Development of colostrum MAF and its clinical application
Recently, immunotherapy has emerged as a new and appealing strategy for cancer treatment and various other acute and chronic diseases. Essential components of the natural immune system—phagocytic cells called macrophages—multiply in response to an infection in the body. The use of a macrophage activating therapy, such as macrophage activating factor (MAF), has extensive applications for treating numerous diseases by activating the natural macrophages of the body to stimulate the immune system. The aim of this review is to provide insight into the features and clinical efficacy of a new type of macrophage-activating factor derived from colostrum, called colostrum MAF.
Immunotherapy, Macrophage Activating Factor (MAF), Colostrum MAF
Many diseases, including cancer and AIDS, develop because of the compromise or failure of the natural immune system. Currently, researchers have learned the stimulation of the natural immune system can arrest or even reverse diseases, such as cancer and AIDS. Recently, the new strategy of immunotherapy has become an appealing strategy for the treatment of cancer, as well as the treatment of various other acute and chronic diseases.
The body’s basic self-defense against disease is the immune system. The immune system can perceive numerous pathogens in the environment, including tumor cells within the body. The immune system’s method of protection consists of two categories of immunity: innate immunity and adaptive immunity. Several types of cells exist in the innate immune system, including phagocytic neutrophils, macrophages, dendritic cells, mast cells, and natural killer cells. The adaptive immune system consists of lymphocytes, including both T cells and B cells, which can distinguish and memorize specific pathogens and their products, including antibodies.
An essential component of the innate immune system, macrophages are phagocytic cells that multiply in response to an infection within the body. Macrophages distinguish, overwhelm, and obliterate pathogens, cancer cells, and foreign substances. These macrophages also circulate cytokines and eliminate cellular debris and cells that have undergone apoptosis. Broadly, macrophages are divided into two classes: tissue-resident macrophages and infiltrating macrophages. Most of the body’s tissues have tissue-resident macrophage populations.
Intestinal macrophages of the gastrointestinal tract, Langerhans cells, dermal macrophages, Kupffer cells, motile liver macrophages, brain microglia, alveolar and interstitial lung macrophages, spleen red pulp macrophages, and bone marrow macrophages are examples of tissue-resident macrophages. By definition, all these macrophages exist in their respective organ tissues and execute homeostatic tissue-specific functions. The source of infiltrating macrophages-inflammatory monocytes-move selectively to areas of inflammation, manufacture inflammatory cytokines, and contribute to both local and systemic inflammation. Infiltrating macrophages occur in pathological environments, including: cancer, atherosclerosis, and metabolic diseases. Macrophages have an important function in wound healing and skin repair. They add to the stimulation of epithelial stem cells and the cyclic stimulation of hair follicle stem cells. The findings could have adaptive implications for skin repairs, hair regrowth, and inflammatory skin diseases.
Known as a vitamin D binding protein-macrophage activating factor (DBP-MAF), Gc protein-derived macrophage activating factor (GcMAF) is a potent endogenous macrophage activator that exists naturally in blood. Recently, MAF has been found to offer health benefits. The purpose of this review is to create awareness about the concepts and clinical efficacy of a new type of macrophage-activating factor currently being developed from colostrum (colostrum MAF).
First generation GcMAF (Purified GcMAF)
Dr. Nobuto Yamamoto discovered GcMAF in 1991. GcMAF is a derivative of the group-specific component (Gc) protein (vitamin D binding protein), which is a component of the albumin superfamily. Purified GcMAF, the first-generation GcMAF, was made using artificial enzymatic treatments of non-specific human Gc protein, which was purified by vitamin D-affinity chromatography. GcMAF is a remarkable serum glycoprotein with numerous biological activities. During an inflammatory response in the body, GcMAF is produced when sialidase of a T-cell and cegalactosidase of an activated B-cell hydrolyze the terminal galactose and sialic acid saccharides of Gc protein. GcMAF exhibits a remarkable biological activity; GcMAF activates macrophages using superoxide radical generation and phagocytic activation, and in vivo, has shown anti-angiogenic and anti-tumor properties. Additionally, GcMAF directly inhibits propagation and migration of human prostate cancer cells or human breast cancer cells, independently from its macrophage activation abilities.
Second generation GcMAF (Serum GcMAF)
A significant problem has been associated with purification of first-generation GcMAF for clinical use. In previous research, an affinity column modified with 25-hydroxy-vitamin D3 was used to produce purified GcMAF. However, contamination is difficult to avoid when a column is repeatedly used. When at room temperature—in an environment with oxygen, and in the absence of antioxidants, such as albumin and uric acid, which are plentiful in blood—purified GcMAF is unstable. To overcome the stability issue with first-generation GcMAF, second-generation GcMAF was produced using artificial enzymatic treatment of human serum without the purification that uses vitamin D-affinity chromatography. In mice, the artificial enzymatic treatment enhanced the phagocytic activity of peritoneal macrophages and extended the survival period among mice with Ehrlich ascites tumors.
Previous studies show that colostrum MAF greatly enhanced phagocytic activity in the peritoneal macrophages and intestinal macrophages of mice, in vitro and in vivo respectively. The consensus has been that materials with a molecular weight over 500 Da do not undergo intestinal absorption. In contrast, it has been reported that, in mice intestinal tracts, peptides of essentially high molecular weight (~15,000 Da) could be absorbed. Therefore, these findings suggest that glycoprotein in the bovine colostrum with a high molecular weight can be absorbed from the intestinal tract.
To activate macrophages in the gut-associated lymphoid tissue (GALT), colostrum MAF is dispensed in the mouth along with Waldeyer’s tonsillar ring (See figure below). Additionally, colostrum MAF may be administered in other areas of the body where macrophages exist. In particular, GALT is considered the largest macrophage pool in the body, having an essential role in maintaining and regulating mucosal immunity. Thus, it has been shown that oral colostrum MAF-within an acid-resistant enteric-coated capsule-has a potential effect for directly activating a large number of macrophages in GALT to stimulate the immune system.
Colostrum MAF has particular advantages over MAF that is produced from serum, regarding practical clinical use-because colostrum MAF is derived from bovine colostrum, a food source, instead of a human serum source-and it is administered orally and sublingually, instead of by invasive injection.
Additionally, colostrum MAF did not mediate production of inflammatory cytokines, including: tumor necrosis factor-α (TNF-α) and and interleukin-1β (IL-1β). If colostrum MAF can be used to suppress the production of inflammatory cytokines, it can be utilised in autoimmune diseases.
Colostrum MAF is able to reach a target tissue such as Waldeyer’s tonsillar ring or GALT by changing dosage form. MAF: macrophage activating factor, GALT: gut-associated lymphoid tissue.
Colostrum MAF has multiple positive attributes, including being a safe food, easy to obtain, and a non-inducer of inflammatory cytokines, and it has also been shown to reach target tissues-such as Waldeyer’s tonsillar ring or GALT-by changing administration forms. Therefore, colostrum MAF is promising as an effective macrophage activator for various immunotherapies. As such, an additional collection of biological and psychological data from clinical applications is needed to confirm the effects of colostrum MAF in the pathology of different diseases.