Disentangling the origin of chemical differences using GHOST
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
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
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
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?
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
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