products and statements. Testimonies may be based on placebo effect, that means perceived results that are in fact false and therefore of short duration. Some statements and testimonies are made by health professional who may recommend our products and who may have conflict of interest. We advise any and all prospective users of our products to use sound and informed judgment before any purchase. There are currently over 3000 publications dealing with clinical uses of TF. Two recent symposia held by the INTERNATIONAL TRANSFER FACTOR SOCIETY in 1996 and 1999 are excellent sources of information on the clinical and therapeutic uses of TF. (http://www.biotransfer.org/art03.html) To enhance the immune response, TF has been used for the therapy of viral diseases such as hepatitis (5, 6), chronic hepatitis B (7, 8), hepatitis C (9), herpes infections (10), ocular herpes (11), genital or labial herpes (12), herpes zoster (13, 14), cytomegalovirus (15, 16), Epstein-Bar Virus (17, 18) and, human immunodeficiency virus/AIDS (19-26). Additionally TF has been utilized in the therapy of bacteria such as Mycobacterium leprae (27) Salmonella cholera suis infection (28), Salmonella B (29), severely infected pediatric patients with pneumonia gastrointestinal infections, repetitive urinary tract infections, vulvovaginitis, skin infections, and herpes simplex infections (30), A number of protozoan infections such as Leishmania (31), Cryptosporidiosis in AIDS patients (32, 33), fungal infections such as coccidiomycosis (34), histoplasmosis (35) and candidacies (36, 37, 38, 39). A great amount of literature (40-45), deals with the use of TF for the treatment of chronic fatigue syndrome (CSF). Anti HHV-6 oral TF administered to two CSF patients, significantly improved the clinical manifestations in one patient (46). In our own studies (Youdim S. and Shima G. Unpublished Data), we observed dramatic improvement in the clinical status of patients with high titer antibodies to CMV, EBV and/or HSV treated with non-specific TF, gamma globulin and interferon alpha. These patients manifested symptoms similar to CSF patients. In another series of studies, we (47, 48, 49) treated a group of patients with allergies, dermatitis, multiple chemical sensitivities and environmental
illness with non-specific TF in addition to other therapeutic modalities. These measures greatly enhanced their quality of life and relief from their symptoms. Transfer factor was also used with some measure of success to treat atopic dermatitis (49-52), hyper IgE syndrome (49, 53), hypereuosiophilia (54), discoid lupus (55), and rheumatoid arthritis (56, 57). These latter uses of TF are of interest as they point to the immunoregulatory, inducer/ suppressor function of TF eluded to earlier (72, 73). A large number of older and recent papers discuss treatment of neurological disorders such as multiple sclerosis (58, 59, 60), amyotrophic lateral sclerosis (61, 62), Guillain-Barre Syndrome (63), autism (64), and senility (65). There are also a great number of publications regarding the use of TF in cancer immune therapy and a vast amount of literature on basic research both of which are outside the scope of this review. REFERENCES
1. Lawrence HS. Transfer factor in cellular immunity. Harvey lecture series 68, New York: Academic Press, 239-350, 1974 2. Lawrence HS. The transfer in humans of delayed sensitivity to Streptococcal M substance and tuberculin with disrupted leukocytes. J Clin Invest 34: 219-232, 1955 3. Transfer factor in the Era of AIDS: The Proceedings of the 9th international Symposium on Transfer Factor, 22-24 June 1995, Bologna, Italy. G Pizza and D. Visa, Guest Eds. Biotherapy 9: 1-187, 1995 4. Khan A, Nagata k, hill NO. etal. Management of Viral infections with transfer factor. In Khan A, Kirkpatrick CH, Hill NO, eds. Immune regulators in transfer factor. New York: Academic Press, 501-511, 1974 5. Khan A, Nagata k, hill NO. etal. Management of Viral infections with transfer factor. In Khan A, Kirkpatrick CH, Hill NO, eds. Immune regulators in transfer factor. New York: Academic Press, 501-511, 1974 6. Shulman ST, Hutio JH, Scott B. Transfer factor therapy of chronic aggressive hepatitis. In Archer MS, Gottlieb AA, Kirkpatrick CH, eds. Transfer factor. Basic properties and clinical applications. New York: Academic Press, 439-448, 1976 7. Sumiyama K, Kobayashi M, Miyashiro E: etal. Combination therapy with transfer factor and high dose stronger neo-minophagen C. in chronic Hepatitis B in children (HBw Ag positive). Acta-Paediatr Jap. 33: 327-343, 1991 8. Iseki M, Aoyama T, Koizumi Y, Osano M. Effect of transfer factor on chronic Hepatitis B in childhood. Kansenshogaku-Zasshi 63: 1329-1332, 1989 9. Langham-Mcnally G, C.C, N. Dopson M.H. Evaluation of specific transfer factor in the treatment of two patients with Hepatitis-C. Two case reports.http://itfs.med.unibo.it/ 10. Visa D, Vich JM, Phillips J, Rosenfeld F. Orally administered specific transfer factor for the treatment of herpes infections. Lymphokine Res. 4: 27-30, 1985 11. Meduri R, Campos E, Scrolli C, etal. Efficacy of transfer factor in treating patients with recurrent ocular herpes infections. Biotherapy 9: 61-66, 1996 12. Pizza G, Visa D, De Vinci C. Orally administered HSV-specific transfer factor (TF) prevents genital or labial herpes relapses. Biotherapy 9: 67-72, 1996 13. Peetom F, Florey MJ. Transfer factor in the treatment of disseminated herpes zoster (HZ) infection in immune-suppressed patients. In Khan A, Kirkpatrick CH, Hill NO. eds. Immune regulators in transfer factor. New York: Academic Press, 489- , 1974 14. Steele WR, Myers MG, Vicent MM. Transfer factor for the prevention of Varicella Zoster infection in childhood Leukemia. N Eng. J. Med. 303: 355-359, 1980 15. Jones JF, Wayburn SJ, Fulgitini VA. Treatment of childhood combined Epstein Barr virus/Cytomegalovirus infection with oral bovine transfer factor. Lancet July 18, 1981.
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39. Kirkpatrick CH, Greenburg LE. Treatment of chronic mucocutaneious candidiasis with transfer factor. In: Khan A, Kirkpatrick CH, Hill NO. eds. Immune regulators in transfer factor. New York: Academic Press, 547-559, 1979. 40. Masi M, De Vinci C, Baricordi OR. Transfer factor in chronic mucocutaneous candidiasis. Biotherapy. 9: 97-103, 1996. 41. Visa D. Can specific transfer factor be an effective treatment for CFS? The CFIDS chronicle, Physicians forum Fall 1993. 42 Levine PH. The use of transfer factor in chronic fatigue syndrome: Prospects and problems. Biotherapy. 9: 77-79, 1996. 43. De Vinci C, Levine PH, Pizza G. etal. Lessons from a pilot study of transfer factor in Chronic Fatigue Syndrome. Biotherapy. 9: 87-90, 1996. 44. Hana I, Vrubel J., Pekarek J and Cech K. The influence of age on transfer factor treatment of cellular immunodeficiency, chronic fatigue syndrome and/or chronic viral infections. Biotherapy. 9: 91-95, 1996. 45. Whitaker JA, Dopson MH, Mattman LH. Etal. Preliminary study of transfer factor (TF) in patients with Fibromyalgia (Fm) Chronic Fatigue Syndrome (Cf) and concomitant Lyme Borreliosis. http://itfs.med.unibo.it/ 46. Fudenburg HH. Therapeutic trial of antgen-specific transfer factor in chronic fatigue immune dysregulation syndrome: evidence of latent virus.http://itfs.med.unibo.it/ 47.Ablashi DV, Levine PH, De Vinci C. etal. Use of anti HHV-6 transfer factor for the treatment of two patients with chronic fatigue syndrome (CSF). Two case reports. Biotherapy. 9: 81-88, 1996. 48.Youdim S, Rea WJ, Liang CH. Treatment of environmentally sensitive patients with transfer factor. Part I: Immunologic studies. Clin.Ecol. 7: 55-61, 1990 49. Youdim S, Rea WJ. Treatment of environmentally sensitive patients with transfer factor. Part II: Clinical studies and immunological correlates. Clin.Ecol. 7: 62-66, 1990. 50. Youdim S, Liang CH, Rea WJ. Treatment of environmentally sensitive patients with transfer factor. Part III: Case studies on three patients. Clin.Ecol. 7: 67-72, 1990. 51. Heim LR. Atopic dermatitis, specific virus infections and Bechet's syndrome, transfer factor therapy. In Khan A, Kirkpatrick CH, Hill NO. eds. Immune regulators in transfer factor. New York: Academic Press, 489- , 1974. 52. Navaro-Cruz D, Serrano-Miranda E, Orea-s. etal. Transfer factor as a good therapeutic agent in moderate and severe atopic dermatitis. http://itfs.med.unibo.it/ 53. Cordero-Miranda MA. Serrano-Miranda E. Flores-Sandoval G. etal. Treatment of atopic dermitits with transfer factor and cyclosporine A. http://itfs.med.unibo.it/ 54. Jones JF, Jeter WS, Hicks MJ. Oral transfer factor (OTF) use in hyper IgE syndrome. In Kirkpatrick CH, Burger DR, Lawrence HS. Eds. Immunobiology of transfer factor. New York: Academic Press, 261-269, 1983, 55. Ayala-De La Cruz MC, Rodriguez-Padilla C, Tamaz-Guerra R. Management of hypereosinophilia with transfer factor. http://itfs.med.unibo.it/ 56. Fudenberg HH. Strlkauskas AJ. Goust JM. Etal. Discoid lupus erythmatosus: Dramatic clinical and immunological response to dialyzable leukocyte extract (transfer factor) Trans. Assoc. am. Phys. 94: 279-291, 1981. 57. Grohn P, Raimo A, Krohn K. The effect of chromatographically purified transfer factor component on juvenile Rheumatoid Arthritis. In Archer MS, Gottleib AA, Kirkpatrick CH. eds. Transfer factor. Basic properties and clinical applications. New York: Academic Press, 613- , 1976. 58. Cozine WS, Stanfield AB, Stephens C.A.L. Transfer factor immunotherapy of Rheumatoid Arthritis. In Archer MS, Gottlieb AA, Kirkpatrick CH. eds. Transfer factor. Basic properties and clinical applications. New York: Academic Press, 617- , 1976.
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