Transcript The immunomodulating properties of estrogens

DEPARTMENT OF IMMUNOLOGY
Chair of Histology and Immunology
Medical University of Gdańsk
Research group
Head: Jolanta Myśliwska, MD, PhD
Professor of immunology
Joanna Więckiewicz, M. Sc.
Dominik Rachoń, MD
Łukasz Hak, M. Sc.
Monika Mlotkowska, M.Sc.
Katarzyna Zorena, PhD
Hanna Suchanek, MD, PhD
RESEARCH PROBLEMS
• AGE-RELATED CHANGES OF IMMUNE
RESPONSE
• HORMONAL MODULATION OF IMMUNE
RESPONSE
• IMMUNOLOGICAL ASPECTS OF
CARDIOVASCULAR DISEASE
PREVIOUS AND CURRENT
AGE-RELATED CHANGES OF
IMMUNE RESPONSE
ROLE OF NATURAL KILLER CELLS IN AGEING
• We found that successful healthy ageing is associated with a
shift towards high cytotoxic activity of Natural Killer cells.
The high values of NK-associated parameters may be
preserved until very old age.
• Healthy elderly people have an increased number of the
regulatory NK cells with intra-cellular IFN .
• This status correlates with anti-viral immune response in the
elderly what we observed on the natural model of vaccination
against influenza.
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Myśliwska J, et al. (1997) Gerontology, 43, 158-167.
Myśliwska J, et al. (2000) Acta Biochem. Pol., 47, 1-11.
Kmieć Z, et al. (2001) Gerontology, 47, 282-288.
Brydak LB, et al. (2003) J. Clin. Immunol., 23:214-222.
Myśliwska J, et al. (2003) Clin Exp. Immunol., accepted
PRO-INFLAMMATORY
STATE IN THE ELDERLY
• We found that ageing process is accompanied by an enhanced expression
of pro-inflammatory cytokines.
• Low immune response to vaccination in the elderly, who stayed apparently
healthy, is associated with an increased expression of genes of such
inflammatory cytokines as; Interleukin 1, TNF, Interleukin 6, Interleukin
12.
• Enhanced expression of pro-inflammatory cytokines was associated with
carrier status of latent CMV infection in the elderly low responders to
influenza vaccination.
Myśliwska J, et al. (1999) Mech. Ageing Dev. ,107: 1-14.
Myśliwska J, et al. (2000) Eur. Cytokine Net. ,11:397-406.
Trzonkowski P, et al. (2002) Mech. Ageing Dev. ,123, 1283-1293.
Trzonkowski P, et al. (2003) Vaccine , 21:3826-3836.
HORMONAL MODULATION OF IMMUNE
RESPONSE
ESTROGENS DOWN-REGULATE PRO-INFLAMMATORY AND UPREGULATE ANTI-INFLAMMATORY CYTOKINES
Non-stimulated ex vivo monocytes of healthy
postmenopausal women express the TNF gene
883bp
b-actin
800bp
692bp
501bp
TNF
420bp
404bp
1
2
3
4
5
6
(-)
pUC
• This may be the effect of estrogen deprivation
(+)
Non-stimulated ex vivo monocytes of healthy
postmenopausal women express the IL-6 gene
883bp
b-actin
800bp
692bp
IL6
628bp
501bp
1
2
3
4
5
6
(-)
(+)
pUC
• This may be the effect of an exaggerated TNF expression
which in turn stimulates IL-6 gene expression
Rachoń D, Myśliwska J, et al. (2002) J Endocrinol.,172, 387-395.
Non-stimulated PBMC of postmenopausal women
produce more bioactive TNF and IL-6 compared to young
controls
In vitro effects of 17b-estradiol on the spontaneous
TNF and IL-6 production by PBMC of postmenopausal
women
In vivo effects of 17b-estradiol treatment on the
spontaneous TNF and IL-6 production by PBMC of
postmenopausal women
Non-stimulated PBMC of postmenopausal women
produce less IL-10 compared to young controls
In vitro effects of 17b-estradiol on the IL-10 gene
expression in the PBMC of postmenopausal women
CURRENT RESEARCH
IMMUNOLOGICAL ASPECTS OF
CARDIOVASCULAR DISEASE
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IL6pg/ml
years
Polymorphism of the human Interleukin 6 (IL6) gene at
position –174G/C in coronary heart disease (CHD)
patients
2
0
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C
G
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Polymorphism of the human atrial natiuretic peptide
(ANP) gene in coronary heart disease (CHD) patients
• Polymorphism is analysed in CHD patients with different
cardiac arrhythmias occurring in (or without) association
with cardiac surgery.
• The A2A2 allele combination carriers constitute 55% of the
whole group of CHD patients and seem to be protective from
atrial fibrillation.
21 bp
67 bp
111 bp
96 bp
117 bp
147 bp
213 bp
190 bp
242 bp
234 bp
INFECTIONS WITH CMV AND CHLAMYDIA
PNEUMONIAE IN CHD PATIENS
185 bp
positive control
sample of mononuclear cells
ROLE OF CD14+CD16+ BLOOD MONOCYTES
IN CORONARY HEART DISEASE
Analysis of function
of CD14+CD16+
monocytes
• detection of monocyte
populations by
cytophotometric technique
• tests revealing presence of
intra-cytoplasmic
cytokines in CD14+CD16+
monocytes
• in vitro cultures analysing
an effect of Lovastatin on
spontaneous and LPSinduced synthesis of intracytpolasmic IL6
% of CD14+CD16+ monocytes
CD14+CD16+ BLOOD monocytes in CORONARY
HEART DISEASE and controls
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
_____*____
Mediana
25%-75%
Min.-Maks.
patients
co ntro ls
LPS-induced IL-6 production
90
80
80
Spontaneous IL-6production
70
70
60
60
50
50
_____*_____
40
40
30
30
20
20
10
10
0
14+16+
Mediana
Min.-Maks.
0
14+16-
14+16+
CD14+ CD16+
90
80
70
60
50
40
30
20
10
0
Mediana
Min.-Maks.
14+16-
___*____
____*____
Mediana
Min.-Maks.
Control
90
Lova
LPS
LPS + Lova
CD14+ CD16-
80
70
60
50
40
30
20
10
Mediana
Min.-Maks.
0
Control
Lova
LPS
LPS + Lova
Human cytokine array system – expression
profile of multiple cytokines
positive
control
positive
control
• In serum of the
patients with
coronary heart
disease, with CCS
3 and 4 grade of
the angina
pectoris, we found
an expression of 18
new cytokines