Imrestor Technical Detail Aides ALo 1-12

Research Brief
Imrestor™ (pegbovigrastim) effects on neutrophils
in periparturient dairy cows
Background
dairy industry. High incidence of disease during this time period is at least partially due to
decreased function of both neutrophils and lymphocytes. The functions of both cell types
decrease gradually—beginning about 3 weeks before calving, reaching a low point at
calving—and then gradually recover 3 or 4 weeks after calving.1,2 All cows undergo
periparturient immune suppression to a certain degree, which has been associated with
a higher incidence of mastitis, retained placenta, and metritis.3,4
and numbers is critical to reducing the economic impact of immune suppression and
improving animal well-being.
To assess the effects of pegbovigrastim on neutrophil function and numbers, studies were
conducted at the Iowa State University (ISU) College of Veterinary Medicine. The hypothesis
tested was that injection of pegbovigrastim at approximately 7 days before parturition and
on the day of calving would help reverse the periparturient suppression of neutrophil
function in dairy cows.
Material and Methods
Animals and treatment groups: 23 Holstein cows in their second lactation kept at the ISU
Dairy Farm were selected and alternately assigned into 2 groups. Control cows received
saline injection (n = 10), and treatment cows received pegbovigrastim (n = 13). Blood
samples were collected from May 16 to August 17, 2012.
Treatment and sampling: 15 mg of pegbovigrastim formulation or saline was administered
subcutaneously twice, approximately 1 week prior to calving and on the day of calving.
calcium (Ca), and complete blood count were evaluated 3 times a week beginning 2 weeks
before expected parturition and continuing until 2 weeks after parturition. Neutrophil function
was evaluated for neutrophil oxidative metabolism, exocytosis of myeloperoxidase (MPO),
Staphylococcus aureus phagocytosis, and formation of neutrophil extracellular traps (NETs).
Trial Objectives
To assess the effects of pegbovigrastim
on neutrophil function and numbers in
periparturient dairy cows
Pegbovigrastim Mode of Action
Pegbovigrastim is the PEGylated form of
the cytokine bovine granulocyte colony
stimulating factor. Cytokines are protein
messenger molecules that regulate the
intensity and duration of the innate and
acquired immune responses. Cytokine
bovine granulocyte colony stimulating
factor is a cytokine that regulates the
growth and differentiation of the precursor
cell in the bone marrow committed to
forming neutrophils. The PEGylation
increases the half-life of the protein
messenger molecule from hours to days.
Results Summary
Pegbovigrastim-supplemented cows
demonstrated increased numbers and
function of neutrophils. Functional
increases were observed in the biological
marker (MPO), indicating the ability
to destroy bacteria was increased.
There was no demonstrated loss in
the neutrophils’ ability to phagocytize
bacteria. Important components of
immune function were restored without
impacting energy balance biomarkers.
Discussion
Pegbovigrastim supplementation aids
cows by increasing one of the most
powerful microbicidal activities of the
neutrophil, as well as the number of
neutrophils around the time of calving,
when immune function is suppressed, with
no negative effects on energy balance.5
Results
around the time of calving (Figure 1)
(Figure 2). This increase
in total neutrophils was mostly due to mature neutrophils. Both groups showed higher NEFA after calving. The pattern of change is similar,
but pegbovigrastim cows had lower NEFA on day 10 and 13 (Figure 3). Plasma BHBA increased after calving in both groups, but it decreased
quickly in pegbovigrastim cows, whereas control cows showed a higher level for a longer time. Overall, BHBA levels did not show any
differences between groups (Figure 4). There was no difference in oxidative metabolism or Staphylococcus aureus phagocytosis. NET
formation tended to be lower in pegbovigrastim cows especially around the time of calving.
Figure 1
Figure 2
NEUTROPHIL FUNCTION
NEUTROPHIL NUMBERS
1
The effect of Imrestor on percentage of myeloperoxidase (MPO)
released from neutrophils
1
The effect of Imrestor on total neutrophil number
70
Imrestor
Control (saline)
% MPO released
60
55
50
45
40
Imrestor
Control (saline)
20
Neutrophil count (X 1000)
65
15
10
5
35
-5
0
5
10
-5
15
0
5
10
Days relative to parturition
Days relative to parturition
*P < 0.05
†P < 0.01
‡P < 0.005
All P values in comparison between groups at same sampling point.
*P < 0.05
†P < 0.01
‡P < 0.005
All P values in comparison between groups at same sampling point.
Figure 3
15
Figure 4
NEFA 5
BHBA 5
The effect of Imrestor on plasma nonesteried fatty acid (NEFA) levels
The effect of Imrestor on plasma betahydroxybutyric acid
(BHBA) levels
0.9
1.6
Imrestor
Control (saline)
1.2
BHBA (mM)
Plasma NEFA (mEq)
1.4
Imrestor
Control (saline)
0.8
1.0
0.8
0.7
0.6
0.5
0.6
0.4
0.4
0.2
-5
0
5
10
15
Days relative to parturition
0
5
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REFERENCES: 1. Kimura K, et al. Effects of the presence of the mammary gland on expression of neutrophil adhesion molecules and myeloperoxidase activity. J Dairy Sci. 1999;82:2385-2392.
2. Nonnecke BJ, et al. Effects of the mammary gland on functional capacities of blood mononuclear leukocyte populations from periparturient cows. J Dairy Sci. 2003;6:2359-2368. 3. Kimura K,
et al. Decreased neutrophil function as a cause of retained placenta in dairy cattle. J Dairy Sci. 2002;85:544-550. 4. Hammon DS, et al. Neutrophil function and energy status in Holstein cows
with uterine health disorders. Vet Immunol Immunopathol. 2006;113:21-29. 5. Elanco Animal Health, Data on File, Study #2012-01-01-01-047.
Imrestor ™ is a trademark for Elanco’s brand of pegbovigrastim. Registered pursuant to the ACVM Act 1997, No. A11027
© 2014 Elanco Animal Health. IR Neut2 May 14
10
Days relative to parturition
15

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