Safety of a Mesenchymal-Like Adherent Stromal Cell (PLX-PAD) in a Human Model of Pulmonary Arterial Hypertension (PAH)
| Autor: | J. Choudhary, I.L. Rapchuk, D. Enever, D. Wall, Stephanie T. Yerkovich, Peter Hopkins, R. Naidoo, L. Samson, I.J. Smith, F. Kermeen, Daniel C. Chambers, W. Hunt |
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| Rok vydání: | 2013 |
| Předmět: |
Pulmonary and Respiratory Medicine
Transplantation medicine.medical_specialty Cardiac output Pathology Thromboxane business.industry medicine.medical_treatment Hemodynamics medicine.disease Thrombosis Cell therapy medicine.anatomical_structure Internal medicine medicine.artery Pulmonary artery medicine Cardiology Vascular resistance Surgery Embolization Cardiology and Cardiovascular Medicine business |
| Zdroj: | The Journal of Heart and Lung Transplantation. 32:S65-S66 |
| ISSN: | 1053-2498 |
| DOI: | 10.1016/j.healun.2013.01.977 |
| Popis: | Purpose A gap remains between the evidence for safety provided by PAH animal models and that needed to commence early phase human studies, particularly for cell therapies where embolisation after intravenous delivery may further embarrass a compromised pulmonary vascular bed. To bridge this gap we developed a human ex-vivo perfused (EVLP) PAH model to assess the acute haemodynamic effects of a promising PAH-targeted cell therapy. Methods and Materials Organs were studied at normothermia on a cellular EVLP circuit (haematocrit 10-15%; flow 40% of donor cardiac output). PAH (target pulmonary vascular resistance (PVR) 800 dyne.sec.cm -5 ) was induced using a thromboxane analogue (U-46619), prior to the infusion of ≈10*10 6 /kg(donor) placenta-derived mesenchymal-like adherent stromal cells (PLX-PAD, Pluristem, Haifa) over 15 minutes, directly into the pulmonary artery. The predefined safety endpoint was a PVR increase > 20%. Results PAH was rapidly and stably induced (n=4, table). The PVR remained stable during and after PLX-PAD infusion (figure). Histopathology revealed occasional intravascular cells, but no clumping, embolization or thrombosis. Conclusions Human models of lung disease can be feasibly developed using EVLP, with the future potential to utilise explanted organs. With this approach we have demonstrated the acute haemodynamic safety of a supratherapeutic dose of PLX-PAD in PAH. AgeSexWeight (kg)Donation processPO 2 at retrievalReason declined for transplantU-46619 dose (μg)MSC dose (*10 6 /kg)60F127DCD469Worsening oedema despite EVLP2609.4540M90DBD304Bilateral consolidation6601063M75DBD400Age, smoking history, emphysema at retrieval28010.6740F50DBD250 (PEEP 10)Gas exchange, smoking history7410.5 |
| Databáze: | OpenAIRE |
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