1. The far-reaching impacts of immunity and inflammation during the transition to lactation
Barry Bradford
June 2015

3. Large dairies

5. Early lactation – a unique challenge
Overview
Early lactation – a unique challenge
Infection and metabolic disease links
Long-lasting effects of early lactation problems
Current research – novel solutions
Transition disorders
What is inflammation per se?
When does it occur, esp. in cows?
Is inflammation involved in metabolic Dos?
Oxidative stress
Overall model
Antioxidants, metabolic modifiers, NSAIDs

6. The transition period ~ 40% metabolic ~ 60% infectious First lactation
Third lactation
~ 40% metabolic
~ 60% infectious
Ingvartsen, 2006

7. Transition cows have decreased immune function
Lymphocyte function
Neutrophil function
Neutrophil function (iodination; ) and lymphocyte function (blastogenesis; ) are impaired during the weeks immediately before and after parturition.
Goff and Horst,1997

8. Transition immune cells
Enhanced inflammatory response
Impaired chemotaxis
Decreased phagocytosis
Reduced killing ability
All talk!
Sordillo et al., 1995; Contreras et al., 2012; Kehrli et al., 1989; Nonnecke et al., 2003

9. Immunosuppression coincides with greater risk of infection
Østergaard et al, 2005

10. Immune function predicts infection risk
Infections 0%
16%
100%***
n = 7
Monocyte proliferation response to endotoxin
n = 19
n = 5
Catalani et al, 2013

11. Infections increase ketosis risk
Gröhn et al., 1989

12. Ketosis increases infection risk
Duffield et al., 2009; Doohoo and Martin, 1984

13. Long-term consequences of transition problems
Risk of leaving herd
3 X X X
Seegers 2003; Deluyker 1991; Wittrock 2011; Ospina 2010; Seifi 2011

14. Suppressed immune function contributes to infectious disorders
Infections promote metabolic disorders
Metabolic problems increase infection risk
Does inflammation provide a mechanistic link?

15. Inflammation Acute inflammation
Associated with immune activation or tissue damage
Swelling
Pain
Fever

16. Inflammation Chronic inflammation No outward signs
Slightly elevated inflammatory mediators
Alterations in signaling

17. Inflammation is associated with transition disorders
Bertoni et al., 2008

18. Subacute, liver inflammation is common in postpartum cows
Explain acute phase protein, especially haptoglobin
Day relative to calving
Sabedra, 2012 (thesis)

19. What causes transition inflammation?

20. Systemic inflammation

21. Systemic inflammation

22. Systemic inflammation

23. Systemic inflammation

24. Systemic inflammation

25. Systemic inflammation

26. Inflammation promotes ketosis
Subclinical
Ketosis 9%
27%
P = 0.02, TNFα vs. control
(18% decrease)
Yuan et al., 2013

27. …and decreases milk yield
P = 0.03, TNFα vs. control
(15% decrease)
C vs. T2
L vs. H3
0.03
0.76
Yuan et al., 2013

28. A vicious cycle
Metabolic disorders
promote
Infections

29. Should we block inflammation?

30. Anti-inflammatories in early lactation (not currently approved)
+9%
P < 0.05
3 doses
+7%
P < 0.05
1 dose

31. Culling Rate
C vs. M: P = 0.04

32. The Big Picture
There is much crosstalk between metabolic and immune systems
Inflammatory signals, driven by a wide variety of stimuli, are a key link
Not always a negative
The physiological milieu in the first week can have long-term impacts

33. A new possibility RNA interference:
A mechanism whereby small RNA molecules can promote degradation of a specific transcript to knock down expression of a certain gene.

34. The discovery of RNAi
Craig Mello and Andrew Fire, 2006 Nobel Prize

35. The central dogma

36. How does it work?

37. Protection and delivery

38. Silencing (knockdown)

39. The central dogma

40. The problem?
Calving
Poor appetite
Ketosis
Displaced abomasum
Cull

41. How this could work Calving Increasing appetite Decreased NEFA Milk!
Small
Interfering
RNA
Increasing appetite
Decreased NEFA
Milk!

42. Why is this exciting
One dose should be effective for at least a week

43. Off target effects can be avoided
Why is this exciting
Off target effects can be avoided
Liver only
Single gene target
No genetic engineering involved
RNA is a very safe “drug residue”

44. Hopefully….

45. CSIRO Australian Animal Health Laboratory

46. Thank you!
Questions/comments: Barry Bradford Kansas State