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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.

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t cell immunoregulation and the response to immunotherapy
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
Role of the T-cell in Asthma

L Cosmi, et al. Allergy 2011;

immunologic response summary
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-,

slide4
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

slide5

Reduction in Rhinitis Symptoms and

Medication from Immunotherapy

100

80

70

80

60

50

60

40

40

30

20

20

10

0

0

(Varney et al. BMJ. 1991;302:265-269.)

Drugs

150

Symptoms

Grass Pollen Count

IT Treatment

IT Treatment

Placebo

Placebo

120

90

Median Score

Counts/m

Median Score

60

30

0

24

April

8 22

May

5 19

June

3 17 31

July

14 28

August

11 25

September

slide6

Early

Response

Late

Response

p<0.001

p<0.0001

50

140

120

40

100

30

80

Skin response (mm)

60

20

40

10

20

0

0

Control Immunotherapy

Control Immunotherapy

Hamid JACI 1997;99:254

late skin response to allergen following successful pollen 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

slide8

IL-12

Immunotherapy

Control

ns

p=0.002

12

8

Cells/high power field

4

0

p=0.02

Diluent

Antigen

Diluent

Antigen

Hamid JACI 1997;99:254

slide9

14

10

r = 0.64

p < 0.05

r = -0.67

p < 0.05

12

8

10

6

8

IFN-g mRNA+ cells/field

IL-4 mRNA+ cells/field

6

4

4

2

2

0

0

0

2

4

6

8

10

12

0

2

4

6

8

10

12

IL-12 mRNA+ cells/field

IL-12 mRNA+ cells/field

Hamid et al, JACI 1997;99:254

slide10
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
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 response12
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 b
Normal Immune Response: Downregulation of Th1 and Th2 Response by IL-10 and TGF-b

20

10

0

Der p 1

Unstimulated

Bet v 1

Unstimulated

*

*

*

*

*

*

[3H] TdR (cpm × 10-9)

Both

Both

Control

Control

sTGFbR

sTGFbR

Anti-IL-10R

Anti-IL-10R

*P < .01. TdR = thymidine. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

il 10 and tgf b mediated t cell suppression during hdm sit
IL-10 and TGF-b Mediated T-Cell Suppression During HDM-SIT

+anti-IL-10R

+sTGF-bR

Der p 1

+ Control Ab

18

12

8

4

0

*

*

*

[3H] TdR [Stim. Index]

*

*

*

0 7 28 70

Days

*P < .01 versus day 0. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

cytokine production during hdm sit
Cytokine Production During HDM-SIT

4

3

2

1

0

IL-10

TGF-b

IFN-g

IL-13IL-5

*

Cytokine (ng/mL)

0 7 28 70

Days

HDM-SIT = house dust mite-specific immunotherapy. *P < .001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

antibody response in healthy controls and changes in allergic individuals during hdm sit

60

40

20

0

60

40

20

0

60

40

20

0

60

40

20

0

Antibody Response in Healthy Controls and Changes in Allergic Individuals During HDM-SIT

*

IgA

IgE

U/mL

U/mL

*

IgG1

IgG4

U/mL

U/mL

Healthy 0 70

Healthy 0 70

Days (SIT)

Days (SIT)

HDM-SIT = house dust mite-specific immunotherapy. *P < .01. †P < .001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

gerald gleich effect of 6 years of immunotherapy on ige and igg antibodies to ragweed 1982
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

slide18

1000

500

100

IgE Antibody to SRW, ng/ml

50

10

J73O

J74O

M J76O

J77O

J78O

J79O

Effect of Ragweed Immunotherapy on Specific IgE Levels

Immunotherapy

G Gleich et al. J Allergy Clin Immunol 1982;70:261-71

immunologic response summary19
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?

slide20
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
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 weeks22
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
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
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

slide25

Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars)

Bet v 1

40

*

*

30

*

Proliferation (dpm x 103)

20

10

0

0

52

4

Time (weeks)

B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

slide26

80

80

60

60

40

40

20

20

0

0

0

0

4

4

52

52

Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars)

Tetanus toxoid

Mal d 1

*

*

*

*

Prolifcration (SI)

Time (weeks)

Time (weeks)

B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

slide27

4.0

*

3.5

3.0

2.5

Fold increase of mRNA

2.0

1.5

1.0

0.5

0

IL-10

FoxP3

IL-4

IFN-

TGF-

Changes from Baseline in mRNA Expression in Unstimulated PBMCs

Open bars 4 weeks: Filled bars 52 weeks

P < .05

B Bohle, et al. JACI 2007;120:707-13

slide28
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