4Life in the Physicians’ Desk Reference (PDR)
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4LIFE TRANSFER FACTOR® TRI-FACTOR® FORMULA
4Life Transfer Factor Tri-Factor Formula combines transfer factors obtained by proprietary filtration methods from bovine colostrum (UltraFactor XF® and NanoFactor®) and chicken egg yolk (OvoFactor®) sources. Transfer factors are proteins and peptides that contain antigen-specific information which educates and enhances the immune system and helps maintain immune system balance.
Transfer factors are proteins and peptides that communicate antigenic immunological information intercellularly between a donor and a recipient. They support immune function through cell-mediated immunity (CMI). Transfer factors, which carry antigen-specific information, are produced by mononuclear cells and serve to support and improve immune-mediated pathways (1; 2). Mammalian transfer factors, including those of humans, are small molecules between 3,500 and 10,000 daltons. (1; 2) Transfer factors are polypeptides that consist of 40 to 44 amino acids (3) and are thought to have a conserved region and a variable region. From a molecular biological standpoint, these two properties are analogous to antibodies; however, transfer factors' functions of CMI differ almost completely from the functions of antibodies. Transfer factors that have a molecular weight of less than 3,500 daltons modulate immune response, but they do not transfer delayed-type hypersensitivity (DTH). (1) 4Life's transfer factors are sourced from the ultrafiltration of colostrum and from chicken egg yolks. (4; 5) Transfer factors obtained from the spray-dried filtrate of bovine colostrum are of two classes: the transfer factors present in the ultra-filtrate of ≤10,000 daltons and other compounds present in the nanofiltrate are ≤3,500 daltons. Transfer factors were first discovered in 1949 by Dr. H. Sherwood Lawrence when he demonstrated that CMI could be transferred from one individual to another by way of low molecular weight extracts of white blood cells. Transfer factors could transfer DTH of a specific form from a skin test positive individual to a skin test negative individual who, after the transfer, would test positive for that antigen. (6) In a subsequent study in 1955, Lawrence demonstrated that DTH could be passed serially, first from a positive individual to a negative individual, who became positive, then six months later from the second individual to another negative individual who then became positive. (7) At the time, antibodies were the focus of immune research and little was known of the importance of DTH and of the involvement of T-cells in immune response. Transfer factors promote wellness via CMI. Transfer factors are components of colostrum, an infant's first meal. (5; 8) They bridge the generational gap by passing CMI from mother to infant. (9)
BIOLOGICAL AND PHYSIOLOGICAL ACTION
Transfer factor preparations contain more than 200 different moieties of polypeptide molecules with a molecular weight of <10,000 daltons; each moiety potentially has a great number of epitope variations. These antigen-specific factors are synthesized in monocytes and stored in the cytoplasm or on the cell membrane. A significant body of evidence indicates that the primary biological function of transfer factors is to recruit and specifically sensitize previously uncommitted lymphocytes. These sensitized T-lymphocytes initiate the events of CMI, thereby promoting immunity not only at the site of antigen challenge but also throughout the body. (10) The effect of transfer factors on antigen-mediated immunity via B-cells is not completely understood; however, our own studies found an increase in particular antibodies, such as IgA and IgG, during 4Life Transfer Factor administration.
Clinical studies have demonstrated that transfer factors' unique ability to express DTH and promote CMI can be transferred from a sensitized donor to a naïve recipient. (1; 11) This antigen-specific effect is well documented and is likely produced through activation of the CD3-antigen and/or TCR sites of T-cells, increased macrophage activation, and interleukin production—which can also enhance natural killer cell function. (1; 12 ;13) Although the exact mechanism of action is unknown, research has shown that transfer factors will bind to antigens. (1; 13) However, the antigen specificity that is "transferred" to recipients is mediated by T-lymphocytes. (3; 13) Current structure function models propose that transfer factors have many, up to eight possible, unique amino acids sequences, which allow transfer factors to be antigen-specific (1). Transfer factors also have highly conserved regions that allow them to be administered across a species barrier without any loss of potency. In fact, research has demonstrated that bovine transfer factors are structurally analogous to human-derived transfer factors with equivalent physiological activity. (14) This is further supported by several studies, which used transfer factors extracted from bovine lymph nodes and colostrum to confer CMI to specific antigens in animals and human recipients. (15; 16) Although most clinical trials with transfer factors have used parental administration, oral administration has also demonstrated successful transfer of DTH and CMI to recipients. (17) Dose-response studies, using various routes of administration, have been performed in both humans and animals. Results of these experiments refute any arguments that the acidic or enzymatic environment of gastrointestinal tract affects oral administration of transfer factors. (17)
CLINICAL AND EXPERIMENTAL STUDIES
Natural Killer (NK) Cell Activity
Peripheral blood mononuclear cells were isolated and pooled from several healthy donors. Sixty thousand cells were added to each well of 96-well microtiter plate. Various immune-modulating ingredients, including 4Life Transfer Factor Tri-Factor Formula, were added to select wells on the plate and the 48-hour incubation started. At end of the incubation period, 30,000 K562 cells were added to each well. MTT assay techniques were used to determine the cytotoxic index. The various 4Life Transfer Factor products resulted in cytotoxic indices of 80-98%. By comparison, mononuclear cells incubated with IL-2 for the same 48-hour period produced a cytotoxic index of 88%.(18)
The NK cell activity of 4Life Transfer Factor has more recently been evaluated via flow cytometry technique. PBMCs derived from six healthy donors were plated in 96-well plates at 96,000/90 μl concentration. UltraFactor XF was solubilized in PBS to 10 mg/ml and added to PBMCs at final concentrations of 10, 100, and 1000 μg/ml. K562 cells were added into wells at 4000 per 90 μl and incubated for 48 hours. IL-2 at 20 ng/ml was used as positive control. Results revealed that UltraFactor XF's cytotoxicity against K562 cells was greater than IL-2 in four out of the six donors and similar to IL-2 in one out of the six donors.(19)
CD4 T-Helper Cell Research
Multiple studies were performed using an FDA-approved diagnostic CD4 T-Helper cell assay kit and/or a T-Cell Memory (CD8) assay kit under development by the same company. Similar to the NK cell research described above, these ex vivo studies were performed on 96-well microtiter plates measuring ATP production via a luciferase-based luminescence reaction. The CD4 assay utilized Phytohaemagglutinin (PHA)-stimulated cells isolated from whole blood via the use of Dynabeads™. An 18-hour incubation of these isolated, stimulated CD4 cells with 4Life Transfer Factor products resulted in a modulation of immune cell activity as exhibited by a decrease in Adenosine Triphosphate (ATP) production without a negative impact on cell viability. It is hypothesized that this reduction on ATP production is a result of a redirection in immune cell focus, essentially diminishing the distraction induced by the addition of PHA to the microtiter wells.(20)
Salivary Secretory IgA (SIgA)-Preliminary Investigation
Twenty-four subjects naïve to 4Life Transfer Factor supplementation were enrolled in a small-scale, preliminary test. Twenty-one were included in the final analysis. Salivary samples were collected from each subject weekly at roughly the same time of day and day of the week. Saliva was collected over a five-minute period via passive drool while subjects chewed on a piece of Parafilm™. The samples were put on ice and then frozen at -70°C until assay. The commercial Salimetrics™ salivary IgA assay kit was used for analysis. Subjects were given 4Life Transfer Factor Tri-Factor Formula at 2 capsules per day for two weeks and then transitioned to 4Life Transfer Factor RioVida Tri-Factor Formula at 60 ml per day for an additional two weeks. At the end of the four-week supplementation period, the group showed an average 73% increase in salivary secretory IgA (SIgA) production over their baseline value. Furthermore, none of the 21 subjects showed a SIgA production rate less than their baseline value at the end of the test.(21)
A study conducted with 30 college students found that either 1× 15 days or 2× 15 days (with a two-week break in between) of 4Life Transfer Factor Classic administered according to label dose helped them maintain their health. In both groups, product administration improved the number of CD8+ T-cells and NK cells to healthier levels. Particularly, those who took the product for 2×15 days showed prolonged health maintenance and improvement of immune cell markers than those who took it for 15 days. Specifically, the maintenance of good health and improvement of immune cell markers remained for up to three months after stopping product administration in those who took the product for 2× 15 days, in comparison to one month in those who took the product for 1×15 days. (22)
In a study of acute toxicity, rats were assessed for 14 days following a single gavage of 4Life Transfer Factor Tri-Factor Formula. Five female SD rats were each gavaged with a dose of 2,000 mg/kg. No treatment-related mortalities occurred and there were no clinical signs of toxicity. No significant difference in body weight occurred. No gross lesions were found at necropsy in any of the animals. Thus, acute toxicity is considered to be greater than 2,000 mg/kg (human equivalent dose of approximately 320 mg/kg). (23)
Another similar single-dose oral toxicity study was conducted in mice. Six female Wistar mice each received 2,000 mg/kg of 4Life Transfer Factor Chewable Tri-Factor Formula via oral gavage and monitored for 14 days. No observable toxicity occurred, as assessed by mortality, body weight gain, histopathology of brain, liver, kidneys, and lungs, or clinical signs of aggression, lethargy, breathing difficulties, diarrhea, mobility, or shivering. Thus, the no-observed adverse effect level was considered to be greater than 2,000 mg/kg in mice, which is equivalent to approximately 9.7 g/day in humans. (24)
Recent toxicity studies performed by an independent toxicology laboratory were conducted to evaluate the mutagenicity and genotoxicity potential of UltraFactor XF (colostrum ultrafiltrate). Mutagenicity was assessed by the Bacterial Reverse Mutation assay. Results revealed that the test article has no mutagenic activity at any of the concentrations tested. Genotoxicity was assessed by the Mammalian Chromosome Aberration test. Results demonstrated that the test article, tested up to the maximum recommended concentration, did not induce structural chromosome aberrations in this mammalian system. The laboratory concluded that UltraFactor XF is considered not clastogenic in this system. (25)
Oral toxicity studies performed by the same toxicology laboratory assessed the potential short-term and long-term toxicity of UltraFactor XF in rats. In both, 14-day and 90-day repeated dose studies, male and female Wistar rats received by oral gavage 1050, 2100, or 4200 mg/kg body weight/day of UltraFactor XF or placebo. Results revealed that no mortality occurred at any given dose. Clinical observations showed no adverse effect of the test article on behavior and physical condition of the animals. No abnormal body weight gain or food consumption was observed. Ophthalmological and hematological evaluations demonstrated no adverse effect by the test article. Similarly, no changes were observed in clinical chemistry, gross pathology, organ weight, or histopathology at any given dose. It was concluded that the no-observed adverse effect level was greater than 4200 mg/kg in rats. This dose is equivalent to 40 g/day in humans (25).
An expert panel of toxicologists have evaluated the above-mentioned toxicity data and concluded that UltraFactor XF is generally recognized as safe (GRAS). (26)
The use of transfer factors is contraindicated in people receiving immunosuppressive therapy, though actual interactions have not been documented. The use of transfer factors during pregnancy and nursing has not been evaluated.
4Life Transfer Factor can be found in the following products:
4Life Transfer Factor® Tri-Factor® Formula 4Life® Transfer Factor Plus® Tri-Factor® Formula 4Life Transfer Factor® RioVida® Tri-Factor® Formula 4Life Transfer Factor® Chewable Tri-Factor® Formula 4Life Transfer Factor® Classic 4Life Transfer Factor® Immune Spray 4Life Transfer Factor® KBU® 4Life Transfer Factor® Belle Vie® 4Life Transfer Factor® Cardio 4Life Transfer Factor® Collagen 4Life Transfer Factor® GluCoach® 4Life Transfer Factor® MalePro® 4Life Transfer Factor® ReCall® 4Life Transfer Factor Reflexion® 4Life Transfer Factor Vista® Renuvo® RiteStart® Men RiteStart® Women RiteStart® Kids & Teens Pre/o Biotics® PRO-TF®
1. Fundenberg, H. and G. Pizza. 1994, Progress in Drug Research, Vol. 42, pp. 309–400.
2. Lawrence, H.S. and W. Borkowsjy. 1996, Biotherapy, Vol. 9, pp. 1–5.
3. Kirkpatrick, C.H. 2000, Mol Med, Vol. 6, pp. 332–41.
4. Hennon, W. and D. Lisonbee. U.P. Office, Editor. 2002, 4Life Research, LC: USA.
5. Wilson, G. and G. Paddock.: U.P. Office, Editor., 1989, Amtron, Inc. USA.
6. Lawrence, H.S. 1949, Proc Soc Exp Biol Med, Vol. 71, pp. 516–22.
7. Lawrence, H.S. 1955, J Clin Invest, Vol. 34, pp. 219–30.
8. Wilson, G.B. et al. 1988, Acta Virol, Vol. 32, pp. 6-18.
9. Schlesinger, J.J. and H.D. Covelli. 1977, Lancet, Vol. 2, pp. 529-32.
10. Levin, A.S., L.E. Spitler, and H.H. Fundenberg. 1973, Annu Rev Med, Vol. 24, pp. 175–208,
11. Fudenberg, H. and H. Fudenberg. 1989, Ann Rev Pharmacol Toxicol, Vol. 29, pp. 475-516.
12. See, D, S. Mason, and R. Roshan. 2002, Immunol Invest, Vol. 31, pp. 137–53.
13. Myles, I.A. et al. 2017, J Leukoc Biol, Vol. 101, pp. 307-20.
14. Dwyer, John M. 1996, Biotherapy, Vol. 9, pp. 7-11.
15. Wilson, G.B., R.T. Newell, and N.M. Burdash. 1979, Cell Immunol, Vol. 47, pp. 1–18.
16. Radosevich, J.K., G.H. Scott, and G.D. Olson. 1985, Am J Vet Res, Vol. 46, pp. 875-8.
17. Kirkpatrick, C.H. 1996, Biotherapy, Vol. 9, pp. 13-6.
18. Kisielevsky, M.V. and E.O. Khalturina. 2003, unpublished. Blokhin Research Center, Russian Academy of Medical Sciences.
19. Vieira-Brock P.L.et al. 2019, poster at Immunology. San Diego, California.
20. 4Life Research, LLC. 2007, unpublished findings.
21. 4Life Research, LLC. 2004, unpublished findings.
22. Klimov, V. and E. Oganova. in Euromedica Hannover 2004. Hannover, Germany: 2004. pp. 15–16.
23. Kabirov, K.K. 2009, unpublished report: University of Illinois at Chicago.
24. Burbano, Z. and G. Sarmiento. 2013. Facultad de Ciencies Quimicas, Universidad de Guayaquil, Ecuador.
25. Thiel, A. et al. 2019, Reg Toxicol Pharmacol, Vol. 104 pp.39-49.
26. Hauswirth, J.W. et al (2019, June 24). Seattle, WA. AIBMR Life Sciences, Inc.
NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.
The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected over dosage, the drug's identity should be verified by chemical analysis.
Our manufacturer, 4Life Research announced a price change starting October 1, 2018 that will affect all web sellers of 4Life products. From now on, all wholesale options and all discount packages will only be available directly through 4LIFE's website.
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