• Lactoferrin and FIV


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  • Bovine lactoferrin has many potential virtues as a supplement for FIV+ cats. An iron-binding protein of the transferrin family produced by humans and other mammals, lactoferrin is an important part of the immune system found in milk, saliva, tears, and intestinal and respiratory secretions. It has a particular affinity for lymphatic and mucosal tissue, where it plays an important role in protection from a number of bacterial, viral, parasitic, and cancerous diseases. Lactoferrin supplements are derived from cows, and, strangely, bovine lactoferrin, which shares about 86% amino acid sequencing with its native human counterpart, has, in some cases, shown more protective action for people [1]. Lactoferrin occurs in vivo in four forms, including an iron-saturated holo-form and an iron-depleted apo-form, both of which are available as supplements. Various claims are made for each, and individual forms of lactoferrin (including the lactoferrin-derived peptide lactoferricin) have shown strikingly different levels of activity in different experimental situations.

  • Several studies have shown that lactoferrin inhibits all three enzymes needed by HIV to reproduce [2][3] and lowers viral counts in HIV-infected children [4], so there is a good chance that it has some inhibiting action against FIV. Recent studies have also shown that it blocks binding of HIV to a type of immune cell (dendritic cells) that spreads infection to the CD4+ T cells whose loss and dysfunction is directly related to immunedeficiency [1]. This same cell type has been been implicated in FIV infection of feline CD4+ T cells [5]. Studies have shown that counts of several important immune cells are higher in HIV-infected people when supplemented with bovine lactoferrin [6]. In a 2002 study with mice, lactoferrin reconstituted immune responsiveness (delayed hypersensitivity and lymphoproliferative) following administration of cyclophosphomide, a powerful immunosuppressive agent used in cancer therapy. "LF also caused substantial restoration of the percentage of the lymphocyte population in circulating blood" and "strongly elevated the pool of CD3+ T cells in normal and CP-immunocompromised mice and CD4+ T cell content. . . .we showed for the first time that lactoferrin, given orally to CP-immunosuppressed mice, could reconstitute a T-cell mediated immune response by renewal of the T cell pool" [17].

  • Lactoferrin works, in part, by stimulating the epithelial and lymphoid tissue in the intestines to release anti-inflammatory signalling proteins ("cytokines") that travel throughout the body. The anti-inflammatory action is related to lactoferrin's ability to inhibit a number of signaling proteins that normally direct the immune system to react in an inflammatory way. Because retroviral infection causes chronic hyperactivation of an inflammatory immune response, this ability is of particular importance. A recent in vitro study using blood samples from both asymptomatic and symptomatic FIV+ cats found that "bLF [bovine lactoferrin] has a protective effect on activated cells by inhibition of apoptosis [programmed cell death] and modulation of proliferation and cell cycle progression" The study reveals that lactoferrin is immunomodulatory rather than immunosuppressive because it resets the level of signaling protein (“cytokine”) expression to or near that characteristic of uninfected cats, without affecting the ability of cells to normally express them (as, for instance, steroids would). And the immunomodulating action was stronger in symptomatic (ARC) than in asymptomatic (AC) cats. "We observed that addition of bLF inhibited . . . increase of IFN-γ and IL-2 expression in PBMC [peripheal blood mononuclear cells] from the ARC group. . . . Bovine LF did not affect the spontaneous expression of IL-1β, TNF-α and IL-12 p40. . . ” [13]. Because Interleukens-2 and -12 are necessary for normal T-cell recruitment and maturation, it is important that they not be suppressed below normal levels.

  • What kinds of specific problems might lactoferrin be of benefit for? In several studies, direct application of lactoferrin to oral tissue of cats lessened the effects of stomatitis [7][14], although it can also be added to food. Additionally, native lactoferrin is produced by probiotics, and it is reasonable to suppose that supplementation has some beneficial activity for inflammatory conditions of the gut [8]. It gets better. Bovine Lactoferrin has also been shown effective against bacterial infections and parasites such as toxoplasmosis , in part through its ability to deprive pathogens of the iron they need in order to replicate [11] and in part through its ability to bind lipopolysaccharides (LPS) in the cell membranes of gram-negative bacteria [16]. It is also active against a number of viruses. The antiviral function of lactoferrin, originally attributed to its iron deprivation capability, may be due to a specific binding to heparin sulfate, a necessary constituent of cell-membrane receptors used by some enveloped viruses [15]. “The greater inhibitory activity of iron-saturated forms may be due to an increased affinity for viral cell receptors as result of the conformational changes induced after iron-binding” [18]. In discrete studies, lactoferrin has been shown to inhibit replication of both feline herpes virus [9] and calici virus[10]; in a small in vivo study, its sister transferrin, ovotransferrin, which has a biochemical action very similar to lactoferrin's, has shown an ability to both prevent and cure feline upper respiratory infections in FIV+ cats [14]. Finally, lactoferrin has shown an ability to inhibit metastisis of a variety of forms of cancer [12a] and to potentiate other cancer treatments by enhancement of T and NK cell activity [12b].
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  • References

  • 1) Fedde Groot,Teunis B. H. Geijtenbeek, Rogier W. Sanders, Christopher E. Baldwin, Marta Sanchez-Hernandez, René Floris, Yvette van Kooyk, Esther C. de Jong, and Ben Berkhout1. Lactoferrin Prevents Dendritic Cell-Mediated Human Immunodeficiency Virus Type 1 Transmission by Blocking the DC-SIGN-gp120 Interaction. J Virol. 2005 March; 79(5): 3009–3015.
  • http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=15709021

  • 2) Ng TB, Lam TL, Au TK, Ye XY, Wan CC. Inhibition of human immunodeficiency virus type 1 reverse transcriptase, protease and integrase by bovine milk proteins. Life Sci. 2001 Sep 28;69(19):2217-23.
  • http://www.ncbi.nlm.nih.gov/pubmed/11669464

  • 3) Wang H, Ye X, Ng TB. First demonstration of an inhibitory activity of milk proteins against human immunodeficiency virus-1 reverse transcriptase and the effect of succinylation. Life Sci. 2000 Oct 20;67(22):2745-52.
  • http://www.ncbi.nlm.nih.gov/pubmed/11105990

  • 4) Zuccotti GV, Salvini F, Riva E, Agostoni C. Oral lactoferrin in HIV-1 vertically infected children: an observational follow-up of plasma viral load and immune parameters. J Int Med Res. 2006 Jan-Feb;34(1):88-94.
  • http://www.ncbi.nlm.nih.gov/pubmed/16604828

  • 5) Aymeric de Parseval, Stephen V. Su, John H. Elder, and Benhur Lee. Specific Interaction of Feline Immunodeficiency Virus Surface Glycoprotein with Human DC-SIGN. J Virol. 2004 March; 78(5): 2597–2600.
  • http://www.pubmedcentral.gov/articlerender.fcgi?artid=369267

  • 6) Laura Burleigh, Pierre-Yves Lozach, Cécile Schiffer, Isabelle Staropoli, Valérie Pezo, Françoise Porrot, Bruno Canque, Jean-Louis Virelizier, Fernando Arenzana-Seisdedos, and Ali Amara1. Infection of Dendritic Cells (DCs), Not DC-SIGN-Mediated Internalization of Human Immunodeficiency Virus, Is Required for Long-Term Transfer of Virus to T Cells. J Virol. 2006 March; 80(6): 2949–2957.

  • 7) Sato R, Inanami O, Tanaka Y, Takase M, Naito Y. Oral administration of bovine lactoferrin for treatment of intractable stomatitis in feline immunodeficiency virus (FIV)-positive and FIV-negative cats. Am J Vet Res. 1996 Oct;57(10):1443-6.
  • http://www.ncbi.nlm.nih.gov/pubmed/8896681

  • 8) Kruzel ML, Harari Y, Chen CY, Castro GA. The gut. A key metabolic organ protected by lactoferrin during experimental systemic inflammation in mice. Adv Exp Med Biol. 1998;443:167-73.
  • http://www.ncbi.nlm.nih.gov/pubmed/9781356

  • 9) Ammendolia MG, Marchetti M, Superti F. Bovine lactoferrin prevents the entry and intercellular spread of herpes simplex virus type 1 in Green Monkey Kidney cells. Antiviral Res. 2007 Dec;76(3):252-62.
  • http://www.ncbi.nlm.nih.gov/pubmed/17881064

  • 10) Addie DD, Radford A, Yam PS, Taylor DJ. Cessation of feline calicivirus shedding coincident with resolution of chronic gingivostomatitis in a cat. J Small Anim Pract. 2003 Apr;44(4):172-6.
  • http://www.ncbi.nlm.nih.gov/pubmed/12703869

  • 11) Yoshitaka OMATA, Maki SATAKE1, Ryuichiro MAEDA, Atsushi SAITO1, Keiichi SHIMAZAKI4, Yuji UZUKA2, Shigeyuki TANABE, Takao SARASHINA, Takeshi MIKAMI and Koji YAMAUCHI. Reduction of the Infectivity of Toxoplasma gondii and Eimeria stiedai Sporozoites by Treatment with Bovine Lactoferricin. Journal of Veterinary Medical Science, Vol. 63 (2001) , No. 2 pp.187-190.
  • http://www.jstage.jst.go.jp/article/jvms/63/2/63_187/_article/-char/en

  • 12a) Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin and Lactoferricin inhibit tumor metastasis in mice. Adv Exp Med Biol. 1998;443:285-91.
  • http://www.ncbi.nlm.nih.gov/pubmed/9781371

  • 12b) Varadhachary A, Wolf JS, Petrak K, O'Malley BW Jr, Spadaro M, Curcio C, Forni G, Pericle F. Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy. Int J Cancer. 2004 Sep 1;111(3):398-403.
  • http://www.ncbi.nlm.nih.gov/pubmed/15221967

  • 13) Kobayashi, S., R. Sato, et al. (2008). "Effect of bovine lactoferrin on functions of activated feline peripheral blood mononuclear cells during chronic feline immunodeficiency virus infection." J Vet Med Sci 70(5): 429-35.
  • http://www.jstage.jst.go.jp/article/jvms/70/5/429/_pdf

  • 14) Ando, Kunio. Use of proteins belonging to the transferrin/lactoferrin family for potentiating the immune system.
  • http://www.freepatentsonline.com/EP0559425.html

  • 15) Baker EN, Baker HM, and Kidd RD. Lactoferrin and transferrin: Functional variations on a common structural framework. Published on the NRC Research Press on 21 December 2001.
  • http://pubs.nrc-cnrc.gc.ca/rp/rppdf/o01-153.pdf

  • 16) Farnaud S, Spiller C, Moriarty LC, Patel A, Gant V, Odell EW, Evans RW. Interactions of lactoferricin-derived peptides with LPS and antimicrobial activity. FEMS Microbiol Lett. 2004 Apr 15;233(2):193-9.
  • http://www.ncbi.nlm.nih.gov/pubmed/15063486

  • 17) Artyma J, Zimeckia M, and Kruzelb KL. Reconstitution of the cellular immune response by lactoferrin in cyclophosphamide-treated mice is correlated with renewal of T cell compartment. Immunobiology. Volume 207, Issue 3, 2003, Pages 197-205.
  • http://www.ingentaconnect.com/content/urban/481/2003/00000207/00000003/art00005

  • 18) Aguila ALO, Brock JH. Lactoferrin: Antimicrobial and Diagnostic Properties. Biotecnologia Aplicada, Vol. 18, No. 2, April 2001, pp. 76-83.
  • https://tspace.library.utoronto.ca/bitstream/1807/22162/3/ba01011.html

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