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T-cell Immunoregulation and the
Response to Immunotherapy
Harold S. Nelson. MD
Professor of Medicine
National Jewish Health and
University of Colorado School of Medicine
Denver, Colorado, USA
Role of the T-cell in Asthma
L Cosmi, et al. Allergy 2011;
Immunologic Response:
Summary
The immunologic response to allergen
immunotherapy involves:
1) A shift from Th2 to Th2 cytokine profile
2) The generation of regulatory T cells
secreting IL-10 and TGF-,
Increases in IL-12 mRNA+
Accompany Inhibition of Allergen
Late Skin Test Responses after
Successful Grass Pollen
Immunotherapy
QA Hamid,et al.J Allergy Clin Immunol 1997;99:254-60
10 subjects who had received 4 years of
grass pollen immunotherapy and 10
allergic controls had skin biopsies 24
hours afterintracutaneous injection of
grass pollen extract.
Reduction in Rhinitis Symptoms and
Medication from Immunotherapy
60
40
20
0
80 Symptoms
70
60
50
40
30
20
10
0
150 Drugs
IT Treatment
Placebo
Median Score
80
Grass Pollen Count
Median Score
Counts/m
100
120
IT Treatment
Placebo
90
60
30
0
24 8 22 5
19 3 17 31 14 28 11
25
April
May
June
July August September
(Varney et al. BMJ. 1991;302:265-269.)
Early
Response
Late
Response
p<0.001
50
p<0.0001
140
Skin response (mm)
120
40
100
30
80
60
20
40
10
20
0
0
Control
Hamid JACI 1997;99:254
Immunotherapy
Control
Immunotherapy
Late Skin Response to
Allergen Following Successful
Pollen Immunotherapy
• At site of late cutaneous response:
- Increased cells with mRNA for IL-12
- Principal source of IL-12 tissue
macrophages
• IL-12+ cells correlated positively with
IFN-+ cells and inversely with IL-4+
cells.
QA Hamid, et al JACI 1997
IL-12
Immunotherapy
Control
ns
p=0.002
Cells/high power field
12
8
4
0
p=0.02
Diluent
Hamid JACI 1997;99:254
Antigen
Diluent
Antigen
14
10
IL-4 mRNA+ cells/field
IFN- mRNA+ cells/field
r = 0.64
p < 0.05
r = -0.67
p < 0.05
12
8
10
6
4
2
0
8
6
4
2
0
0
2
4
6
8
10
IL-12 mRNA+ cells/field
Hamid et al, JACI 1997;99:254
12
0
2
4
6
8
10
IL-12 mRNA+ cells/field
12
IL-10 and TGF- Cooperate in the
Regulatory T Cell Response to
Mucosal Allergens in Normal Immunity
and Specific Immunotherapy
M Jutel, et al. Eur J Immunol 2003;33:1205-14
Examined the normal immunoregulatory
mechanism and the immunologic basis
of specific immunotherapy (SIT) to Der
p 1 and Bet v 1
Regulatory T Cell Response
• In normal immunity to HDM and birch
pollen an allergen-specific peripheral T
cell suppression to Der p 1 and Bet v 1
was observed.
• This was characterized by:
- suppressed proliferative T cell, (Th1)
INF-, and (Th2) IL-5, IL-13 responses
- increased IL-10 and TGF- secretion
by allergen-specific T cells.
Regulatory T Cell Response
• Specific immunotherapy induced an
allergen-specific suppressive activity in
CD4+ CD25+ T cells of allergic individuals.
• Suppression was induced by IL-10 and TGF
• These results demonstrate a deviation
towards a regulatory/suppressor T cell
response during SIT similar to the “healthy”
immune response to mucosal allergens.
Normal Immune Response:
Downregulation of Th1 and Th2
Response by IL-10 and TGF-
[3H] TdR (cpm × 10-9)
Der p 1
Unstimulated
20
*
*
*
10
0
*P < .01.
TdR = thymidine.
Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
*
*
*
Bet v 1
Unstimulated
[3H] TdR [Stim. Index]
IL-10 and TGF- Mediated T-Cell
Suppression During HDM-SIT
+anti-IL-10R
+sTGF-bR
Der p 1
+ Control Ab
18
*
*
12
*
8
*
4
*
0
0
7
*
28
Days
*P < .01 versus day 0.
Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
70
Cytokine Production During
HDM-SIT
IL-10
TGF-b
IFN-g
IL-13
IL-5
Cytokine (ng/mL)
4
*
3
2
1
0
0
7
Days
HDM-SIT = house dust mite-specific
immunotherapy.
*P < .001.
Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
28
70
Antibody Response in Healthy Controls and
Changes in Allergic Individuals During HDM-SIT
U/mL
40
60
IgE
40
20
20
0
60
0
60
40
*
U/mL
U/mL
U/mL
60
IgG1
20
0
40
*
IgA
†
IgG4
20
Healthy
0
70
0
Days (SIT)
HDM-SIT = house dust mite-specific immunotherapy.
*P < .01. †P < .001.
Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
Healthy
0
70
Days (SIT)
Gerald Gleich: Effect of 6 Years of
Immunotherapy on IgE and IgG
Antibodies to Ragweed (1982)
 Antibody levels were monitored 2 years before and
4 years following institution of ragweed
immunotherapy.
 Before immunotherapy patients ragweed-specific
IgE rose with each pollen season and declined off
season.
 With immunotherapy there was an abrupt rise in
specific IgE, but the seasonal increases were
blocked, and IgE levels gradually declined.
 Specific IgG rose with immunotherapy and
remained high.
G Gleich et al. J Allergy Clin Immunol 1982;70:261-71
Effect of Ragweed Immunotherapy
on Specific IgE Levels
1000
IgE Antibody to SRW, ng/ml
500
100
50
Immunotherapy
10
J73O
J74O
M J76O
J77O
J78O
J79O
G Gleich et al. J Allergy Clin Immunol 1982;70:261-71
Immunologic Response:
Summary
The immunologic response to allergen
immunotherapy involves:
1) A shift from Th2 to Th1cytokine profile
2) The generation of regulatory T cells
secreting IL-10 and TGF-,
What is the relationship between the two
immune responses?
Sublingual Immunotherapy Induces
IL-10-producing T Regulatory Cells,
Allergen-specific T-cell Tolerance,
and Immune Deviation
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
• 9 subjects underwent SLIT with a 4-week
build up to a daily dose of birch pollen
extract containing 4.5 mcg Bet v 1.
• Assessments were made prior to
treatment, on reaching maintenance after
4 weeks and after one year.
Immune Response to Sublingual
Immunotherapy: 4 Weeks
After 4 weeks of SLIT:
• Circulating CD4+CD25+ cells were increased
(from 15% to 35%)
• PBMC proliferation in response to Bet v 1, Mal d
1 (apple) and tetanus toxoid were decreased
from baseline.
• Before treatment depletion of CD4+CD25+ cells
decreased proliferation. After 4 weeks depletion
resulted in increased proliferation with all 3
antigens.
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Immune Response to Sublingual
Immunotherapy: 4 Weeks
• mRNA expression in antigen stimulated Tcells was decreased for IL-4 and IFN- and
increased for IL-10.
• Neutralization of IL-10 in cultures
significantly increased PBMC proliferation.
• FoxP3 expression in CD3+ T-cells was
increased.
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Immune Response to Sublingual
Immunotherapy: 52 Weeks
After 52 weeks of SLIT:
• Circulating CD4+CD25+ cells were
decreased (from 35% to 21%)
• PBMC proliferation in response to Bet v 1,
was decreased from baseline, but
response to Mal d 1 and TT returned to
baseline.
• CD4+CD25+ depletion decreased
proliferation to antigen.
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Immune Response to Sublingual
Immunotherapy: 52Weeks
• mRNA expression in antigen stimulated Tcells was decreased for IL-4 and IL-10
compared to baseline, while mRNA for
IFN- was increased.
• FoxP3 expression in CD3+ T-cells was
normal.
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Proliferation (dpm x 103)
Allergen stimulated proliferation of PBMCs (solid
bars) and CD25+ depleted PBMCs (open bars)
Bet v 1
40
*
30
*
*
20
10
0
0
4
Time (weeks)
52
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Allergen stimulated proliferation of PBMCs (solid
bars) and CD25+ depleted PBMCs (open bars)
Prolifcration (SI)
80
Tetanus toxoid
Mal d 1
*
60
*
80
60
*
40
40
20
20
0
0
0
4
Time (weeks)
52
*
0
4
52
Time (weeks)
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Changes from Baseline in mRNA
Expression in Unstimulated PBMCs
Open bars 4 weeks: Filled bars 52 weeks
Fold increase of mRNA
4.0
*
3.5
P < .05
3.0
2.5
2.0
1.5
1.0
0.5
0
IL-4
IFN-
IL-10
TGF-
FoxP3
B Bohle, et al. JACI 2007;120:707-13
SLIT Induces IL-10-producing T
Regulatory Cells, Allergen-specific
T-cell Tolerance, and Immune
Deviation: Conclusions
• The early immune response to SLIT is IL10 secreting regulatory T cells with nonallergen specific T cell suppression.
• By one year, regulatory T cells have
declined, replaced by allergen-specific T
cell suppression and enhanced IFN-
production.
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13