A Hassle A Day May Keep The Doctor Away:Stress & The Augmentation of Immune Function

Firdaus Dhabhar

Stanford University

HEALTH

endocrine systemnervous system

immune system

stress

pessimism

anxiety

depression

fatigue personality

Psycho-Neuro-Immunology (PNI)

Stress can be defined as a cluster of events that beginswith a stimulus (stressor), precipitates a reaction in thebrain (stress perception), and subsequently results inthe activation of fight / flight systems in the body (stressresponse).

(Dhabhar & McEwen, Brain Behavior & Immunity, 1997, 11: 286.)

Acute stress = minutes to hoursChronic stress = weeks to months to years &

dysregulation of diurnal rhythm

STRESS

• Most biomedical research is focused on pathogens& disease

• While my laboratory also studies disease, our mainemphasis is on understanding the biologicalmechanisms that maintain or restore HEALTH

• The following presentation will suggest that theacute/short-term, fight-or-flight stress response isnature’s fundamental survival system and one of itsprincipal health-promoting mechanisms

Our Initial Hypothesis: Just as the stress responseprepares the cardiovascular, musculoskeletal, andneuroendocrine systems for fight or flight, undersome conditions, it may also prepare the immunesystem for challenges (wounding or infection) thatmay be imposed by a stressor (predator)(Brain, Behavior, & Immunity, 1994)

Short-term stressors will ENHANCE immunefunction within compartments (e.g. skin) that arelikely to be compromised by the actions of a“stressor” (e.g. predator, surgery)…

Q: What happens to immune cell numbers inthe blood during acute / short-term stress?

Collaboration with: Ickovics, Jokl, Rosenberger, Fulkerson, & colleagues, Yale; & Epel (UCSF)

Surgery stress induced changes in blood leukocyte numbers

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

base 0h 2h 4h

Patient A

Time (before, during, & after surgery)1wk

surgeryCTL

(CD

3CD

8) n

umbe

r (10

00/µ

l)

Similar redistribution patterns seen duringstress in mouse, rat, horse, monkey, andother species…

spleen

marginated pool

bone marrow?

BLOODBARRACKS BOULEVARDS

duration of stress

Integrated Model

BATTLESTATIONS

skin lymph nodes

functionalconsequences?

genes & proteins?

hormones?clinical

ramifications?

early

# LY, MO

late

Dhabhar et al, 1995, Journal of Immunology, 154, 5511

Efficient wound healing requires rapid leukocyteinfiltration into a wound site

Q: Can acute stress experienced at the time ofwounding/surgery accelerate the rate of leukocyteentry at the site of wounding/surgery?

Does acute stress ↑ leukocyte traffic to a site of surgery?

Absorbable Surgical Sponge• hemostatic plug• repair wound cavities, ear drums, tooth extraction sockets• “filler” in some surgical procedures

0

5

10

15

20

25

30

35

40

6h 24h 48h 72h

NS

leuk

ocyt

e nu

mbe

r (1

000/

µl)

implant sponge sc

extract sponge@ 6, 24, 48, 72 h

enumerate & IDleukocytes,

cytokines, etc

NS STRor

Viswanathan & Dhabhar, PNAS, Vol 102

stress

Finding: Acute stress increases immune celltraffic into a site of immune activation

Q: Does this increase the magnitude/robustness ofthe ensuing immune response?

A: Yes (J Immunol, 1996; PNAS 1999, 2000)

Implication: Harness acute stress physiology toenhance vaccine efficacy…

Hypothesis: Mice that are acutely stressed beforeprimary immunization will show higher numbersof memory cells in sentinel lymph nodes

Dhabhar & Viswanathan, Amer J. Physiology

No Stress Acute Stress

immunize with modelvaccine antigen (KLH)

1 week

quantify memory T cells in sentinel lymph nodes

Time Line Of Experiment

Dhabhar & Viswanathan, Amer J. Physiology

Acute stress ↑↑ memory T cells in sentinel lymph nodes

Dhabhar & Viswanathan, Amer J. Physiology

Implication: ↑↑ memory for the immunizing antigen

central memoryeffector

Hypothesis: Mice that were acutely stressed atthe time of primary immunization will show anenhanced immune response upon antigen re-exposure months later

Dhabhar & Viswanathan, Amer J. Physiology

9 months!!!

re-expose to antigen at novel site (mimics infection)

Time Line Of Follow-up Experiment

No Stress Acute Stress

immunize with modelvaccine antigen (KLH)

quantify immune response

Acute stress at primary immunization enhances asecondary immune response 9 months later

0

10

20

30

40

50

DTH Response

no stress @ immunizationstress @ immunization

*

Dhabhar & Viswanathan, Amer J. Physiology

Implication:↑↑ effector function↑↑ protection

CMI response

incr

ease

in p

inna

thic

knes

s (%

bas

elin

e)

Acute stress before primary immunization ↑↑ Type 1 cytokine levels atsite of secondary immune response 9 months later

Dhabhar & Viswanathan, Amer J. Physiology

Implication: ↑↑ effector function, ↑↑ protection

Natural stressors (aggression, predation, accidents)invariably activate the immune system

Immune activation (wounding, surgery, vaccination)invariably induces a stress response

The acute stress response may act as a natural,endogenous adjuvant that boosts immune responsesthat are coupled with stress

In many clinical situations (vaccination, surgery,infection, cancer), we may need to turn this responseON to enhance protective immunity

In patients with proinflammatory or autoimmunedisease, we need to turn this response OFF to inhibitexacerbation of pathological immune reactions

Some individuals mount robust, adaptive, acutestress responses, but others may not

Q: What are the hormones that mediate an acutestress induced enhancement of skin immune function?

A: Epinephrine (1-24 h) & corticosterone (24 h…)

Dhabhar & McEwen, 1999, PNAS, 96: 1059

Clinical Relevance of Acute Stress Induced Leukocyte Redistribution

Study: Acute Stress & Recovery From Knee Surgery

Aim 1: Identify blood leukocyte redistribution profiles ofpatients undergoing knee surgery (meniscal repair, ACLreconstruction)

Aim 2: Examine whether profiles predict recovery

Hypothesis: “Adaptive” leukocyte redistribution duringsurgery will predict/mediate enhanced recovery

Collaboration with: Ickovics, Jokl, Rosenberger, Fulkerson, & colleagues, Yale; & Epel (UCSF)

BARRACKS BOULEVARDS

spleen

marginated pool

bone marrow?

BLOOD

time during surgery

A priori definition of “adaptive” leukocyteredistribution during stress of surgery:

early

LY, MO

late

lymph nodes

BATTLESTATIONS

skin

site ofsurgery

Some patients show “adaptive” leukocyte redistributionduring surgery stress, others do not…

lym

phoc

yte

num

ber (

1000

/µl)

Can thesedifferencespredictrecovery?

Collaboration with: Ickovics, Jokl, Rosenberger, Fulkerson, & colleagues, Yale; & Epel (UCSF)

High redistributors show enhanced recovery

patients who showed adaptive redistribution

MEN WOMEN

Collaboration with: Ickovics, Jokl, Rosenberger, Fulkerson, & colleagues, Yale; & Epel (UCSF)

Goals:

• Identify low versus high responders beforepatient goes in for surgery

• Identify factors mediating gender differences

• Design behavioral and pharmacologicalinterventions to put low responders into highresponder state during surgery

BENEFICIAL:wound healing

vaccinationinfectioncancer?

HARMFUL:psoriasis, dermatitis,

asthma, IBD, inflammatory,autoimmune,

cardiovascular disease,

STRESS PHYSIOLOGY ↑ IMMUNE FUNCTION

elucidate mechanisms……translate to clinic...

What about stress & immunosuppression?

STRESSThe Stress-Immune Spectrum

Dhabhar & McEwen, Brain, Behavior, & Immunity, 1997

ACUTE / EUSTRESS• brief (0.5 - 2.5 h)• normal circadian rhythm• adaptive response• ↑ leukocyte mobilization• ↑ immune responses

J Immunology, 95, 96a,bPNAS, 00, 02, 05Am J Psychiatry, 03Am J Physiology, 05; Int Imm 05

CHRONIC / DISTRESS• long (wks, mns, yrs)• dysregulated rhythm• maladaptive response• ↓ leuko base & mobilizn• ↓ protective immune resp• ↑ dysregulationBBI, 97, 02; Neuroendocrinol, 97PNAS, 99, 04JNCI, 05; J Proteome Res, 07

RESILIENCE??mechanisms??

Overall Conclusion:

Acute stress directs immune cell traffic topotential “battle stations” in the body,enhances immune cell function, and augmentsprimary (innate), and secondary (adaptive)immune responses

We need to study, and clinically harness, the acutestress survival response, that evolution has alreadyfinely chiseled and sculpted, just as much as westudy its maladaptive ramification (chronic stress)that evolution yet has to catch up with…

(Dhabhar, Abelson Seminar, AAAS, 2008)

My LabJean Tillie*Vivian ChouCaroline HuRebecca VuJillian CampbellStephanie HwangPhillip ChuiMariya KalashnikovaRachel KnoppTuong Phan

Kavitha Viswanathan*Alison Saul*Kanika GhaiChristine DaughertyCynthia WalterCarrie SymmondsAllison LitzingerHeather Petrasek

UCSFElissa Epel *Elizabeth BlackburnOwen WolkowitzJue Lin, et al.

YaleJeannette Ickovics*Patty Rosenberger*Peter Jokl, et al. *

CornellMarty AltemusRichard Granstein

Univ. LouisvilleSandie Sephton

NIH: AI48995, AR46299, CA107498

Dana Foundation, MacArthur Foundation

StanfordDavid Spiegel & labDavid LyonsJamie ZeitzerJames Gross

Rockefeller Bruce McEwen*

Ohio StateTatiana OberyszynWilliam MalarkeyStanley LemeshowRandy NelsonNing Quan

Hoffmann La-RocheHorst Blüethmann