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The role of the dendritic cell in allergy and immunotherapy

Speaker: Natalija Novak

29 September 2012


Dendritic cells in allergy and allergen specific immunotherapy Natalija Novak, MD & Jean-Pierre Allam, MD Department of Dermatology and Allergy University of Bonn, Germany

29 September 2012


Disclosures Prof. Dr. Natalija Novak, Department of Dermatology and Allergy, University of Bonn, Germany

3

Lecture fees: ALK, Bencard Allergy Therapeutics, LEO Pharma, Astellas

Industry-sponsored grant (institution): ALK

Consultancy: Leti Pharma, HAL Allergy, LEO Pharma 29 September 2012


Dendritic cells as Janus cells between tolerance and immunity

Tolerance

4

DC

Immunity

29 September 2012


Characteristics of Dendritic cells

5

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Dendritic cells are located close to the body surfaces

Skin

6

Oral Mucosa

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DCs express the high affinity receptor for IgE

FcRI expression on DCs 60

mDC

Trimeric FcRI (2g)

FcRI (rFI)

50

40 30 20 10

0

Non- Atopic Atopic

Non- Atopic Atopic

Skin

Oral mucosa

Allam et al, J Allergy Clin Immunol 2003 7

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DCs express several other receptors DCs in the skin (epidermis) 1.1%

CD14

DCs in the oral mucosa 68%

CD14

SabattĂŠ et al., Cytokine & Growth Factor Reviews 2007 8

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DCs are capable to prime naive T cells

DC

Inflammatory

Regulatory

IL-12, IL-18

IFN-g

Th1

IL-10, TGF-1 IL-23

IL-4, IL-5 IL-13

Th2

Treg Th17

TGF-1, IL-10

IL-17A, IL-17F IL-22 9

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The dark side of dendritic cells‌

10

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Atopic dermatitis

Th2 Th2

Th2

Th0

LC

Skin

IL- 4, IL- 5 IL-13

IDEC

LC

Chemotactic signals

Inflammation

Th1

Mo

Th1 Th1

Blood

11

IFN-g

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Stronger allergic hypersensitivity reactions in the skin in the absence of LCs

grade of hypersensitivity reaction LC

LC

Bobr et al., J Immunology, 2010 Bobr et al., J Immunology, 2010 12

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The bright side of dendritic cells‌

13

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Langerhans cells predominate in the oral muocsa

? Allam et al, J Allergy Clin Immunol 2003 14

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A setting to study the allergen uptake by oral mucosal DCs

PBS/ Gras allergen-FITC 4h

Mucosa

1. 2.

3.

Medium

15

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Allergen uptake of DCs reaches a threshold

DC [100 µg/ml Phl p5]

[10 µg/ml Phl p5] 10.3±0.9

10 5

CD1a+ oLCs

4°C (Control)

10 5

10

4

10

4

10

3

10

3

10

2

10

2

8.1±2.1

0

0

0

10 2

10 3

10 4

10

4

10

3

10

2

0

10 2

10 3

10 5

10 4

10 5

45.2±3.5*

0

4

10

4

10

4

10

3

10

3

10

3

10

2

10

2

10

2

0

0

0

10 2

10 3

10 4

10 5

10 2

10 3

10 4

10 5

51.1±3.9*

10 5

10

37°C

13.7±2.3

10 5

0

10 5

17.0±0.1

10 5

[1000 µg/ml Phl p5]

0

0

10 2

10 3

10 4

10 5

0

10 2

10 3

10 4

10 5

FITC-Phl p5

allergen dose 16

Allam et al, J Allergy Clin Immunol 2010 29 September 2012


Oral mucosal DCs release tolerogenic cytokines after allergen-uptake

DC

TGF-1

IL-10

Phl p5

Phl p5

Phl p5

Phl p5

4°C

37°C

4°C

37°C

105

105

105

4

10

4

10

4

10

3

10

3

10

3

10

102

102

102

9.1%±1.0

0

0

10

2

10

3

10

4

10

7.2%±1.0

0

5

105

0

10

2

10

3

10

4

10

9.1%±1.0 0

10

2

10

3

10

4

10

3

0

105

4

4

10

4

10

4

10

3

10

10

3

10

3

3

10

102

102

23.8%±3.8 0

10

2

10

3

10

4

10

5

10

2

10

3

10

4

10

5

105

10

0

7.2%±1.0

0

IgG

105

102

17

10

5

IgG 105

4

102

0

5

10

38.4%±4.2*

0

0

10

2

10

3

10

4

10

5

102

17.3%±1.8

0

0

10

2

10

3

10

4

10

5

30.5%±3.0*

0

0

10

2

10

3

10

4

10

5

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Attenuated maturation of oral mucosal DCs after allergen uptake Phl p5-FITC 10

5

DC

CD1a

10 4

Phl p5neg oLCs

10

3

10

2

Phl p5pos oLCs

0

0

10

10

2

3

10 Phlp5

5

10

10

3

10

2

4

10

DC

5

5

10 4

CD1a

CD1a

CD1a

10 4

10

5.7%±1.1

0

0

10

2

3

10 IgG

10

4

10

10

3

10

2

7.6%±1.2

0

5

0

10

2

3

10 IgG

10

4

10

5

IgG 5

10

10 4

10

3

10

2

<PE-A>: CD1a

<PE-A>: CD1a

CD1a

10

10

3

10

2

65.2%±.1

0

5

10 4

59.2%±3.6

0

0

0

10

2

3

10 10 <APC-A>: CD207

4

10

10

2

3

10 10 <APC-A>: CD207

5

4

10

5

CD207 10 5

5

10

3

10

2

CD1a

10 4

CD1a

CD1a

10

30.6%±2.5

0

0

10

2

3

10 CCR6

10

4

10

10

4

10

3

10

2

26.3%±4.0

0

5

0

10

2

10

2

3

10 CCR6

10

4

10

5

CCR6 5

10

10

3

10

2

5

10 4

CD1a

10 4

CD1a

CD1a

10

22.4%±5.5

0

0

10

2

3

10 CCR7

10

4

10

10

3

10

2

8.1%±4.0*

0

5

0

3

10 CCR7

10

4

10

5

CCR7 5

10

10 4

10

3

10

2

5

10 4

CD1a

<PE-A>: CD1a

CD1a

10

37.4%±6.7

0

0

10

2

3

10 CD83

10

4

10

5

10

3

10

2

25.5%±4.7*

0

0

10

2

3

10 CD83

10

4

10

5

CD83 18

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The maturation stage of DCs is decisive for their character

Immature DC

DC

Tolerance

19

Semi-mature DC

DC

Mature DC

DC

Immunity

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Close contact of DCs and T cells within the oral mucosa

50Âľm

CD1a 20

50Âľm

CD3 29 September 2012


The micromilieu of DCs is an important co-factor TGF-ď ˘

Foxp3

IL-17

IL-10

IFN-g

Allam et al., Allergy, 2011 21

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Relevance of direct interaction of DCs with T cells within the oral mucosa? Antimicrobial Peptides Salivary glands DC

Epithelium

P

B

Tr DC

DC

T

Th3 Th2 Th1

Blood

Th17

Lymphoid foci

Lamina propria

B

Th3 DC

T

Tr Th2 Th17Th1

Lymphoid tissue 22

Novak al., Mol Novaketet al.,Trends Trends MolMedicine Medicine2008 2008 29 September 2012


Distribution of DCs within the oral mucosa mouth

hard palatum

soft palatum

buccal uvula pharynx lingua

attached gingiva

sublingual vestibulum

skin

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LC/Mast cell ratio within the oral mucosa

DC

M

1.2

1.1

1.4

1.5

0.4

0.4

1.5

oLC/oMC r atio

70

n cells/HPF

60 50 oLC

40

oMC 30 20 10 0

24

Vestibulum Bucca

Palatum

Lingua Sublingua Gingiva

Skin

Allam et al., Allergy 2008 29 September 2012


Consequences for the clinical practice

Allam et al., EAACI 2012 25

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Consequences for the clinical practice

Allam et al., EAACI 2012 26

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Summary

 Dendritic cells are „Janus cells“ in allergic diseases capable to initiate and amplify inflammatory as well as tolerogenic immune reactions  There is not much knowldege about the role of DCs in subcutaneous allergen specific immunotherapy  DCs play a key role during allergen application to the oral mucosa and promote tolerogenic immune reactions in vitro

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Acknowledgement: Jean-Pierre Allam, MD Thomas Bieber, MD, PhD Department of Dermatology and Allergy, University of Bonn Bern Niederhagen, MD Torsten Appel, MD Department of Oto-Maxillo-Facial Surgery, University of Bonn

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29 September 2012


Thank you

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29 September 2012

Natalija Novak  
Natalija Novak  
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