Nutritional Immunomodulators

Abstract

“Let food be thy medicine and let medicine be thy food.” This aphorism refers to the pivotal role played by nutrition in medicine. The door of a “nutrition renaissance” has been opened with the striking disclosure of the relationship between nutrition and microbiota in the pathogenesis of many diseases, which has been better understood in the recent years. A person, once again, is “what he/ she eats.” Foods become “functional” after their integration into the unique features of the intestinal immune system, such as oral tolerance, secretory Immunoglobulin A, local lymphoid foci, regulator cellular immunity, and diversity of commensal microbiome. It is possible to achieve strong immunomodulatory effects through an appropriate selection of probiotics, prebiotics, and synbiotics. Animal proteins and plant-derived peptides also exert immunomodulatory effects. It has been reported that the use of glutamine supplements from wheat protein (gluten) in patients helps in lowering the nosocomial infection rate and the duration of mechanical ventilation. Vitamin A contributes immensely in maintaining the mucosal epithelial integrity and aids in strengthening the neutrophil response to infectious agents. Vitamin B12 has a strong immunomodulatory effect and facilitates the increase in CD8+ T lymphocyte count and natural killer cell activity. Vitamin C has well-defined antioxidant efficacy. Vitamin D strengthens the innate immune response by stimulating cell proliferation and differentiation. The regulatory effects of many foods and food ingredients such as turmeric, garlic, carrot, eggplant, kiwi, and honey in our kitchen on both innate and adaptive immunity serve as the foundation for anticancer, anti-inflammatory, and antioxidant nutrition therapies. Thus, our food continues to be our medicine.

Keywords

• Food
• immunomodulator
• probiotic
• vitamin
• mineral

Gıda Kaynaklı İmmünomodülatörler

Abstract

“Gıdanız ilacınız, ilacınız gıdanız olsun aforizması beslenmenin tıptaki merkezi rolüne atıfta bulunur. Patogenezi son yıllarda anlaşılan bir çok hastalığın beslenme ve mikrobiyota ile ilişkisinin çarpıcı şekilde ortaya konması ile adeta bir “beslenme rönesansı”nın kapısı aralanmıştır. İnsan, bir kez daha; “yediğinden ibaret”tir. Gıdalar; bağırsak bağışıklık sisteminin oral tolerans, salgısal IgA, lokal lenfoid odaklar, regülatör hücresel immünite ve kommensal mikrobiyomun çeşitliliği gibi kendine özgü özellikleri ile bütünleşebildikleri ölçüde “fonksiyonel” hale gelmektedir. Doğru seçilmiş probiyotik, prebiyotik ve sinbiyotikler ile güçlü immünomodülatör etkiler elde edilebilmektedir. Hayvansal proteinler ve bitki kaynaklı peptidlerin de immünomodülatör etkileri bulunmaktadır. Yatan hastalarda buğday proteini (gluten) kaynaklı glutamin takviyesi yapıldığında nozokomiyal enfeksiyon oranlarında ve mekanik ventilasyon gereken gün sayısında düşüş sağlandığı görülmüştür. Vitaminlerden; A vitamininin mukozal epitelyal bütünlüğün korunması ve enfeksiyon etkenlerine karşı güçlü nötrofil yanıtında önemli katkıları vardır. B12 vitamini güçlü immünomodülatör etki göstermekte, özellikle CD8+ T lenfosit sayılarında ve NK hücre aktivitesinde artışa katkıda bulunmaktadır. Vitamin C önemli bir antioksidandır. D vitamini, hücre proliferasyon ve diferansiyasyonunu uyararak doğal immün yanıtı güçlendirmektedir. Mutfağımızda yer bulan zerdeçal, sarımsak, havuç, patlıcan, kivi, bal gibi pek çok gıda ve gıda bileşeninin gerek doğal gerekse edinsel bağışıklık üzerindeki düzenleyici etkileri; anti-kanser, anti-enflamatuvar, anti-oksidan beslenme kürlerine dayanak oluşturmakta; gıdamız ilacımız olmaya devam etmektedir.

Keywords

• Gıda
• immünomodülatör
• probiyotik
• prebiyotik
• vitamin
• mineral

References

1. 1. Georgiou NA, Garssen J, Witkamp RF. Pharma-nutrition interface: the gap is narrowing. European Journal of Pharmacology 2011; 651(1-3): 1-8. [CrossRef]
2. 2. TF. M. Functional Food - A Review. European Academic Research 2016(6): 5695-702.
3. 3. Salman F, Erten G, Unal M, Kiran B, Salman S, Deniz G, et al. Effect of acute maximal exercise on lymphocyte subgroups in type 1 diabetes. Acta Physiol Hung 2008; 95(1): 77-86. [CrossRef]
4. 4. Suzuki K, Kawamoto S, Maruya M, Fagarasan S. GALT: organization and dynamics leading to IgA synthesis. Advances in immunology 2010; 107: 153-85. [CrossRef]
5. 5. Hekim N, Ş. A. Bağışıklık Bilimi. İstanbul: Nobel Tıp Kitabevleri; 2017.
6. 6. Rezende RM, Weiner HL. History and mechanisms of oral tolerance. Seminars in Immunology 2017; 30: 3-11. [CrossRef]
7. 7. Shiokawa A, Kotaki R, Takano T, Nakajima-Adachi H, Hachimura S. Mesenteric lymph node CD11b(-) CD103(+) PD-L1(High) dendritic cells highly induce regulatory T cells. Immunology 2017; 152(1): 52-64. [CrossRef]
8. 8. Sato A, Hashiguchi M, Toda E, Iwasaki A, Hachimura S, Kaminogawa S. CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive B cells. Journal of Immunology 2003; 171(7): 3684-90. [CrossRef]

9. 9. Goodrich ME, McGee DW. Preferential enhancement of B cell IgA secretion by intestinal epithelial cell-derived cytokines and interleukin-2. Immunological Investigations 1999; 28(1): 67-75. [CrossRef]
10. 10. Hattori M, Taylor TD. The human intestinal microbiome: a new frontier of human biology. DNA research: An International Journal for Rapid Publication of Reports on Genes and Genomes 2009; 16(1): 1-12. [CrossRef]
11. 11. Yanagibashi T, Hosono A, Oyama A, Tsuda M, Suzuki A, Hachimura S, et al. IgA production in the large intestine is modulated by a different mechanism than in the small intestine: Bacteroides acidifaciens promotes IgA production in the large intestine by inducing germinal center formation and increasing the number of IgA+ B cells. Immunobiology 2013; 218(4): 645-51. [CrossRef]
12. 12. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. Journal of Immunology 1997; 159(4): 1739-45.
13. 13. Kang HJ, Im SH. Probiotics as an Immune Modulator. Journal of Nutritional Science and Vitaminology 2015; 61(Suppl): S103-5. [CrossRef]
14. 14. Saad N, Delattre C, Urdaci M, Schmitter JM, P.Bressollier. An overview of the last advances in probiotic and prebiotic field. LWT - Food Science and Technology 2013; 50(1): 1-16. [CrossRef]
15. 15. Schiavi E, Smolinska S, O'Mahony L. Intestinal dendritic cells. Current Opinion in Gastroenterology 2015; 31(2): 98-103. [CrossRef]
16. 16. Konieczna P, Ferstl R, Ziegler M, Frei R, Nehrbass D, Lauener RP, et al. Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms. PloS One 2013; 8(5): e62617. [CrossRef]
17. 17. Wong TH, Chen HA, Gau RJ, Yen JH, Suen JL. Heme Oxygenase-1-Expressing Dendritic Cells Promote Foxp3+ Regulatory T Cell Differentiation and Induce Less Severe Airway Inflammation in Murine Models. PloS One 2016; 11(12): e0168919. [CrossRef]
18. 18. Dasgupta S, Erturk-Hasdemir D, Ochoa-Reparaz J, Reinecker HC, Kasper DL. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host & Microbe 2014; 15(4): 413-23. [CrossRef]
19. 19. Habil N, Abate W, Beal J, Foey AD. Heat-killed probiotic bacteria differentially regulate colonic epithelial cell production of human beta-defensin-2: dependence on inflammatory cytokines. Beneficial Microbes 2014; 5(4): 483-95. [CrossRef]
20. 20. Hemaiswarya S, Raja R, Ravikumar R, IS C. Mechanism of action of probiotics. Braz Arch Biol Technol 2013; 56: 113-9. [CrossRef]
21. 21. Scully P, Macsharry J, O'Mahony D, Lyons A, O'Brien F, Murphy S, et al. Bifidobacterium infantis suppression of Peyer's patch MIP-1alpha and MIP-1beta secretion during Salmonella infection correlates with increased local CD4+CD25+ T cell numbers. Cellular Immunology 2013; 281(2): 134-40. [CrossRef]
22. 22. Lin R, Jiang Y, Zhao XY, Guan Y, Qian W, Fu XC, et al. Four types of Bifidobacteria trigger autophagy response in intestinal epithelial cells. Journal of Digestive Diseases 2014; 15(11): 597-605. [CrossRef]
23. 23. Elian SD, Souza EL, Vieira AT, Teixeira MM, Arantes RM, Nicoli JR, et al. Bifidobacterium longum subsp. infantis BB-02 attenuates acute murine experimental model of inflammatory bowel disease. Beneficial Microbes 2015; 6(3): 277-86. [CrossRef]
24. 24. Kim HJ, Kim YJ, Lee SH, Yu J, Jeong SK, Hong SJ. Effects of Lactobacillus rhamnosus on allergic march model by suppressing Th2, Th17, and TSLP responses via CD4(+)CD25(+)Foxp3(+) Tregs. Clinical Immunology 2014; 153(1): 178-86. [CrossRef]
25. 25. Zhang M, Zhang S, Hua Z, X Z. Long-term use of Bifidobacterium longum alleviates colorectal colitis in rats by regulating inflammatory cytokines and Treg cells. Erciyes Üniversitesi Veterinerlik Fakültesi Dergisi 2017(10): 7543-52.
26. 26. Zhang M, Zhou L, Zhang S, Yang Y, Xu L, Hua Z, et al. Bifidobacterium longum affects the methylation level of forkhead box P3 promoter in 2, 4, 6-trinitrobenzenesulphonic acid induced colitis in rats. Microbial Pathogenesis 2017; 110: 426-30. [CrossRef]
27. 27. Konieczna P, Schiavi E, Ziegler M, Groeger D, Healy S, Grant R, et al. Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1. PloS One 2015; 10(3): e0120261. [CrossRef]
28. 28. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013; 500(7461): 2326. [CrossRef]
29. 29. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504(7480): 446-50. [CrossRef]
30. 30. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504(7480): 451-5. [CrossRef]
31. 31. Milligan G, Ulven T, Murdoch H, Hudson BD. G-protein-coupled receptors for free fatty acids: nutritional and therapeutic targets. The British Journal of Nutrition 2014; 111(Suppl 1): S3-7. [CrossRef]
32. 32. Owaga E, Hsieh RH, Mugendi B, Masuku S, Shih CK, Chang JS. Th17 Cells as Potential Probiotic Therapeutic Targets in Inflammatory Bowel Diseases. International Journal of Molecular Sciences 2015; 16(9): 20841-58. [CrossRef]
33. 33. Sakai F, Hosoya T, Ono-Ohmachi A, Ukibe K, Ogawa A, Moriya T, et al. Lactobacillus gasseri SBT2055 induces TGF-beta expression in dendritic cells and activates TLR2 signal to produce IgA in the small intestine. PloS One 2014; 9(8): e105370. [CrossRef]
34. 34. Rosser EC, Oleinika K, Tonon S, Doyle R, Bosma A, Carter NA, et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nature Medicine 2014; 20(11): 1334-9. [CrossRef]
35. 35. Liao HY, Tao L, Zhao J, Qin J, Zeng GC, Cai SW, et al. Clostridium butyricum in combination with specific immunotherapy converts antigen-specific B cells to regulatory B cells in asthmatic patients. Scientific Reports 2016; 6: 20481. [CrossRef]
36. 36. Enani SM, Childs CE, Przemska A, Maidens C, Dong H, Rowland I, et al. Effects of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486 with prebiotic on the B-cell response to influenza vaccination. Proceedings of the Nutrition Society 2014(73): E9. [CrossRef]
37. 37. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nature reviews Gastroenterology & Hepatology 2017; 14(8): 491-502. [CrossRef]
38. 38. Shokryazdan P, Faseleh Jahromi M, Navidshad B, Liang JB. Effects of prebiotics on immune system and cytokine expression. Medical Microbiology and Immunology 2017; 206(1): 1-9. [CrossRef]
39. 39. Dwivedi M, Kumar P, Laddha NC, Kemp EH. Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity. Autoimmunity Reviews 2016; 15(4): 379-92. [CrossRef]
40. 40. Bindels LB, Delzenne NM, Cani PD, Walter J. Towards a more comprehensive concept for prebiotics. Nature reviews Gastroenterology & Hepatology 2015; 12(5): 303-10. [CrossRef]
41. 41. Oozeer R, van Limpt K, Ludwig T, Ben Amor K, Martin R, Wind RD, et al. Intestinal microbiology in early life: specific prebiotics can have similar functionalities as human-milk oligosaccharides. The American Journal of Clinical Nutrition 2013; 98(2): 561S-71S. [CrossRef]
42. 42. Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome. Frontiers in Microbiology 2014; 5: 494. [CrossRef]
43. 43. Douellou T, Montel MC, Thevenot Sergentet D. Invited review: Anti-adhesive properties of bovine oligosaccharides and bovine milk fat globule membrane-associated glycoconjugates against bacterial food enteropathogens. Journal of Dairy Science 2017; 100(5): 3348-59. [CrossRef]
44. 44. Manthey CF, Autran CA, Eckmann L, Bode L. Human milk oligosaccharides protect against enteropathogenic Escherichia coli attachment in vitro and EPEC colonization in suckling mice. Journal of Pediatric Gastroenterology and Nutrition 2014; 58(2): 165-8. [CrossRef]
45. 45. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016; 535(7610): 75-84. [CrossRef]
46. 46. Chu H, Khosravi A, Kusumawardhani IP, Kwon AH, Vasconcelos AC, Cunha LD, et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 2016; 352(6289): 1116-20. [CrossRef]
47. 47. Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nature Reviews Microbiology 2016; 14(1): 20-32. [CrossRef]
48. 48. Wu RY, Maattanen P, Napper S, Scruten E, Li B, Koike Y, et al. Non-digestible oligosaccharides directly regulate host kinome to modulate host inflammatory responses without alterations in the gut microbiota. Microbiome 2017; 5(1): 135. [CrossRef]
49. 49. Seifert S, Watzl B. Inulin and oligofructose: review of experimental data on immune modulation. The Journal of Nutrition 2007; 137(11 Suppl): 2563S-7S. [CrossRef]
50. 50. Vogt L, Meyer D, Pullens G, Faas M, Smelt M, Venema K, et al. Immunological properties of inulin-type fructans. Critical Reviews in Food Science and Nutrition 2015; 55(3): 414-36. [CrossRef]
51. 51. Vulevic J, Drakoularakou A, Yaqoob P, Tzortzis G, Gibson GR. Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. The American Journal of Clinical Nutrition 2008; 88(5): 1438-46.
52. 52. Capitan-Canadas F, Ortega-Gonzalez M, Guadix E, Zarzuelo A, Suarez MD, de Medina FS, et al. Prebiotic oligosaccharides directly modulate proinflammatory cytokine production in monocytes via activation of TLR4. Molecular Nutrition & Food Research 2014; 58(5): 1098-110. [CrossRef]
53. 53. Zhu J, Zhang Y, Wu G, Xiao Z, Zhou H, Yu X. Inhibitory effects of oligochitosan on TNF-alpha, IL-1beta and nitric oxide production in lipopolysaccharide-induced RAW264.7 cells. Molecular Medicine Reports 2015; 11(1): 729-33. [CrossRef]
54. 54. Herfel TM, Jacobi SK, Lin X, Fellner V, Walker DC, Jouni ZE, et al. Polydextrose enrichment of infant formula demonstrates prebiotic characteristics by altering intestinal microbiota, organic acid concentrations, and cytokine expression in suckling piglets. The Journal Of Nutrition 2011; 141(12): 2139-45. [CrossRef]
55. 55. Agati G, Brunetti C, Di Ferdinando M, Ferrini F, Pollastri S, Tattini M. Functional roles of flavonoids in photoprotection: new evidence, lessons from the past. Plant Physiology and Biochemistry : PPB 2013; 72: 35-45. [CrossRef]
56. 56. Tsao R. Chemistry and biochemistry of dietary polyphenols. Nutrients 2010; 2(12): 1231-46. [CrossRef]
57. 57. Mao X, Gu C, Chen D, Yu B, He J. Oxidative stress-induced diseases and tea polyphenols. Oncotarget 2017; 8(46): 81649-61. [CrossRef]
58. 58. Scholz S, Williamson G. Interactions affecting the bioavailability of dietary polyphenols in vivo. International journal for vitamin and nutrition research Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung Journal International de Vitaminologie et de Nutrition 2007; 77(3): 224-35. [CrossRef]
59. 59. de Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA, Cassidy A, et al. The pharmacokinetics of anthocyanins and their metabolites in humans. British Journal of Pharmacology 2014; 171(13): 326882. [CrossRef]
60. 60. Ruggiero P, Tombola F, Rossi G, Pancotto L, Lauretti L, Del Giudice G, et al. Polyphenols reduce gastritis induced by Helicobacter pylori infection or VacA toxin administration in mice. Antimicrobial Agents and Chemotherapy 2006; 50(7): 2550-2. [CrossRef]
61. 61. Huang S, Zhao L, Kim K, Lee DS, Hwang DH. Inhibition of Nod2 signaling and target gene expression by curcumin. Molecular Pharmacology 2008; 74(1): 274-81. [CrossRef]
62. 62. Olivera A, Moore TW, Hu F, Brown AP, Sun A, Liotta DC, et al. Inhibition of the NF-kappaB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. International Immunopharmacology 2012; 12(2): 368-77. [CrossRef]
63. 63. Derikx LA, Dieleman LA, Hoentjen F. Probiotics and prebiotics in ulcerative colitis. Best Practice & Research Clinical Gastroenterology 2016; 30(1): 55-71. [CrossRef]
64. 64. Childs CE, Roytio H, Alhoniemi E, Fekete AA, Forssten SD, Hudjec N, et al. Xylo-oligosaccharides alone or in synbiotic combination with Bifidobacterium animalis subsp. lactis induce bifidogenesis and modulate markers of immune function in healthy adults: a double-blind, placebo-controlled, randomised, factorial crossover study. The British Journal of Nutrition 2014; 111(11): 1945-56. [CrossRef]
65. 65. Hartmann R, Meisel H. Food-derived peptides with biological activity: from research to food applications. Current Opinion in Biotechnology 2007; 18(2): 163-9. [CrossRef]
66. 66. Santiago-Lopez L, Hernandez-Mendoza A, Vallejo-Cordoba B, Mata-Haro V, Gonzalez-Cordova AF. Food-derived immunomodulatory peptides. Journal of the Science of Food and Agriculture 2016; 96(11): 3631-41. [CrossRef]
67. 67. Wagar LE, Champagne CP, Buckley ND, Raymond Y, Green-Johnson JM. Immunomodulatory properties of fermented soy and dairy milks prepared with lactic acid bacteria. Journal of Food Science 2009(74): M423-M30. [CrossRef]
68. 68. Meisel H. Biochemical properties of peptides encrypted in bovine milk proteins. Current Medicinal Chemistry 2005; 12(16): 1905-19. [CrossRef]
69. 69. Saint-Sauveur D, Gauthier SF, Boutin Y, A M. Immunomodulating properties of a whey protein isolate, its enzymatic digest and peptide fractions. International Dairy Journal 2008(18): 260-70. [CrossRef]
70. 70. Jang A, Jo C, Kang K-S, ML. Antimicrobial and human cancer cell cytotoxic effect of synthetic angiotensin converting enzyme (ACE) inhibitory peptides. Food Chemistry 2008(107): 327-36. [CrossRef]
71. 71. Jacquot A, Gauthier SF, Drouin R, YB. Proliferative effects of synthetic peptides from beta-lactoglobulin and alpha-lactalbumin on murine splenocytes. International Dairy Journal 2010(20): 51421. [CrossRef]
72. 72. Sutas Y, Soppi E, Korhonen H, Syvaoja EL, Saxelin M, Rokka T, et al. Suppression of lymphocyte proliferation in vitro by bovine caseins hydrolyzed with Lactobacillus casei GG-derived enzymes. The Journal of Allergy and Clinical Immunology 1996; 98(1): 216-24. [CrossRef]
73. 73. Matar C, Valdez JC, Medina M, Rachid M, Perdigon G. Immunomodulating effects of milks fermented by Lactobacillus helveticus and its non-proteolytic variant. The Journal of Dairy Research 2001; 68(4): 601-9. [CrossRef]
74. 74. Jolles P, Fiat A-M, Migliore-Samour D, Douet L, J C. Peptides from milk proteins implicated in antithrombosis and immunomodulation. New Perspectives in Infant Nutrition: Symposium Antwerp. New York, NY: Thieme Medical Publishers; 1992. p. 160-72.
75. 75. Rupa P, L. Schnarr, Mine Y. Effect of heat denaturation of egg white proteins ovalbumin and ovomucoid on CD4+ T cell cytokine production and human mast cell histamine production. Journal of Functional Foods 2015(18): 28-34. [CrossRef]
76. 76. Lee JH, Paik HD. Anticancer and immunomodulatory activity of egg proteins and peptides: a review. Poultry Science 2019; 98(12): 6505-16. [CrossRef]
77. 77. Duarte J, Vinderola G, Ritz B, Perdigon G, Matar C. Immunomodulating capacity of commercial fish protein hydrolysate for diet supplementation. Immunobiology 2006; 211(5): 341-50. [CrossRef]
78. 78. Chalamaiah M, Jyothirmayi T, Diwan PV, Dinesh Kumar B. Antiproliferative, ACE-inhibitory and functional properties of protein hydrolysates from rohu (Labeo rohita) roe (egg) prepared by gastrointestinal proteases. Journal of Food Science and Technology 2015; 52(12): 8300-7. [CrossRef]
79. 79. Achour A, Lachgar A, Astgen A, Chams V, Bizzini B, Tapiero H, et al. Potentialization of IL-2 effects on immune cells by oyster extract (JCOE) in normal and HIV-infected individuals. Biomedicine & pharmacotherapy = Biomedecine & Pharmacotherapie 1997; 51(10): 427-9. [CrossRef]
80. 80. Horiguchi N, Horiguchi H, Suzuki Y. Effect of wheat gluten hydrolysate on the immune system in healthy human subjects. Bioscience, Biotechnology, and Biochemistry 2005; 69(12): 2445-9. [CrossRef]
81. 81. Wischmeyer PE, Riehm J, Singleton KD, Ren H, Musch MW, Kahana M, et al. Glutamine attenuates tumor necrosis factor-alpha release and enhances heat shock protein 72 in human peripheral blood mononuclear cells. Nutrition 2003; 19(1): 1-6. [CrossRef]
82. 82. Boelens PG, Houdijk AP, Fonk JC, Nijveldt RJ, Ferwerda CC, Von Blomberg-Van Der Flier BM, et al. Glutamine-enriched enteral nutrition increases HLA-DR expression on monocytes of trauma patients. The Journal of Nutrition 2002; 132(9): 2580-6. [CrossRef]
83. 83. Tao KM, Li XQ, Yang LQ, Yu WF, Lu ZJ, Sun YM, et al. Glutamine supplementation for critically ill adults. The Cochrane Database of Systematic Reviews 2014(9): CD010050. [CrossRef]
84. 84. Girón-Calle J, Alaiz M, J V. Effect of chickpea protein hydrolysates on cell proliferation and in vitro bioavailability. Food Research International 2010; 43(5). [CrossRef]
85. 85. Kong X, Guo M, Hua Y, Cao D, Zhang C. Enzymatic preparation of immunomodulating hydrolysates from soy proteins. Bioresource Technology 2008; 99(18): 8873-9. [CrossRef]
86. 86. Chang HC, Lewis D, Tung CY, Han L, Henriquez SM, Voiles L, et al. Soypeptide lunasin in cytokine immunotherapy for lymphoma. Cancer Immunology, Immunotherapy : CII 2014; 63(3): 283-95. [CrossRef]
87. 87. Mahima, Ingle AM, Verma AK, Tiwari R, Karthik K, Chakraborty S, et al. Immunomodulators in day to day life: a review. Pakistan Journal of Biological Sciences : PJBS 2013; 16(17): 826-43. [CrossRef]
88. 88. Quadro L, Gamble MV, Vogel S, Lima AA, Piantedosi R, Moore SR, et al. Retinol and retinol-binding protein: gut integrity and circulating immunoglobulins. The Journal of Infectious Diseases 2000; 182(Suppl 1): S97-S102. [CrossRef]
89. 89. Ertesvag A, Engedal N, Naderi S, Blomhoff HK. Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. Journal of Immunology 2002; 169(10): 5555-63. [CrossRef]
90. 90. Huang Z, Liu Y, Qi G, Brand D, Zheng SG. Role of Vitamin A in the Immune System. Journal of Clinical Medicine 2018; 7(9). [CrossRef]
91. 91. Pereira WF, Ribeiro-Gomes FL, Guillermo LV, Vellozo NS, Montalvao F, Dosreis GA, et al. Myeloid-derived suppressor cells help protective immunity to Leishmania major infection despite suppressed T cell responses. Journal of Leukocyte Biology 2011; 90(6): 1191-7. [CrossRef]
92. 92. Shrestha S, Kim SY, Yun YJ, Kim JK, Lee JM, Shin M, et al. Retinoic acid induces hypersegmentation and enhances cytotoxicity of neutrophils against cancer cells. Immunology Letters 2017; 182: 24-9. [CrossRef]
93. 93. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94(4): 1192200. [CrossRef]
94. 94. Sakane T, Takada S, Kotani H, Tsunematsu T. Effects of methyl-B12 on the in vitro immune functions of human T lymphocytes. Journal of Clinical Immunology 1982; 2(2): 101-9. [CrossRef]
95. 95. Ingram CF, Davidoff AN, Marais E, Sherman GG, Mendelow BV. Evaluation of DNA analysis for evidence of apoptosis in megaloblastic anaemia. British Journal of Haematology 1997; 96(3): 576-83. [CrossRef]
96. 96. Tamura J, Kubota K, Murakami H, Sawamura M, Matsushima T, Tamura T, et al. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clinical and Experimental Immunology 1999; 116(1): 28-32. [CrossRef]
97. 97. Hosseinzadeh H, Moallem SA, Moshiri M, Sarnavazi MS, Etemad L. Anti-nociceptive and anti-inflammatory effects of cyanocobalamin (vitamin B12) against acute and chronic pain and inflammation in mice. Arzneimittel-Forschung 2012; 62(7): 324-9. [CrossRef]
98. 98. Guerra BA, Bolin AP, Otton R. Carbonyl stress and a combination of astaxanthin/vitamin C induce biochemical changes in human neutrophils. Toxicology in vitro : an international journal published in association with BIBRA 2012; 26(7): 1181-90. [CrossRef]
99. 99. Hartel C, Strunk T, Bucsky P, Schultz C. Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine 2004; 27(4-5): 101-6. [CrossRef]
100. 100. El-Zayat SR, Sibaii H, FA. M. Micronutrients and many important factors that affect the physiological functions of toll-like receptors. Bulletin of the National Research Centre 2019; 43: 123. [CrossRef]
101. 101. Korf H, Decallonne B, Mathieu C. Vitamin D for infections. Current opinion in Endocrinology, Diabetes, and Obesity 2014; 21(6): 4316. [CrossRef]
102. 102. Myszka M, Klinger M. [The immunomodulatory role of Vitamin D]. Postepy Higieny i Medycyny Doswiadczalnej 2014; 68: 865-78. [CrossRef]
103. 103. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. European Journal of Immunology 2006; 36(2): 361-70. [CrossRef]
104. 104. Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa R, et al. Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology 2011; 54(5): 1570-9. [CrossRef]
105. 105. Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber G, Maixent JM. Vitamin D metabolism, functions and needs: from science to health claims. European Journal of Nutrition 2013; 52(2): 429-41. [CrossRef]
106. 106. Pettengill MA, van Haren SD, Levy O. Soluble mediators regulating immunity in early life. Frontiers in Immunology 2014; 5: 457. [CrossRef]
107. 107. Pekmezci D. Vitamin E and immunity. Vitamins and Hormones 2011; 86: 179-215. [CrossRef]
108. 108. Wu D, Meydani SN. Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention. Journal of Leukocyte Biology 2008; 84(4): 900-14. [CrossRef]
109. 109. Malmberg KJ, Lenkei R, Petersson M, Ohlum T, Ichihara F, Glimelius B, et al. A short-term dietary supplementation of high doses of vitamin E increases T helper 1 cytokine production in patients with advanced colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2002; 8(6): 1772-8.
110. 110. Wessels I, Maywald M, Rink L. Zinc as a Gatekeeper of Immune Function. Nutrients 2017; 9(12). [CrossRef]
111. 111. Hojyo S, Fukada T. Roles of Zinc Signaling in the Immune System. Journal of Immunology Research 2016; 2016: 6762343. [CrossRef]
112. 112. Gammoh NZ, Rink L. Zinc in Infection and Inflammation. Nutrients 2017; 9(6). [CrossRef]
113. 113. Veldhuis NA, Valova VA, Gaeth AP, Palstra N, Hannan KM, Michell BJ, et al. Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATPase. The International Journal of Biochemistry & Cell Biology 2009; 41(12): 240312. [CrossRef]
114. 114. Katona P, Katona-Apte J. The interaction between nutrition and infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008; 46(10): 1582-8. [CrossRef]
115. 115. Albiger B, Sandgren A, Katsuragi H, Meyer-Hoffert U, Beiter K, Wartha F, et al. Myeloid differentiation factor 88-dependent signalling controls bacterial growth during colonization and systemic pneumococcal disease in mice. Cellular Microbiology 2005; 7(11): 160315. [CrossRef]
116. 116. Balounova J, Vavrochova T, Benesova M, Ballek O, Kolar M, Filipp D. Toll-like receptors expressed on embryonic macrophages couple inflammatory signals to iron metabolism during early ontogenesis. European Journal of Immunology 2014; 44(5): 1491-502. [CrossRef]
117. 117. Hoeft K, Bloch DB, Graw JA, Malhotra R, Ichinose F, Bagchi A. Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis. Anesthesiology 2017; 127(1): 121-35. [CrossRef]
118. 118. Wang C, Zhang R, Wei X, Lv M, Jiang Z. Metalloimmunology: The metal ion-controlled immunity. Advances in Immunology 2020; 145: 187-241. [CrossRef]
119. 119. Guven E, Duus K, Laursen I, Hojrup P, Houen G. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway. PloS One 2013; 8(9): e74445. [CrossRef]
120. 120. Wenzel BE, Chow A, Baur R, Schleusener H, Wall JR. Natural killer cell activity in patients with Graves' disease and Hashimoto's thyroiditis. Thyroid 1998; 8(11): 1019-22. [CrossRef]
121. 121. Venturi S, Donati FM, Venturi A, Venturi M, Grossi L, Guidi A. Role of iodine in evolution and carcinogenesis of thyroid, breast and stomach. Adv Clin Path 2000; 4(1): 11-7.
122. 122. Zhao SJ, Sun FJ, Tian EJ, Chen ZP. [The effects of iodine/selenium on the function of antigen presentation of peritoneal macrophages in rats]. Zhonghua Yu Fang Yi Xue Za Zhi 2008; 42(7): 485-8.
123. 123. Sampson HA. Food allergy. Part 1: immunopathogenesis and clinical disorders. The Journal of Allergy and Clinical Immunology 1999; 103(5 Pt 1): 717-28. [CrossRef]
124. 124. Ashkenazy Y, Moshonov S, Fischer G, Feigel D, Caspi A, Kusniec F, et al. Magnesium-deficient diet aggravates anaphylactic shock and promotes cardiac myolysis in guinea pigs. Magnes Trace El 1990; 9(5): 283-8.
125. 125. Puertollano MA, Puertollano E, de Cienfuegos GA, de Pablo MA. Dietary antioxidants: immunity and host defense. Curr Top Med Chem 2011; 11(14): 1752-66. [CrossRef]
126. 126. Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2012; 16(7): 705-43. [CrossRef]
127. 127. Ren F, Chen X, Hesketh J, Gan F, Huang K. Selenium promotes T-cell response to TCR-stimulation and ConA, but not PHA in primary porcine splenocytes. PloS One 2012; 7(4): e35375. [CrossRef]
128. 128. Buyukozturk S, Gelincik A, Ozseker F, Genc S, Savran FO, Kiran B, et al. Nigella sativa (black seed) oil does not affect the T-helper 1 and T-helper 2 type cytokine production from splenic mononuclear cells in allergen sensitized mice. J Ethnopharmacol 2005; 100(3): 295-8. [CrossRef]
129. 129. Jacob A, Wu R, Zhou M, Wang P. Mechanism of the Anti-inflammatory Effect of Curcumin: PPAR-gamma Activation. PPAR Research 2007; 2007: 89369. [CrossRef]
130. 130. Al-Suhaimi EA, Al-Riziza NA, Al-Essa RA. Physiological and therapeutical roles of ginger and turmeric on endocrine functions. The American journal of Chinese Medicine 2011; 39(2): 215-31. [CrossRef]
131. 131. Arreola R, Quintero-Fabian S, Lopez-Roa RI, Flores-Gutierrez EO, Reyes-Grajeda JP, Carrera-Quintanar L, et al. Immunomodulation and anti-inflammatory effects of garlic compounds. Journal of Immunology Research 2015; 2015: 401630. [CrossRef]
132. 132. Onbaşlı D, Çelik GY, Kahraman S, MK. Apiterapi ve İnsan Sağlığı Üzerine Etkileri Erciyes Üniversitesi Veterinerlik Fakültesi Dergisi 2019; 16(1): 49-56. [CrossRef]
133. 133. Elberry AA, Mufti S, Al-Maghrabi J, Abdel Sattar E, Ghareib SA, Mosli HA, et al. Immunomodulatory effect of red onion (Allium cepa Linn) scale extract on experimentally induced atypical prostatic hyperplasia in Wistar rats. Mediators of Inflammation 2014; 2014: 640746. [CrossRef]
134. 134. Im K, Lee JY, Byeon H, Hwang KW, Kang W, Whang WK, et al. In Vitro antioxidative and anti-inflammatory activities of the ethanol extract of eggplant (Solanum melongena) stalks in macrophage RAW 264.7 cells. Food and Agricultural Immunology 2016; 27(6): 758-71. [CrossRef]
135. 135. Cherng JM, Chiang W, LC. C. Immunomodulatory activities of common vegetables and spices of Umbelliferae and its related coumarins and flavonoids. Food Chemistry 2008; 106(3): 944-50. [CrossRef]
136. 136. Skinner MA, Bentley-Hewitt K, Rosendale D, Naoko S, Pernthaner A. Effects of kiwifruit on innate and adaptive immunity and symptoms of upper respiratory tract infections. Advances in Food and Nutrition Research 2013; 68: 301-20. [CrossRef]
137. 137. Iwasawa H, Morita E, Ueda H, MY. Influence of kiwi fruit on immunity and its anti-oxidant effects in mice. Food Science and Technology Research 2010(16): 135-42. [CrossRef]
138. 138. Tezuka H, Imai S. Immunomodulatory Effects of Soybeans and Processed Soy Food Compounds. Recent Patents on Food, Nutrition & Agriculture 2015; 7(2): 92-9. [CrossRef]
139. 139. Yamazaki K, Murray JA, Kita H. Innate immunomodulatory effects of cereal grains through induction of IL-10. The Journal of Allergy and Clinical Immunology 2008; 121(1): 172-8 e3. [CrossRef]
140. 140. Ye M, Liu JK, Lu ZX, Zhao Y, Liu SF, Li LL, et al. Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, inhibits tumor cell growth by inducing apoptosis in vitro. FEBS Letters 2005; 579(16): 3437-43. [CrossRef]
141. 141. Rahayu RP, Prasetyo RA, Purwanto DA, Kresnoadi U, Iskandar RPD, Rubianto M. The immunomodulatory effect of green tea (Camellia sinensis) leaves extract on immunocompromised Wistar rats infected by Candida albicans. Veterinary World 2018; 11(6): 765-70. [CrossRef]
142. 142. Surjushe A, Vasani R, Saple DG. Aloe vera: a short review. Indian Journal of Dermatology 2008; 53(4): 163-6. [CrossRef]
143. 143. Kim HS, Kacew S, Lee BM. In vitro chemopreventive effects of plant polysaccharides (Aloe barbadensis miller, Lentinus edodes, Ganoderma lucidum and Coriolus versicolor). Carcinogenesis 1999; 20(8): 1637-40. [CrossRef]