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P.J. HansenDept. of Animal Sciences, University of Florida

Importance of Immune Function for Optimal Reproduction of Dairy Cows

Laval

Daugh

ter Pr

egnanc

y Rate

2426283032343638

Year2004 2006 2008 2010 2012 2014 2016

Milk y

ield (lb

)

2600026500270002750028000

RECENT CHANGES IN FERTILITY AND MILK YIELD IN US HOLSTEINS

• Genetic selection• Timed AI

The Next Major Increase in Fertility Will Occur by Enhancing Dairy Cow Health

Sick cow Healthy cowInfertile cow Fertile cow

MAIN POINT 1 HEALTHY COWS ARE FERTILE COWS

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Sick cow Healthy cow

Immune-compromised cow Immunocompetent cow

Infertile cow Fertile cow

MAIN POINT 2 – COWS ARE OFTEN SICK BECAUSE THEY HAVEPOOR IMMUNE FUNCTION

Sick cow Healthy cow

Immune-compromised cow Immunocompetent cow

Infertile cow Fertile cow

MAIN POINT 3: IMPROVING IMMUNE FUNCTION SHOULD INCREASE FERTILITY

improved immune function

Sick cow Healthy cowInfertile cow Fertile cow

MAIN POINT 1 HEALTHY COWS ARE FERTILE COWS

ImagesDenise RichLavalwww.heidihanskoch.comresumption of cyclicity

Establishment of pregnancy

Survival to term

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Category Cyclic, % Adjusted OR (95% CI) PHealthy 84.1 1.00 ---1 case of disease 80.0 0.97 (0.72 – 1.30) 0.83> 1 case of disease 70.7 0.60 (0.44 – 0.82) 0.001

Type of health problemCalving problem 70.5 0.52 (0.40 – 0.68) < 0.001Metritis 63.8 0.37 (0.28 – 0.50) < 0.001Clinical endometritis 68.9 0.51 (0.37 – 0.71) < 0.001Fever postpartum 80.0 0.55 (0.40 – 0.74) < 0.001Mastitis 81.5 0.87 (0.55 – 1.36) 0.53Clinical ketosis 77.7 0.71 (0.47 – 1.07 0.10Lameness 85.0 0.82 (0.52 – 1.30) 0.40Pneumonia 88.9 1.78 (0.22 – 14.34) 0.59Digestive problem 60.7 0.54 (0.25 – 1.17) 0.12

5,719 postpartum dairy cows evaluated daily for health disorders in seven dairy farms in the US.

Health Problems in the First 60 DIM and Resumption of Estrous Cyclicity in Dairy Cows

Santos et al. (2010) Reprod. Dom. Rum. VII:387-404

Category Pregnant, % Adjusted OR (95% CI) P

Healthy 51.4 1.001 case of disease 43.3 0.79 (0.69 – 0.91) 0.001> 1 case of disease 34.7 0.57 (0.48 – 0.69) < 0.001

Type of health problemCalving problem 40.3 0.75 (0.63 – 0.88) < 0.001Metritis 37.8 0.66 (0.56 – 0.78) < 0.001Clinical endometritis 38.7 0.62 (0.52 – 0.74) < 0.001Fever postpartum 39.8 0.60 (0.48 – 0.65) < 0.001Mastitis 39.4 0.84 (0.64 – 1.10) 0.20Clinical ketosis 28.8 0.50 (0.36 – 0.68) < 0.001Lameness 33.3 0.57 (0.41 – 0.78) < 0.001Pneumonia 32.4 0.63 (0.32 – 1.27) 0.20Digestive problem 36.7 0.78 (0.46 – 1.34) 0.38

5,719 postpartum dairy cows evaluated daily for health disorders in seven dairy farms in the US

Health Problems in the First 60 DIM and Pregnancy in Dairy Cows

Category Loss, % Adjusted OR (95% CI) PHealthy 8.9 1.00 ---1 case of disease 13.9 1.73 (1.25 – 2.39) < 0.001> 1 case of disease 15.8 2.08 (1.36 – 3.17) < 0.001

Type of health problemCalving problem 15.9 1.67 (1.16 – 2.40) < 0.01Metritis 11.3 1.01 (0.71 – 1.60) 0.76Clinical endometritis 15.1 1.55 (1.04 – 2.32) 0.03Fever postpartum 18.0 2.00 (1.24 – 3.14) < 0.01Mastitis 19.8 2.62 (1.48 – 4.64) < 0.001Clinical ketosis 14.6 1.64 (0.75 – 3.59) 0.22Lameness 26.4 2.67 (1.38 – 5.12) < 0.01Pneumonia 16.7 1.87 (0.40 – 8.69) 0.42Digestive problem 15.8 1.81 (0.52 – 6.32) 0.35

Health Problems and Pregnancy Loss in the First 60 d of Gestation in Dairy Cows

5,719 postpartum dairy cows evaluated daily for health disorders in seven dairy farms in the US.Santos et al. (2010) Reprod. Dom. Rum. VII:387-404

Health status Value Adjusted odds ratio

P% cyclic at day 49 postpartumNo disease 91.1 1.00 --1 clinical disease 88.3 0.74 0.22> 1 clinical disease 77.8 0.34 <0.01% pregnant at first AINo disease 66.9 1.00 --1 clinical disease 56.5 0.64 <0.01> 1 clinical disease 40.8 0.34 <0.01% pregnancy loss, day 30 and 65No disease 9.2 1.00 --1 clinical disease 12.3 1.38 0.34> 1 clinical disease 26.7 3.58 <0.01

Association of disease with postpartum reproduction in 957 cows on two dairies in Florida (Ribeiro et al. J Dairy Sci. 96:5682, 2013)

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Ribeiro et al., J Dairy Sci 99:2201 (2016)

It is Not Only Uterine Disease That Causes InfertilityResults from 5085 cows bred by AI or ET

ImagesDenise RichLavalwww.heidihanskoch.comresumption of cyclicity

Establishment of pregnancy

Survival to term

Body temperature

Cytokines and otherimmune and inflammatoryproducts

Uterine infectious disease

Bacterial toxins

Energy balance

IMMUNE & INFLAMMATORY

SYSTEMSINFECTIOUS AGENTS

energy consumption feed intake metabolism

Hypothalamic-pituitary axis

Ovary

Bacterial toxins

Cytokines & inflammatory products

TISSUE DAMAGE

Sick cow Healthy cow

Immune-compromised cow Immunocompetent cow

Infertile cow Fertile cow

MAIN POINT 2 – COWS ARE OFTEN SICK BECAUSE THEY HAVEPOOR IMMUNE FUNCTION

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Bullvine

INSULT TO HEALTH(injury, inflammation, bacteria, virus)

Resolves insult Does not resolve

--------Immune system------

Sheldon et al., Biol. Reprod. 81:1025 (2009)

Incidence of Uterine Infections and Disease During the Postpartum Period in Cattle

Cows prone to metritis and endometritis experience poor neutrophil function before calving

Hammon et al., Vet ImmunolImmunopathol 113:21 (2006)

endometritis

No uterine disease

metritis

Cytoch

rome c

reduct

ionMy

elopero

xidase a

ctivity

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CON DES implant Days PP

C% (n)

M% (n)

P% (n)

C% (n)

M% (n)

P% (n)

16 33 (3) 33 (3) 33 (3) 16 70 (7) 0 30 (3)23 56 (5) 11 (1) 30 (3) 23 80 (8) 20 (2) 030 60 (6) 10 (1) 20 (2) 30 70 (7) 30 (3) 037 50 (5) 40 (4) 0 37 90 (9) 10 (1) 0Overall 50 (19) 24 (9) 21 (8) 78 (31) 15 (6) 7.5 (3)

Frequencies of cervical discharge scores during the postpartum period for CON and DESL implant groups (Silvestre and Thatcher)

OR=3.2Imp1, CI=0.80 – 12.82; P=0.09Implant added 1-4 days postpartum C = Clean; M = mucupurulent; P = purulent

n=699

Immunize type 1 and 2 test Ag wk -8,-3, 0 rel to calving

Measure Ab titerswk -8,-3,0 and +2 rel to calving

Antibody-mediated immune response(AMIR)Cell-mediated immune response(CMIR)

Skin hypersensitivity test to type 1 Agwk +1 rel to calving DiseaseincidenceIR=Average of AMIR + CMIRCalculated EBV for immune responses using pedigree information

Incidence of Disease (%) as affected byEBV for Overall Immune Response (IR)Disease Low EBV for

IR (n=153)Average EBV for IR (n=407)

High EBV for IR (n=139)

Mastitis 25.7ab 29.0a 19.4bMetritis 7.2 4.7 4.3Ketosis 5.9 5.7 5.8Displaced abomasum

5.8a 1.7b 3.6ab

Retained fetal membranes

13.1a 5.9b 5.0b

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Thompson-Crispi et al., Clin. Vaccine Immunol 20:106 (2013)

Incidence Rate of Clinical Mastitis for Cows Classified by EBV for Antibody-Mediated Immune Responses (cases/100 cow-years)

Administration of Pegylated G-CSF Increases Neutrophil Number and Reduces Incidence of Clinical Mastitis

Canning et al., J Dairy Sci 100:6504 (2017)

~7 d before and 24 h after calving

Bred heifers: 4 g/45 kg BW as daily top-dress 60 d before calving (n=20) or grain mix control (n=20)

A proprietary product that modulates the immune response to a pathogen challenge, especially during periods of immune suppression or dysfunction.

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Effects of OmniGen-AF on Incidence of Adverse Health Effects

Nace et al., Vet Immunol Immunopathol 161:240 (2014)

Effects of OmniGen-AF on Mammary Infection, SCC and Milk Yield

Sick cow Healthy cow

Immune-compromised cow Immunocompetent cow

Infertile cow Fertile cow

MAIN POINT 2 – COWS ARE OFTEN SICK BECAUSE THEY HAVEPOOR IMMUNE FUNCTION

• Cows that get metritis have lower PMN function• Progesterone is immunosuppressive; concentrations are related to incidence of uterine disease• Cows with genetic merit for low immune response are less likely to develop disease• Boosting immune function decreases incidence of specific disease

Sick cow Healthy cow

Immune-compromised cow Immunocompetent cow

Infertile cow Fertile cow

MAIN POINT 3: IMPROVING IMMUNE FUNCTION SHOULD INCREASE FERTILITY

improved immune function

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Neutrophils (green) phagocytosing E. coli (red) injecteds.c. into zebrafish larvaeColucci-Guyon et al., J Cell Sci 2011; 124:3053

Strategies to Enhance Immune Function in Postpartum Dairy Cows• Regulation of calcium metabolism to reduce hypocalcemia• Improving energy balance• Administer nonsteroidal anti-inflammatory molecules• Feed nutritional supplements that enhance immune function (OmniGen-AF)• Administer biologicals that regulate immune function (Imrestor)• Select for cows with superior genetics for immune function

Administration of G-CSF Increases Neutrophil Numberand Reduces Incidence of Clinical Mastitis

Canning et al., J Dairy Sci 100:6504 (2017)

~7 d before and 24 h after calving

Canning et al., J Dairy Sci 100:6504 (2017)

Saline G-CSFMetritis 3.0% (9/300) 4.8% (14/290)Failure to be detected in estrus, day 80

9.4% (27/286) 4.6% (13/285)*Failure to conceive at first service

61.8% (160/259) 57.4% (156/272)

Incidence of Reproductive Problems as Affected by Pegylated G-CSF

10,238 primiparous and multiparous Holsteins from 17 dairies in MexicoTreatment with Imrestor® (i.e, pegbovigrastrim; i.e., pegylated G-CSF) at~ day 7 before calving and at 24 h after calving

Untreated G-CSFIncidence of clinical mastitis (%) 4.9 3.7**Incidence of retained placenta (%) 5.8 5.6Incidence of metritis (%) 8.4 9.8*

G-CSF treated cows had 5.8% greater chance of being inseminated by day 100 PP(Cox-Hazard ratio=1.058; P<0.05)

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ImagesDenise RichLavalwww.heidihanskoch.comresumption of cyclicity

Establishment of pregnancy

Survival to term

Manage transition nutrition toavoid excessive NEB, hypocalcemia

Consider treatmentsthat boost immunity

Possibly prevent negative effectsof overactivation of immune function – chronic inflammationSelect for genes controlling immune function

Pete Hansen hansen@animal.ufl.edu