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Title:   Author  item
                                            Loving, Crystalitem
                                            Kehrli Jr, Marcusitem
                                            Brockmeier, Susanitem
                                            Bayles, Darrellitem
                                            Michael, Daviditem
                                            Schlink, Sarahitem
                                            Lager, Kelly
  Submitted to: Biologicals
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/2/2013
                                    Publication  Date: 7/24/2013
                                    Citation: Loving, C.L., Kehrli, M.E., Brockmeier, S.L., Bayles, D.O., Michael, D.D., Schlink, S.N., Lager, K.M. 2013. Porcine granulocyte-colony stimulating factor (G-CSF) delivered via replication-defective adenovirus induces a sustained increase in circulating peripheral blood neutrophils. Biologicals. Available: http://dx.doi.org/10.1016/j.biologicals.2013.07.001.Interpretive Summary: Antibiotics are commonly used in food-production animal medicine to treat and prevent disease. However, acceptable alternatives to antibiotic use need to be explored to decrease the use of antibiotics in food animals. Methods to boost the animal’s own immune system to prevent disease are one possible alternative. Cytokines, which are chemical messengers of the immune system, can be used to increase the ability of the animal to fight infection through a variety of mechanisms. One particular cytokine called G-CSF, can increase the number of disease fighting cells (neutrophils) in the bloodstream and has been used in people when undergoing certain cancer treatments. It has also been used to prevent mammary gland infection in dairy cows. The same response occurs in pigs given G-CSF, but the increase in blood neutrophils was only for about a week. Using another method to deliver G-CSF, we were able to increase the number of neutrophils in the blood for more than three weeks. This longer duration is preferable to provide a longer duration of protection by the animal’s own immune system. This provides the potential for disease control mediated by the animal itself instead of by antibiotics, which is of benefit to swine producers as antibiotic usage is increasingly discouraged.
                                Technical Abstract: The use of immunomodulators is a promising area for biotherapeutic, prophylactic, and metaphylactic use to prevent and combat infectious disease, particularly during periods of peak disease incidence. Cytokines, including granulocyte colony-stimulating factor (G-CSF), are one class of compounds that have been investigated for potential value as biotherapeutic proteins. G-CSF enhances the production and release of neutrophils from the bone marrow and is already licensed for use in humans for the treatment of neutropenia. A limitation of cytokines as immunomodulators is their short half-life which may limit their usefulness as a one-time injectable in production-animal medicine. In order to circumvent the need for production of recombinant protein we elected to use a replication-defective adenovirus (Ad5) encoding porcine G-CSF for in vivo administration. Here we report that administration of human recombinant G-CSF (pegfilgrastim) induces a transient neutrophilia in pigs; however, delivery of porcine G-CSF encoded in the Ad5 vector significantly increased the neutrophilia pharmacodynamics effect. Neutrophil counts following pegfilgrastim treatment remained elevated compared to pretreatment values for 4-7 days in a dose-dependent manner. By comparison, pigs given one intramuscular injection of the Ad5-G-CSF also had a neutrophilia (>2-fold increase) by 1 day post injection; however, the neutrophil counts peaked between days 3 to 11 post-treatment with a range of 6- to 8-fold increases in peak neutrophil counts. Neutrophil counts remained elevated compared to pretreatment values for up to 21 days. Neutrophils isolated from Ad5-G-CSF treated pigs were fully functional based on their ability to release neutrophil extracellular traps and oxidative metabolism after in vitro stimulation. Since acceptable alternatives to the use of antibiotics in food-animal production need to be explored, we provide evidence that G-CSF is a likely candidate. G-CSF has the potential to eliminate or reduce the need for antibiotic usage for the prevention or treatment of infectious disease, especially during typical times of stress and peak pathogen shedding and exposure.


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