03_Domingo_Sesión de formación. Presente y futuro en el manejo del asma grave con fármacos biológicos

1. 30/03/2023
www.brn.cat
BRN Trustees:
Investigación médica aplicada en el
asma: nuevos horizontes
Chairs: Dr. Carlos Martínez (H. Germans Trias i Pujol), Dr. Iñigo Ojanguren (H. Vall
d’Hebron)
Speakers: Dra. Irina Bobolea (H. Clínic), Dra. Elena Curto (H. Santa Creu i Sant Pau), Dr.
Christian Domingo (H. Parc Taulí), Dr. Xavier Muñoz (H. Vall d’Hebron) & Dra. Pilar Ausín
(Hospital del Mar)
With the sponsorship of:

2. Presente y futuro en el manejo del asma grave
con fármacos biológicos
Dr. Christian Domingo-Ribas
(cdomingo@tauli.cat)
BRN Trustees:
Investigación médica aplicada en el asma: nuevos horizontes
With the sponsorship of:
30/03/2023
www.brn.cat

3. Int. J. Mol. Sci. 2023, 24, 2716. https://doi.org/10.3390/ijms24032716

4. Pathophysiology of allergic cascade
Domingo et al. Recent Patents Inflamm Allergy Drug Discov. 2007; 1: 151-164

5. Allergens
Cytotoxic
proteins,
enzymes,
leukotrienes
Allergic
symptoms
Remodelling
Eosinophil
IL-5
IL-4
B
lymphocyte
Plasma
cell
Histamine,
tryptase
prostaglandins
leukotrienes,
cytokines
Th0
lymphocyte
Th2 lymphocyte
Mast cell,
basophil
IL-13
Late phase of allergic cascade
Modificado de: Domingo CH. Omalizumab for severe asthma: efficacy beyond the atopic patient?. Drugs 2014: 74:521-533.

6. APC (CD)
Th Th2
IL-4
IL-5
Tr
Th1
IT
IT
IL-10
(TGF-β)
B
IgG4
(IgA)
B
+
ALLERGIC
RESPONSE
Eos
IFN-γ
IgE
IL-12
Inmunotherapy: mode of action (I)

7. CD inmadura
Th2
Tr
Th1
IL-10 y TGF-β
Eosinophil activation
-
-
- +
+
-
CD1
CDr
CD2
IgG4
IgE dependent Mast cells
activation
Allergens
Parasites
IT?
IT
Inmunotherapy: mode of action (II)

8. Skin Prick test
Histamine
Blood analysis:
Total IgE
Specific IgE
Acute phase of the allergic reaction: the crosslinking effect
Cell membrane
IgE receptors
(FCɛRI)
Allergen
Domingo Ch. . Drugs 2017; 77:1769-1787

9. Chronicity phase of allergic reaction
Modificado de: Domingo CH. Omalizumab for severe asthma: efficacy beyond the atopic patient?. Drugs 2014: 74:521-533.

10. Modified from: Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787
OMALIZUMAB
Pharmachologic effect of omalizumab

12. Allergens
Cytotoxic
proteins,
enzymes,
leukotrienes
Allergic
symptoms
Remodelling
Eosinophil
IL-5
IL-4
B
lymphocyte
Plasma
cell
Histamine,
tryptase
prostaglandins
leukotrienes,
cytokines
Th0
lymphocyte
Th2 lymphocyte
Mast cell,
basophil
IL-13
Late phase of allergic cascade
Modificado de: Domingo CH. Omalizumab for severe asthma: efficacy beyond the atopic patient?. Drugs 2014: 74:521-533.

13. Bronchial epithelium
Allergens, virus, pollution Bronchial epithelium
disruption
IL-4 IL-13
Mucus
production
IL-5
Eosinophil
IgE
B lymphocyte
IgE
ILC2
Innate immunity in asthma (I)
Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787

14. IFN-γ
Bronchial
epithelium
apoptosis
ILC3
Bacteria
NKT
IL-17
Neutrophil
infiltration
IL-5 IL-4 IL-13
B lymphocyte IgE
Eosinophil
Smooth
muscle
cell
Innate immunity in asthma (II)
Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787

15. BENRALIZUMAB
MEPOLIZUMAB
RESLIZUMAB
Overlapping effects of new monoclonal antibodies
Modified from: Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787c

16. IL-4
IL-5
IL-13
T2 inflammation
Th2 inflammation
Epithelium
Histamine
Cytokines
Tryptase
PGD2
LTD4
IL-4
IL-5
B
lymphocyte
Allergens Smoke
Viruses
Allergens
Bacteria
ILC3
Neutrophil
IL-17
APC
Th0
lymphocyte
Th2
lymphocyte
Serum-free
IgE
Basophil
Mast cell
Plasma
cell
Mucus production
and AHR
Eosinophil
Cytotoxic proteins
Leukotrienes
Enzymes
00
IL-13
IL-4
IL-5
ILC2 NKT
IFN-γ
IL-4
IL-5
IL-13
Figure adapted from Domingo C. Drugs 2017;77:1769–1787
AHR, airway hyperresponsiveness; APC, antigen-presenting cell; IgE, immunoglobulin E; IL, interleukin; IFN, interferon; ILC2, type 2 innate lymphoid cell; ILC3, type 3 innate lymphoid cell; LTD4, leukotriene D4; NKT, natural killer T;
PGD2, prostaglandin D2; T2, type 2; Th, T helper; TSLP, thymic stromal lymphopoietin
1. Domingo C. Drugs 2017;77:1769–1787; 2. Fahy J.V. Nat Rev Immunol 2015;15:57–65; 3. Chang Y-J, et al. J Leukoc Biol;94:933–940 ; 4. Robinson D, et al. Clin Exp Allergy 2017;47:161–175
Interrelations between innate and adaptive immunity

17. DUPILUMAB
Overlapping effects of new monoclonal antibodies
Modified from: Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787c

18. Leukotrienes
ECP, EPO,
EDN
iEos
APC iEos
Bone
marrow
GM-CSF
Eotaxin
IL-3, IL-5
CCR3
Chemokines
(eotaxin)
IL-4
Bronchial
mucosa
Allergens
APC
B
lymphocyte
Th0
lymphocyte
Th2
lymphocyte
Plasma cell
Lung vessel Eosinophil
VCAM-1
IL-4
IL-5
IL-13
Figure adapted from Domingo C. Drugs 2017;77:1769–1787
APC, antigen-presenting cell; CCR3, C-C chemokine receptor type 3; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; iEos, inflammatory eosinophil; GM-CSF, granulocyte-macrophage
colony-stimulating factor; IL, interleukin; Th, T helper; VCAM-1, vascular cell adhesion molecule 1
1. Domingo C. Drugs 2017;77:1769–1787; 2. Doran E, et al. Front Med;4:139
This symposium is organised and funded by Amgen and AstraZeneca. The information displayed during the meeting is exclusively for Healthcare Professionals empowered to prescribe or dispense medicinal products.
Please do not distribute in media, supporting materials or communication channels aimed at the general public. La información mostrada durante la reunión está dirigida exclusivamente a Profesionales Sanitarios
facultados para prescribir o dispensar medicamentos. Por favor no distribuir en medios, soportes o canales de comunicación dirigidos a público general.
Veeva ID: ESS-1787; date of preparation: August 2022. © 2022 AstraZeneca. All Rights Reserved. This information is intended for healthcare professionals only.
Biology of the eosinophil

19. What is the role of the epithelium; why is it important
that the epithelium stays intact, and how does the
airway epithelium differ in patients with severe
asthma versus healthy individuals?

20. Ciliary motility

21. Ciliary motility

22. IL-4 IL-13
Mucus
production
Bronchial epithelium
Allergens, virus, pollution Bronchial epithelium
disruption
IL-5
Eosinophil
IgE
B lymphocyte
IgE TSLP, IL-25, IL-33
ILC2
Innate immunity in asthma (I)
Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787

23. IFN-γ
Bronchial epithelium
apoptosis ILC3
Bacteria
IL-33
TSLP
NKT
IL-17
Neutrophil
infiltration
IL-5 IL-4 IL-13
B lymphocyte IgE
Eosinophil
Smooth
muscle
cell
Innate immunity in asthma (II)
Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787

24. IL-4
IL-5
IL-13
TSLP, IL-33, IL-25
T2 inflammation
Th2 inflammation
Epithelium
Histamine
Cytokines
Tryptase
PGD2
LTD4
IL-4
IL-5
B
lymphocyte
Allergens Smoke
Viruses
Allergens
Bacteria
ILC3
Neutrophil
IL-17
APC
Th0
lymphocyte
Th2
lymphocyte
Serum-free
IgE
Basophil
Mast cell
Plasma
cell
Mucus production
and AHR
Eosinophil
Cytotoxic proteins
Leukotrienes
Enzymes
00
IL-13
IL-4
IL-5
ILC2 NKT
IFN-γ
IL-4
IL-5
IL-13
Figure adapted from Domingo C. Drugs 2017;77:1769–1787
AHR, airway hyperresponsiveness; APC, antigen-presenting cell; IgE, immunoglobulin E; IL, interleukin; IFN, interferon; ILC2, type 2 innate lymphoid cell; ILC3, type 3 innate lymphoid cell; LTD4, leukotriene D4; NKT, natural killer T;
PGD2, prostaglandin D2; T2, type 2; Th, T helper; TSLP, thymic stromal lymphopoietin
1. Domingo C. Drugs 2017;77:1769–1787; 2. Fahy J.V. Nat Rev Immunol 2015;15:57–65; 3. Chang Y-J, et al. J Leukoc Biol;94:933–940 ; 4. Robinson D, et al. Clin Exp Allergy 2017;47:161–175
This symposium is organised and funded by Amgen and AstraZeneca. The information displayed during the meeting is exclusively for Healthcare Professionals empowered to prescribe or dispense medicinal products.
Please do not distribute in media, supporting materials or communication channels aimed at the general public. La información mostrada durante la reunión está dirigida exclusivamente a Profesionales Sanitarios
facultados para prescribir o dispensar medicamentos. Por favor no distribuir en medios, soportes o canales de comunicación dirigidos a público general.
Veeva ID: ESS-1787; date of preparation: August 2022. © 2022 AstraZeneca. All Rights Reserved. This information is intended for healthcare professionals only.
Interrelations between innate and adaptive immunity

25. IL-4, IL-5 and IL-13
2500x
ILC2
TSLP, IL-33, IL-25
NKT cell
APC
APC, antigen-presenting cell; IL, interleukin; ILC2, type 2 innate lymphoid cells; NKT, natural killer T; TSLP, thymic stromal lymphopoietin
What happens beneath the epithelium?
Domingo Ch and Mirapeix RM. Int. J. Mol. Sci. 2023, 24, 2716. https://doi.org/10.3390/ijms24032716

26. TEZEPELUMAB
Overlapping effects of new monoclonal antibodies
Modified from: Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787c

27. IL-4
IL-5
IL-13
TSLP, IL-33, IL-25
T2 inflammation
Th2 inflammation
Epithelium
Histamine
Cytokines
Tryptase
PGD2
LTD4
IL-4
IL-5
B
lymphocyte
Allergens Smoke
Viruses
Allergens
Bacteria
ILC3
Neutrophil
IL-17
APC
Th0
lymphocyte
Th2
lymphocyte
Serum-free
IgE
Basophil
Mast cell
Plasma
cell
Mucus production
and AHR
Eosinophil
Cytotoxic proteins
Leukotrienes
Enzymes
00
IL-13
IL-4
IL-5
ILC2 NKT
IFN-γ
IL-4
IL-5
IL-13
Figure adapted from Domingo C. Drugs 2017;77:1769–1787
AHR, airway hyperresponsiveness; APC, antigen-presenting cell; IgE, immunoglobulin E; IL, interleukin; IFN, interferon; ILC2, type 2 innate lymphoid cell; ILC3, type 3 innate lymphoid cell; LTD4, leukotriene D4; NKT, natural killer T;
PGD2, prostaglandin D2; T2, type 2; Th, T helper; TSLP, thymic stromal lymphopoietin
1. Domingo C. Drugs 2017;77:1769–1787; 2. Fahy J.V. Nat Rev Immunol 2015;15:57–65; 3. Chang Y-J, et al. J Leukoc Biol;94:933–940 ; 4. Robinson D, et al. Clin Exp Allergy 2017;47:161–175
Interrelations between innate and adaptive immunity

28. BENRALIZUMAB
MEPOLIZUMAB
RESLIZUMAB
DUPILUMAB
OMALIZUMAB
TEZEPELUMAB
Overlapping effects of new monoclonal antibodies
Modified from: Domingo Ch. Overlapping effects of new monoclonal antibodies for severe asthma. Drugs 2017; 77:1769-1787c

29. Domingo Ch et al.(2020) Dual Monoclonal Antibody Therapy for
a Severe Asthma Patient. Front. Pharmacol. 11:587621
Dual Monoclonal Antibody Therapy for a Severe Asthma
Patient

30. Domingo Ch et al.(2020) Dual Monoclonal Antibody Therapy
for a Severe Asthma Patient. Front. Pharmacol. 11:587621
Dual Monoclonal Antibody Therapy for a Severe Asthma
Patient

31. Domingo Ch et al.(2020) Dual Monoclonal Antibody Therapy for a Severe Asthma Patient. Front. Pharmacol. 11:587621
Dual Monoclonal Antibody Therapy for a Severe Asthma
Patient

32. Gràcies per l’atenció!