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Immunointervention transcutanée –
Vaccination et induction de tolérane
From immunology to clinical practice
SKIN IMMUNITY INTRADERMAL
SKIN TOLERANCE VACCINATION
Skin immunization induces Interest of ID vaccination in
potent immune responses immunocompromized patients
Skin anatomy and physiology
Stratum corneum
Epidermis
Papillary
Dermis Lymphatic
Blood vessel
Microvascular dermal unit
Skin dendritic cells : Langerhans cells and dermal DC
Antigen
Vaccine
Innate Immunity
Danger signals
TNF- α IL-1αα Immune tolerance
β IL-6
IL-1β
Lack of T & B cell priming
Activation of Treg cells
Memory cells of tolerance ?
Effector & memory
Immune response
Recruitment Antibody production
of innate cells Effector CD4+ & CD8+ T cells
Memory T & B cells
DC migration Immunization
B & T cell priming
Lymph vessel
CD4+T
B cells
LYMPH NODE
CD8+T
ALLERGIC CONTACT DERMATITIS
Contact Hypersensitivity
Skin DTH reaction
Hapten-specific T cells
HAPTENS
Non protein chemicals
Interact with aminoacid residues
DNP et TNP: lysin
Ni: histidin
- Strong H: DNP, TNP, oxazolone
ACD in 90% of people
- Weak H : metals (Ni, Cr, Cu)
ACD in 20% of people
- Very weak H:
Professional ACD
Pathophysiology of antigen-specific skin inflammation
Sensitization Hapten Elicitation
Protein Effector T cell response
Innate response
Skin allergy Skin inflammation
T cell priming Skin irritation
ICD Eczema
Drug allergy EPIDERMIS
TNF- α IL-1αα Dendritic cells
β IL-6
IL-1β Th1
Keratinocytes Th2
Recruitment Th17 DERMIS
of innate cells
Effector T cells Eos
Neut
Mast cell Mono
Dendritic cell Endothelial cell Regulatory T cells
Blood vessel
T cell priming
DC migration
sensitization
Lymph vessel
Treg cells
Treg cells
LYMPH NODE
Teff cells
in vivo Immunisation High dose DNFB
Sensitization Challenge
DNFB J0, back DNFB, J5, Ear épidermis
C57Bl/6
dermis
Allergic contact dermatitis
Contact Hypersensitivity - Mouse ear swelling assay
200 Down-regulatory
T cells (Treg) cartilage
(ear swelling - µm)
Skin inflammation
100
Effector
0 T cells
1 2 3 4 5 6 7
Days post-challenge
Allergic contact dermatitis
CD8+ T cells are effectors and CD4+ T cells are regulatory
Gocinski & Tigelar, J Immunol, 1990
400
CD4+ T cell deficient
-MHC class II°/°
-Anti-CD4 mab depletion
300
(mmx10-3)
Ear swelling (mmx
200 Normal C57BL/6 or BALB/C mice
CD8+ T cell deficient
-MHC class I°/°
100
-Anti-CD8 mab depletion
Hélène BOUR et al., Eur J Immunol, 1995
Xu H. et al. J Exp Med, 1996
0 Bouloc A. et al. J invest Dermatol, 1998
0 2 4 6 8 10 Maya KRASTEVA et al., J Immunol, 1998
Jeanne KEHREN et al., J Exp Med, 1999
Days post-challenge Hitoshi AKIBA et al., J Immunol, 2002
Pierre SAINT-
SAINT-MEZARD et al. J Immunol, 2003
La qualité de la régulation LT CD4+ conditionne l’intensité et la chronicité
Marc VOCANSON deDermatol,
et al. J Invest l’eczéma2006
REGULATORY MECHANISMS – TOLERANCE TO STRONG HAPTENS
Low doses of DNFB
• does not induce ACD
• induces antigen-specific tolerance
Low dose DNFB Tolerization Phase Sensitization Challenge Ear swelling
• 0,01% DNFB 0,5% DNFB 0,15% DNFB measurements
7 days 5 days D1-D5
ACD response: 48h Hapten-specific
T cell response
TolerizationSensitization Challenge
- DNFB DNFB
DNFB DNFB DNFB
DNFB low DNFB DNFB
- - DNFB
Ear swelling (µm) Number of IFN-g SFC / LN
Vocanson M
QUESTIONS ?
1) Phenotype of the Tregs primed upon tolerogenic conditions
2) How primed Tregs prevent the development of allergen-specific effector T cells ?
3) Which DC initiate tolerance? (role of Langerhans cells - collab. D. Kaiserlian)
REGULATORY MECHANISMS – TOLERANCE TO WEAK HAPTENS
Sensitization Challenge Ear swelling measue
Fragrance allergens (HCA, EUG, HDCL) 3 sensitizations
24-96 h
5 days
200
Weak hapten
µm)
Anti-CD4 mAb depleted
Œdème de l’oreille (µ
150
C57BL/6
Les CD4 sont tolérogènes
100
Weak hapten
C57BL/6
50
Souris tolérante
0
0 2 4 6 8 10Sujet non allergique
Sensitization Chemical Elicitation
Weak hapten / Fragrances Effector T cell response
Innate response
T cell priming Skin irritation No skin allergy Skin inflammation
ICD No ACD
EPIDERMIS
TNF- α IL-1αα Dendritic cells
β IL-6
IL-1β
Keratinocytes
Recruitment DERMIS
of innate cells
Effector CD8+ T cells
Mast cell
Dendritic cell Endothelial cell Regulatory CD4+ T cells
Blood vessel
Low T cell priming
DC migration
sensitization
Lymph vessel
LYMPH NODE
T cell primingPatient allergique
Sensitization Chemical Elicitation
Allergic patients / Fragrance allergy models Effector T cell response
Innate response
Stong skin allergySkin inflammation
T cell priming Skin irritation
ICD Severe ACD
EPIDERMIS
TNF- α IL-1αα Dendritic cells
β IL-6
IL-1β
Keratinocytes
Recruitment DERMIS
of innate cells
Effector CD8+ T cells
Mast cell
Dendritic cell Endothelial cell Regulatory CD4+ T cells
Blood vessel
High T cell priming
DC migration
sensitization
Lymph vessel
Treg cells
LYMPH NODE
Teff cellsPOINTS IMPORTANTS • La tolérance cutanée aux allergènes passe par un mécanisme actif de suppression due (en partie) à l’activation de LT CD4+ régulateurs (Treg) • L’exposition permanente aux allergènes active les T reg et prévient le développement d’une allergie • L’exposition aux allergènes de l’environnement maintient un état de tolérance cutanée • Le traitement futur des eczémas reposera sur une immunothérapie spécifique capable d’activer les Treg et de ré-induire une tolérance immunitaire aux haptènes
New targets – New vaccines
ID vaccination improves immunity
in immunocompromized patients
ID injection INTRADERMAL
VACCINATION
Flu ID vaccination improves immunity
in immunocompromized patientsMicrovax program: To improve vaccine efficiency and vaccination coverage
Flu ID Vaccination – INTANZA® - IDflu®
Hopitaux de Lyon
MERIAL
The MICROVAX Team ENVétérinaire de Lyon
RCTS
Biomatech-NemsaID route is efficient for
immunization
• RABIES: Low doses of vaccine induce an optimal immune
response
• HEPATITIS B: dialysis patients unresponsive to IM vaccination
respond to ID hepatitis B vaccine
Micozkadioglu H et al. Ren Fail. 2007;29(3):285-8IMMUNOGENICITY OF FLU INTRADERMAL
VACCINATION IN RENAL TRANSPLANTED PATIENTS
Phase II controled, open, randomized, clinical study
Kidney transplanted patients (18-60 year old)
Transplantation > 6 months,
Classical immunosuppressive therapy
Renal fonctions stable
• Neprology Departement Hopital E Herriot – E Morelon, S Daoud, JL Touraine
• Neprology Departement Hopital Lyon-Sud - C Pouteil-Noble, R Cahen
• URCI-Lyon-Sud - C Goujon-Henry
The Microvax team
• INSERM U 851 – Team D Kaiserlian, B Dubois; Team A Hennino, JF Nicolas
• Sanofi pasteur - F Weber, MJ Quentin-Millet
• Beckton-Dickinson - P Laurent200 patients IM vaccinated in 2006
Vaxigrip® (15 µg A/H1N1, A/H3N2, B)
67 patients
35 patients non responding 32 patients non responding
non responding to the 2 A strains to the 3 strains
to A/H3N2 (HA3,5
GMT ratio
3
EMEA threshold
2,5
ID 15µg
GMT ratio
2
IM 15µg
1,5
1
0,5
0
A/H1N1 A/H3N2 B
Geometric mean ratio of titres between pre-and post-vaccination
80
Seroprotection EMEA threshold
Seroprotection rate (%)
70
60
50
40
30
20
10
0
A/H1N1 A/H3N2 B
Proportion of patients with a post-vaccination titre of ≥40 for each strainConclusions
• Immunogenicity
– ID route allows seroconversion and seroprotection to flu in
immune compromized patients unresponsive to other
vaccination routes
– Immune response is stronger for all strains and for all EMEA
criteria
– Proportion of patients responding to A/H3N2 is higher after
ID than IM vaccination
• Tolérance
– Tolerance profile of the ID vaccination is similar to IM
(EMEA criteria)
– Local reactions are more frequent and always benign
– Systemic reactions are similar in ID and IM groupsAllergologie et Immunologie clinique Lyon-Sud / Gerland
Equipe 8 – INSERM U851
Service Allergologie
et Immunologie Clinique Lyon-Sud
Marc VOCANSON, Inserm U851
Unité de recherche clinique
Lyon-Sud2. REGULATORY MECHANISMS – PROJECTS
Mechanisms and new strategies of immunotherapy
B - Allergen-specific skin immunotherapy (SIT)
> ECZEMA PATIENTS
-> Proof of concept study that SIT can improve eczemas
AD PATIENTS
• allergic to Der f(house dust mite)
• positive skin tests
IMMUNOTHERAPY
• repeated skin exposure to Der f
• SIT versus sublingal IT
Clinical score Negativation of Allergen-specific T cells responses
skin patch tests
Skin IT versus SLIT
Low doses DER f
Elispot
T effectors & T regs
Hennino A2. REGULATORY MECHANISMS – RESULTS
CD4+ Tregs
• CD4+ T cells control skin allergy
400 Strong allergens
5 days CD8+ ICOS+
Ear swelling (µm)
300
Sensitization 200 CD4+ ICOS+
Challenge
100
0 2 4 6 8 10
Days after challenge
• Skin immunization with strong or weak allergens activates CD4+ T cells
• Allergen-specific CD4+25+ T cells inhibit T cell priming and allergic responses
5 days Transferred DNFB-specific
Donors cells T cell response
Sensitization dLNs - PBS
IV transfer CD4+CD25+
DNFB CD4+CD25-
CD4+ T cell subsets
CD4+CD25+
OXA CD4+CD25-
5 days
% control response
Sensitization2. REGULATORY MECHANISMS – RESULTS
CD4+ Tregs
• Several allergen-specific Treg subsets are able to suppress skin inflammation
• ICOS is a marker for a highly suppressive Treg cell population
ICOS expression define a highly suppressive Treg subset Human (AD patients)
Gate: CD4+ DNFB ICOS
cells 104 sensitized 40 0.0106
Naive 7.2 3.66
FoxP3+ ICOS+ Highly
10
4
8.4 1.46 A
10
3 suppressive Tregs 30
103
(IL-10,
10
2
10
2 IL-17,RoRgT) 20
1
10
1 10
10
87.2 2.96
100
CD25
CD25
0 1 2 3 4
10 10 10 10 10
0 76.1 13.1 0
10
0 1 2 3 4
Atopic Non-atopic
10 10 10 10 10
ICOS ICOS
Clinical relevance: Allergic AD patients have a diminished numbers of circulating ICOS+ Tregs
Vocanson M et al. J Allergy Clinical Immunol in revision / Hennino A et al. personal data.You can also read
