| | | | | The scientific and clinical experience with VDBP and |
| Abstract: | | | | Gc-MAF are very encouraging. Several clinical trials |
| The recent proliferation of published studies outlining | | | | are underway in the Bahamas at the Immune |
| the role of vitamin D in the prevention of many | | | | Augmentation Therapy Centre to reproduce and |
| diseases associated with a weakened immune | | | | confirm the current clinic studies, as well as to |
| system has brought to light the importance of | | | | answer several clinical questions that have not yet |
| monitoring the serum levels of 25(OH) vitamin D. (1) | | | | been reported in the scientific literature about VDBP |
| Specifically, the direct correlation of vitamin D levels in | | | | and Gc-MAF. If you would like to enrol any clients |
| the human serum with increased levels of cathelicidin | | | | with cancer or immune suppression in a trial with |
| and the potentiating role cathelicidin plays in the | | | | Gc-MAF, please contact the author of this review. |
| immune response to infections, cancer, autoimmune | | | | Citations: |
| disease, and especially acute viral infections. (2) | | | | 1. Bikie DD, "Vitamin D and immune function: |
| While research into vitamin D needs to continue, the | | | | understanding common pathways" Curr Osteoporos |
| importance of vitamin D binding protein (VDBP) has | | | | Rep. 2009 Jul;7(2):58-63 |
| been demonstrated to have synergistic yet | | | | 2. Yuk JM, Shin DM, Lee HM, Yang CS, Jin HS, Kim |
| independent functions in the human immune | | | | KK, Lee SH, Kim JM, Jo EK, "Vitamin D3 induces |
| system.(3) This article will outline the emerging role | | | | autophagy in human monocytes/macrophages via |
| of VDBP in the field of immunology. | | | | cathelicidin" Cell Host Microbe. 2009 Sep 17;6(3):231-43 |
| Method: | | | | 3. Chkri M et al, "Production of human macrophages |
| A review of the scientific literature pertaining to | | | | with potent antitumoral properties (MAK) by culture |
| vitamin D binding protein and its derivatives identified | | | | of monocytes in the presence of GM-CSF and |
| in human serum and produced in the laboratory. | | | | 1,25-dihydroxy vitamin D3." Anticancer Res. 1992 |
| Results: | | | | Nov-Dec;12(6B):2257-60 |
| Vitamin D binding protein, also known as Gc-protein, is | | | | 4. Christiansen M et al, "Protein chemical |
| a group of isoform proteins with O-linked glycans. | | | | characterization of Gc-gobulin (vitamin D-binding |
| The dominant isoform of VDBP are non-glycosylated | | | | protein) isoforms; Gc-f1, Gc-s, and Gc-2." Biochem |
| 656 Da proteins produced mainly in the liver.(4) | | | | Biophys Acta. 2007 Apr; 1774(4):481-92 |
| Vitamin D binding protein participates in liver cell | | | | 5. Gressner OA et al, "Gc-globulin (vitamin D binding |
| stability and regeneration through Calcium dependent | | | | protein) is synthesized and secreted by hepatocytes |
| interaction with the megalin/gp330 receptor.(5) | | | | and internalized by hepatic stellate cells through Ca2+ |
| There are 4 important roles VDBP has in humans. It | | | | dependent interaction with megalin/gp330 receptor." |
| binds circulating vitamin D for transport and storage, | | | | Clinica ChimiceActa 2008 Apr 390;1-2:28-37 |
| it is the most important scavenger of extracellular | | | | 6. Nagasawa H et al, "Gc-protein (vitamin D-binding |
| G-actin, it enhances the chemotactic activity of C5a | | | | protein): Gc genotyping and GcMAF precursor |
| for neutrophils in inflammation, and it activates | | | | activity." Anticancer Res. 2005 Nov-Dec; |
| macrophages thru GaINAc-modified Gc-protein. (6) | | | | 25(6A):3689-95 |
| Additionally, low levels of VDBP have been found to | | | | 7. Jorgensen CS et al, "Large-scale purification and |
| correlate with multiple organ failure sepsis, and | | | | characterization of non-glycosylated Gc-protein |
| non-survival in fulminant liver failure and traumatic liver | | | | (vitamin D binding protein) from plasma fraction IV." |
| failure.(7) The non-glycosylated isoform of VDBP is | | | | Biotechnol Appl Biochem. 2006 Apr;44(pt1):35-44 |
| able to mask the presence of endotoxins by | | | | 8. Zella LA et al, "Vitamin D-binding protein influences |
| 20%.(7) Therapy with VDBP may increase survival | | | | total circulating levels of 1,25-dihydroxyvitamin D3 but |
| in trauma, sepsis and fulminant liver failure.(7) | | | | does not directly modulate the bioactive levels of the |
| The function of VDBP is independent of the hormone | | | | hormone in vivo." Endocrinology. 2008 |
| actions of 1,25(2OH) vitamin D and it has limited | | | | Jul;149(7):3656-67 |
| impact on the extracellular pool of 1,25(OH) vitamin | | | | 9. Winters SJ et al, "Influence of obesity on vitamin |
| D.(8) Vitamin D binding protein has virtually no | | | | D-binding protein and 25-hydroxy vitamin D levels in |
| impact on the distribution, uptake, activation profile, | | | | African and white women." Metabolism. 2009 |
| or biological potency of the hormone vitamin D.(8) | | | | Apr;58(4):438-42 |
| Vitamin D binding protein is not affected by race or | | | | 10. Schiodt FV et al, "Increased turnover of |
| adiposity the way vitamin D levels are affected.(9) | | | | Gc-protein in patients with hepatic encephalopathy." |
| The serum levels of VDBP are decreased by trauma, | | | | Scand J Gastroenterol. 2001 Sep;36(9):998-1003 |
| septic infections, and chronic or acute liver | | | | 11. Schiodt FV et al, "Gc-globulin and prognosis in |
| diseases.(10) The normal levels of serum VDBP are | | | | acute liver failure." Liver Transpl. 2005 |
| 350-50 mg/L and low levels below 80 mg/L yield a | | | | Oct;11(10):1223-7 |
| positive and negative mortality predictive value 85% | | | | 12. Homma S et al, "Vitamin D-binding protein |
| and 43% respectively.(11) | | | | (group-specific component) is the sole serum protein |
| While vitamin D binding protein is a primary | | | | required for macrophage activation after treatment |
| macrophage activating factor, several glycosylated | | | | of peritoneal cells with lyso-phosphatidylcholine." |
| isoforms have more potent and specific macrophage | | | | Immunol Cel Biol. 1993 Aug;71(pt4):249-57 |
| activating properties.(12) The most potent serum | | | | 13. Yamamoto N et al, "Conversion of vitamin D3 |
| macrophage activation factor (MAF) is produced by a | | | | binding protein (group-specific component) to a |
| series of glycosylation reactions performed by the | | | | macrophage activating factor by stepwise action of |
| B-cells and T-cells.(13) Vitamin D-MAF as a potent | | | | beta-galactosidase of B-celss and sialidase of T-cells." |
| adjuvant activity for immunization and healthy serum | | | | J Immunol. 1993 Sep 1;151(5):2794-802 |
| levels of MAF prevent tumours from being able to | | | | 14. Yamamoto N et al, "Structurally well-defined |
| transplant into mice.(14) Other roles for VDBP | | | | macrophage activating factor derived from vitamin |
| derived MAF have been described, including an | | | | D3-binding protein has a potent adjuvant activity for |
| anti-angiogenesis function through blocking | | | | immunization." Immunol Cell Biol. 1998 Ju;76(3):237-44 |
| VEGF-induced angiogenesis.(15) | | | | 15. Kallunte S et al, "Inhibition of angiogenesis by |
| Laboratory derived MAF from serum VDBP has the | | | | vitamin D-binding protein: characterization of |
| advantage of activating macrophages and not being | | | | anti-endothelial activity of DBP-MAF." Angiogenesis. |
| deglycosylated by N-acetylgalactosaminidase | | | | 2005;8(4):349-60 |
| enzymes (NaGaLase) produced by cancer cells and | | | | 16. Yamamoto N et al, "Immunotherapy of |
| infectious bacteria, viruses and fungi.(16) The clinical | | | | metastatic colorectal cancer with vitamin D-binding |
| dose required to have a sustained systemic activation | | | | protein derived macrophage activating factor, |
| of macrophages in 100 mcg injected weekly.(16) A | | | | Gc-MAF." Cancer Immunol Immunotherapy |
| novel MAF (Gc-MAF) can be produced in the lab with | | | | 2008;57:1007-16 |
| cancer specific activity that targets undifferentiated | | | | 17. Yamamoto N et al, "Immunotherapy of |
| cancer cells better than well differentiated cancer | | | | metastatic breast cancer patients with vitamin |
| cells.(17) Several prospective clinical trials of | | | | D-bindng protein-derived macrophage activating |
| treatment of cancer and HIV with Gc-MAF have | | | | factor (GcMAF)." Int J Cancer. 2008;122:461-467 |
| been reported and three trials with metastatic colon, | | | | 18. Yamamoto N, Suyama H, Yamamoto N |
| breast and prostate cancer have provided 100% | | | | "Immunotherapy for prostate cancer with Gc |
| remission rate beyond the five years since Gc-MAF | | | | protein-derived macrophage activating factor, |
| treatment.(16)(17)(18) | | | | GcMAF." Transl Oncol. |
| Discussion: | | | | |