Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management
Abstract
:1. Introduction
2. Immune Cells and Inflammatory Mediators in PAH
2.1. Immune Cells
2.1.1. T Lymphocytes
2.1.2. B Lymphocytes
2.1.3. Macrophages
2.1.4. Mast Cells
2.1.5. Dendritic Cells
2.1.6. Neutrophils
2.2. Cytokines
2.2.1. TGF-β
2.2.2. IL-6
2.2.3. IL-1
2.2.4. MCP-1
3. Inflammation-Related Signaling Pathways in PAH
3.1. JAK-STAT
3.2. Nf-κB
3.3. TLR
4. Anti-Inflammatory and Immunosuppressive PAH Therapy
4.1. Tocilizumab
4.2. Rituximab
4.3. Sotatercept
4.4. Seralutinib
5. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Type | Position | Mechanism | Expression |
---|---|---|---|
Endothelial cells | intima |
| IL-1α, IL-6, IL-8, IL-12, CCL2, TNF-α, ICAM-1, VCAM-1, E-selectin, P-selectin. |
Smooth muscle cells | tunica media | IL-6, TGF-β, TNF-α, CXCL8, ICAM-1, VCAM-1, P-selectin. | |
Fibroblasts (Myofibroblasts) | adventitia | IL-1β, IL-6, TGF-β, CCL2, CXCL12, CCR7, CXCR4, VCAM-1. |
Immune Cells | Inflammatory Cytokines | Mechanism | Drug Strategy |
---|---|---|---|
T lymphocytes | IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-14, IL-17, IL-21, IL-22, IL-23, IL-35, TGF-β, IFN-γ, CCL2, CCL3, CCL4 |
|
|
B lymphocytes | IL-2, IL-4, IL-6, IL-35, TGF-β, IFN-γ, CCL17, CCL22 |
|
|
macrophages | IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, IL-18, IL-23, TNF-α, TGF-β, IFN-γ, CCL1, CCL2, CCL5, CCL17, CCL18, CCL22, CCL24, CXCL9, CXCL13, CXCL16, M-CSF, GM-CSF, VEGF, PDGF |
|
|
mast cells | IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-11, IL-13, IL-16, IL-33, TNF-α, TGF-β, CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL9, CCL10, CCL17, CXCL2, CXCL8, CXCL10, G-CSF, NGF, FGF, SCF, PDGF, VEGF |
|
|
dendritic cells | IL-1, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-16, IL-17, IL-18, IL-23, IFN, TNF-α, CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10 | Dendritic cells interact with T cells and B cells by producing and activating certain cytokines, contributing to disease pathogenesis of PAH. |
|
neutrophils | IL-1, IL-4, IL-6, IL-8, IL-10, TNF-α, TGF-β, IFN-γ, CCL2, CCL3, CCL5, CXCL1, CXCL8, CXCL10, G-CSF, VEGF | Neutrophils, neutrophil elastase (NE), and neutrophil extracellular traps (NETs) are interrelated with vascular remodeling progression and PAH pathogenesis. |
|
Drug | Target | Mechanism | Disease | Model | Status |
---|---|---|---|---|---|
Ruxolitinib [115,116] | JAK1, JAK2 | JAK1 and JAK2 inhibitor | PAH | Human PASMCs of IPAH patients, rats with MCT-induced, mice with Hox-induced | Preclinical models of PAH |
CTEPH | Rats induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres | Animal models of CTEPH | |||
Fedratinib (TG-101348) [112] | JAK2 | JAK2 inhibitor | PAH | Human PASMCs with hypoxia-induced | In vitro |
Cucurbitacin I (JSI-124) [111] | JAK2, STAT3 | JAK2 inhibitor | PH | Human PAECs and PASMCs of IPF patients, rats with bleomycin-induced | Preclinical models of PH |
Magnolol [118] | JAK2 | JAK2 inhibitor | PAH | Rats with hypoxia-induced, rat heart-derived H9c2 cells with hypoxia-induced | Preclinical models of PAH |
Drug | Target | Mechanism | Disease | Phase | ClinicalTrials.gov. Identifier | Outcome |
---|---|---|---|---|---|---|
Sotatercept [82] | ActRIIA | IgG-ActRIIA fusion protein and TGF-β inhibition | PAH | III | NCT03496207 | Completed |
Seralutinib [129] | CSF1R, c-Kit, PDGFR | kinase inhibitor | PAH | III | NCT05934526 | Recruiting |
Tocilizumab [130] | IL-6R | IL-6 receptor antagonist | PAH | II | NCT02676947 | Completed |
Anakinra [100] | IL-1R | IL-1 receptor antagonist | PAH | Ib/II | NCT03057028 | Completed |
Rituximab [35] | CD20+ B cells | anti-CD20 chimeric monoclonal antibody | SSc-PAH | II | NCT01086540 | Completed |
Satralizumab [131] | IL-6R | anti-IL-6 receptor antibody | PAH | II | NCT05679570 | Recruiting |
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Zhang, Y.; Li, X.; Li, S.; Zhou, Y.; Zhang, T.; Sun, L. Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management. Int. J. Mol. Sci. 2024, 25, 8427. https://doi.org/10.3390/ijms25158427
Zhang Y, Li X, Li S, Zhou Y, Zhang T, Sun L. Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management. International Journal of Molecular Sciences. 2024; 25(15):8427. https://doi.org/10.3390/ijms25158427
Chicago/Turabian StyleZhang, Yihan, Xing Li, Shang Li, Yu Zhou, Tiantai Zhang, and Lan Sun. 2024. "Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management" International Journal of Molecular Sciences 25, no. 15: 8427. https://doi.org/10.3390/ijms25158427