Recombinant human lactoferrin is a natural immunomodulatory protein that has demonstrated preclinical efficacy in treating asthma.
Nearly one in five American households includes one or more family members who have asthma, according to the American Lung Association, which estimates that medical care and missed time from school and work contributed to United States asthma costs of $11.3 billion in 1998.1
Lactoferrin is found in breast milk and mucosal surfaces, where it functions as a primary component of the first line of host defenses against inflammation and infection. Other applications are also possible and are being studied. Lactoferrin research is also covering therapeutic applications in wound healing and oncology. Recombinant human lactoferrin is a natural immunomodulatory protein that has demonstrated preclinical efficacy in treating asthma. It has been shown to shift the cytokine profile from splenic T-helper cell type 2 (Th2) to Th1, favoring the development of cell-mediated immunity and protecting against allergic diseases.
Lactoferrin is a potent, time-dependent inhibitor of human tryptase,2 a neutral serine protease in mast-cell granules. It constitutes up to 20% of total cellular protein. The active enzyme is released with other mediators (such as heparin, histamine, and chymase) upon mast-cell degranulation. The presence of tryptase in biological matrices is an indicator of mast-cell degranulation in anaphylaxis and allergic reaction. Lactoferrin released from the activated neutrophils could inhibit mast-cell tryptase activity by associating with enzyme-bound heparin.
A role for lactoferrin as an integral part of the innate immune system is supported by the widespread localization of lactoferrin in mucosal secretions and by the potent antimicrobial properties of this protein. It is likely that the iron-binding bactericidal activity and receptor-binding properties contribute to the many protective roles of lactoferrin against infection and inflammation.3
In preclinical studies, lactoferrin has demonstrated efficacy in sheep and primate models of asthma. Such preclinical study results have predicted human clinical efficacy for a number of asthma drugs in the past. Both oral and inhaled lactoferrin, when administered to sheep, reduced the peak late-phase lung inflammatory response by 75% to 90%. Lactoferrin also completely eliminated airway hypersensitivity. In longer-term administration (lasting 14 to 28 days), lactoferrin inhibited the peak early-phase response by up to 77%. It also reduced lung accumulation of inflammatory cells that have been linked to asthma following allergen challenge.4
Lactoferrin is being studied in two ongoing phase-2 human clinical trials in asthma: an allergen-challenge trial in subjects with mild asthma taking place in the United Kingdom, and a placebo-controlled US trial in steroid-naive patients with mild-to-moderate asthma.
New Findings Presented at 2004 ATS
William Abraham, PhD, director of research at Mount Sinai Medical Center, Miami Beach, Fla, has been studying lactoferrins effect on asthma for the past 6 years. His latest work on the subject will be presented at the American Thoracic Societys 100th Annual International Conference, to be held in Orlando, Fla, in May 2004. He says, From a preclinical standpoint, lactoferrin has potential. It may work as an immunomodulator. The latest work indicates that an oral formulation of lactoferrin has protective effects against the responses to airway allergen challenge in a large-animal model of asthma.
Abraham has been testing lactoferrin in the allergic-sheep model of asthma. The sheep develop early-phase and late-phase bronchoconstriction and an associated increase in bronchial responsiveness following antigen (Ascaris suum) challenge. Sheep treated with lactoferrin (10 mg in 3 mL of phosphate-buffered saline, delivered as an aerosol) half an hour before and 4 hours and 24 hours following antigen challenge had substantial reductions in both late-phase bronchoconstriction (4 hours to 8 hours following antigen challenge) and airway hyperresponsiveness to carbachol (24 hours following antigen challenge). The magnitude of the early phase (0 to 4 hours) was not significantly reduced by lactoferrin treatment; however, the duration of early-phase bronchoconstriction appeared to be shortened as a result of treatment.2
Laura Gater is a contributing writer for RT.
1. American Lung Association. Available at: http://www.lungusa.org/
site/pp.asp? c=dvLUK9O0E&b=22893. Accessed April 13, 2004.
2. Elrod KC, Moore WR, Abraham WM, Tanaka RD. Lactoferrin, a potent tryptase inhibitor, abolishes late-phase airway responses in allergic sheep. Am J Respir Crit Care Med. 1997;156:375-381.
3. Ward PP, Uribe-Luna S, Connelly OM. Lactoferrin and host defense. Biochem Cell Biol. 2002;80:95-102.
4. Agennix. Respiratory disease. Available at: http://www.agennix.com/contentpages/ respiratory.htm. Accessed April 11, 2004.