Highlights from the FLARE fellowship

A search for new markers

of immunological competence

Dietmar Herndler-BrandstetterErwin Schroedinger Fellow

The consequences of an “aged” immune system

� Increased prevalence of infectious diseases(Pneumonia, urinary tract infections, skin and soft tissue infections, Herpes Zoster, tuberculosis)

� Increased morbidity and mortality caused by infectiousdiseases

� Decreased efficacy of vaccinations

� Age-related increase in pro-inflammatory cytokinesmay contribute to the development of chronic diseases(Atheriosclerosis, rheumatoid arthritis, Alzheimer‘sdisease)

Vaccination efficacy in the elderly

Disease Vaccine typeVaccine efficacy in

elderly persons

Recommended booster intervals for persons

≥ 60 years (Austria)

InfluenzaInactivated virus, subunit vaccine, adjuvanted subunit vaccine, virosomal vaccine

< 50% annually

Pneumonia Conjugated and non-conjugated polysaccharide vaccine < 65% 5 years

Herpes Zoster Live-attenuated vaccine < 61% n. d.

Tetanus, Diphtheria Toxoid > 84% 5 years

Poliomyelitis Inactivated virus > 99% 10 years

Age-dependent involution of the thymus gland, leads to a decline in T lymphocytes

THYMUSMORPHOLOGY

Pool of naiveT lymphocytes

Modified from:Sempowski et al., J Immunol, 2006Nikolich-Zugich, Nat Rev Immunol, 2008

Novel biomarkers identify the efficacy of influenza vaccination in elderly people

Youngindividuals

Elderly people(group 1)

Elderly people(group 2)

0

100

200

300

400

500

600

700

Protective antibodyconcentration (≥ 40)

A / Beijing / H1N1A / Sydney / H3N2B / Harbin / 7 / 94

Ant

ibod

y tit

er Influenzavaccine

CD45RA

100 101 102 103 104

FL1-H100 101 102 103 104

CD45 RA FITC100 101 102 103 104

CD

28

5% 24% 3%

CD28– CD8 T lymphocytes

CD25+ CD8 T lymphocytes

The bone marrow promoteslong-term survival of immunological memory

Memory T lymphocytes: killing of infected host cells

Plasma cells: antibody production

Tokoyoda et al., Nat Rev Immunol, 2010

IL-15-producing cells form a survival niche for memory T lymphocytes in the human BM

CD3 IL-15

5 µm 5 µm

CD3IL-15

0

2

4

6

8

10

**

fold

upre

gula

tion

of IL

-15

in B

MM

C

0

5

10

15

% C

D3+

T c

ells

inco

ntac

twith

IL-1

5+ce

lls

Young

2 10

Elderly

(log2)

T cell activation

Inflammation mediated bychemokine and cytokine signaling

B cell activation

Negative regulation of apoptosis

Toll receptor signaling

Cell cycle

UP

-R

EG

ULA

TE

D

DU

RIN

G A

GIN

G

DO

WN

-R

EG

ULA

TE

DD

UR

ING

AG

ING

Protein metabolic process

Nucleic acid metabolic process

Number of genes10010203040

Ras pathway

0 2 4 6 8

IL-6

IL-24

IL-19

IL-32

IL-15

*

*

***

Fold up-regulation during aging

46 y 28 y 80 y 79 y

Human aging is associated with an increasein pro-inflammatory cytokines in the BM

0

10

20

30

% C

D69

-exp

ress

ing

CD

8+T

cel

ls

*

IL-15 IL-15+ IL-6.

-40

-30

-20

-10

0

% d

ecre

ase

of C

D28

MF

I

IL-15 IL-15+ IL-6.

**

The aged BM microenvironment does not affect BM cellularity

You

ngE

lder

ly

CD4 CD8 CD20

You

ngE

lder

lyCD138 CD14 CD11c

You

ngE

lder

ly

The high number of BM-resident polyfunctionalmemory T lymphocytes is maintained during aging

Young Elderly

CD8 T lymphocytes

CD4 T lymphocytes1 2 3

Number of cytokines

CD28 and CD57 can distinguish functional BM-resident memory T cells from senescent T cells

0

20

40

60

0

20

40

60%

CD

69+

cells

*

% C

D28

–ce

lls**

CD4 CD8

ElderlyYoung

CD69

BM PB

CD

28

19 7

42 32

30 1

65 4

0

25

50

75

CD28–CD28+

**

BM PBCD57

CD

28

BM

PB

36 3

52 9

Elderly

CD4 CD8

19 4

12 65 % C

D69

+ce

lls

Proposed model for the “survival niche” of memory T lymphocytes in the human BM

IL-15-producing BM cell

IL-15

BM-residentmemory T cell

CD69

CCR5

IL-2TNF-αIFN-γγγγ

MIP-1β

IL-15Rα

IL-15Rβ

Bcl-xL

cγ

T-bet

↑↑↑↑ T cell function

↑↑↑↑ T cell survivalRegulation of

migratory properties

Summary

Novel biomarkers in the peripheral blood can predict theefficacy of influenza vaccination in elderly people

The bone marrow microenvironment is important formaintaining the number and function ofmemory T lymphocytes in old age

FLARE mobility part (6 months)

MRC Centre for Immune RegulationUniversity of Birmingham, UK

� Close collaboration with clinicians

� Analyze the role of the immune system in elderly people

suffering from osteoarthritis (research still ongoing)

� Goal: to identify new treatment options for osteoarthritis

patients

What‘s next?

Erwin Schrödinger Research Fellowat Yale School of Medicine, USA

� Develop a highly innovative mouse model to study human

immune responses and autoimmune diseases

� To facilitate translation of research results from bench to bedside

Acknowledgements

Institute for Biomedical Aging Research,Austrian Academy of SciencesInnsbruck, AustriaGrubeck-Loebenstein LabKatja LandgrafStefan BrunnerBrigitte JeneweinMichael Keller

Lepperdinger LabRegina BrunauerGerhard T. Laschober

University Hospital Basel, SwitzerlandAlexandar Tzankov

Medical University InnsbruckRobert GassnerFrank KlossWalther ParsonMichael Schirmer

MRC Centre for Immune RegulationUniversity of BirminghamBirmingham, UKLord LabMark PearsonHema Chahal

Royal Orthopaedic HospitalBirmingham, UK

Edward T. DavisMatthew RevellAdam M. Pearson

List of selected publicationsduring my FLARE fellowship periodOriginal articles� Brunner, Herndler-Brandstetter et al. Upregulation of miR-24 is associated with a decreased DNA damage response

in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death. Aging Cell 11: 579-587, 2012

� Herndler-Brandstetter et al. The impact of aging on memory T cell phenotype and function in the human bone marrow. Journal of Leukocyte Biology 91: 197-205, 2012

� Huang, Park, Wang-Zhu, Larange, Arens, Bernardo, Olivares-Villagómez, Mendez-Fernandez, Herndler-Brandstetter et al. Mucosalmemory CD8+ T cells are selected in the periphery by an MHC class I molecule. Nature Immunology 12: 1086-1095, 2011

� Herndler-Brandstetter et al. Human bone marrow hosts polyfunctional memory CD4+ and CD8+ T cells with close contact to IL-15-producing cells. The Journal of Immunology 186: 6965-6971, 2011

� Herndler-Brandstetter et al. Post-thymic regulation of CD5 levels in human memory T cells is inversely associatedwith the strength of responsiveness to interleukin-15. Human Immunology 72: 627-631, 2011

� Mück, Herndler-Brandstetter et al. Two functionally distinct isoforms of TL1A (TNFSF15) generated by differential ectodomainshedding. J Gerontol A Biol Sci Med Sci 65: 1165-1180, 2010

� Hackl, Brunner, Fortschegger, Schreiner, Micutkova, Mück, Laschober, Lepperdinger, Sampson, Berger, Herndler-Brandstetter et al. miR-17, miR-19b miR-20a and miR-106a are down-regulated in human aging. Aging Cell 9: 291-296, 2010

� Weinberger, Welzl, Herndler-Brandstetter et al. CD28-CD8+ T cells do not contain unique clonotypes and are therefore dispensable. Immunology Letters 127: 27-32, 2009

� Lazuardi, Herndler-Brandstetter et al. Microarray analysis reveals similarity between CD8+CD28– T cells from young and elderly persons, but not of CD8+CD28+ T cells. Biogerontology 10: 191-202, 2009

� Herndler-Brandstetter et al. Non-regulatory CD8+CD45RO+CD25+ T lymphocytes may compensate for the loss of antigen-inexperienced CD8+CD45RA+ T cells in old age. Biological Chemistry 389: 561-568, 2008

Review articles & Book chapters� Herndler-Brandstetter et al. The aging of the adaptive immune system. Current Immunology Reviews 7: 94-103, 2011� Brunner, Herndler-Brandstetter et al. Persistent viral infections and immune aging. Ageing Research Reviews 10: 362-369, 2011� Herndler-Brandstetter et al. The Challenge of Inducing Vaccine Protection in the Elderly. In „New Generation Vaccines“ (Levine ed.),

Informa Healthcare, 4th edition, chapter 23, 234-241, 2009� Weinberger, Herndler-Brandstetter et al. Biology of immune responses to vaccines in elderly persons. Clinical

Infectious Diseases 46: 1078-1084, 2008