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T-cell Immunoregulation and the Response to Immunotherapy
Harold S. Nelson. MDProfessor 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
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.
QA Hamid,et al.J Allergy Clin Immunol 1997;99:254-60
100
80
60
40
20
0
Co
un
ts/m
Grass Pollen Count
Med
ian
Sco
re
80706050403020100
SymptomsIT Treatment
Placebo
Med
ian
Sco
re
150
120
90
60
30
0
DrugsIT Treatment
Placebo
24April
8 22May
5 19June
3 17 31July
14 28August
11 25September
Reduction in Rhinitis Symptoms and Medication from Immunotherapy
(Varney et al. BMJ. 1991;302:265-269.)
EarlyResponse
LateResponse
p<0.001 p<0.0001
50
40
30
20
10
0
Ski
n r
esp
on
se (
mm
)
140
120
100
80
60
40
20
0
Control Immunotherapy Control Immunotherapy
Hamid JACI 1997;99:254
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-12Control Immunotherapy
ns
p=0.02
Cel
ls/h
igh
po
wer
fie
ld
Diluent DiluentAntigen Antigen
Hamid JACI 1997;99:254
12
8
4
0
p=0.002
r = 0.64p < 0.05
r = -0.67p < 0.05
IFN
-
mR
NA
+ c
ells
/fie
ld
IL-4
m
RN
A+
cel
ls/f
ield
10
8
6
4
2
0 0
2
4
6
8
10
12
14
0 2 4 6 8 10 12
IL-12 mRNA+ cells/field IL-12 mRNA+ cells/field0 2 4 6 8 10 12
Hamid et al, JACI 1997;99:254
IL-10 and TGF- Cooperate in the Regulatory T Cell Response to
Mucosal Allergens in Normal Immunity and Specific Immunotherapy
Examined the normal immunoregulatory mechanism and the immunologic basis of specific immunotherapy (SIT) to Der p 1 and Bet v 1
M Jutel, et al. Eur J Immunol 2003;33:1205-14
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-
*P < .01. TdR = thymidine. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
20
10
0
Contro
l
Anti-I
L-10
R
sTGFbR
Both
Contro
l
Anti-I
L-10
R
sTGFbR
Both
Der p 1Unstimulated
[3 H] T
dR (
cpm
× 1
0-9)
* ** * * *
Bet v 1Unstimulated
IL-10 and TGF- Mediated T-Cell Suppression During HDM-SIT
*P < .01 versus day 0. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
* *
**
* *
18
12
8
4
0
[3H
] TdR
[Stim
. In
dex]
0 7 28 70Days
+anti-IL-10R+sTGF-bRDer p 1+ Control Ab
Cytokine Production During HDM-SIT
HDM-SIT = house dust mite-specific immunotherapy. *P < .001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
*4
3
2
1
00 7 28 70
Days
IL-10TGF-bIFN-gIL-13IL-5
Cyt
okin
e (
ng/m
L)
Antibody Response in Healthy Controls and Changes in Allergic Individuals During HDM-SIT
HDM-SIT = house dust mite-specific immunotherapy. *P < .01. †P < .001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.
60
40
20
060
40
20
0
U/m
LU
/mL
Healthy 0 70
IgE
IgG1
Days (SIT)
60
40
20
060
40
20
0
†
Healthy 0 70
IgA
IgG4
Days (SIT)
U/m
LU
/mL
*
*
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
J73O J74O J77O J79OM J76O J78O
1000
500
100
50
10
IgE
An
tibo
dy
to S
RW
, n
g/m
l
Effect of Ragweed Immunotherapy on Specific IgE Levels
Immunotherapy
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
• 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.
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
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 T-cells 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 T-cells 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
Time (weeks)
*
**
Bet v 140
20
0 4 52
30
10
Pro
life
rati
on (
dp
m x
103 )
0
Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars)
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Pro
lifc
rati
on (
SI)
Time (weeks)
0 4 52 0 4 52
Time (weeks)
**
**
Mal d 1 Tetanus toxoid
60
80
40
20
0
60
80
40
20
0
Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars)
B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13
Fol
d in
crea
se o
f m
RN
A
IL-4 IFN-
*
1.5
2.0
2.5
3.0
3.5
4.0
1.0
0.5
0
IL-10 TGF- FoxP3
Changes from Baseline in mRNA Expression in Unstimulated PBMCs
Open bars 4 weeks: Filled bars 52 weeks
B Bohle, et al. JACI 2007;120:707-13
P < .05
SLIT Induces IL-10-producing T Regulatory Cells, Allergen-specific
T-cell Tolerance, and Immune Deviation: Conclusions
• The early immune response to SLIT is IL-10 secreting regulatory T cells with non-allergen 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
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