An explorative study for halting inflammation in patients with emphysema by intravenous administration of autologous bone marrow derived mesenchymal stromal cells.

INTERVENTION: Product Name: autologous bone marrow derived mesenchymal stromal cells Product Code: MSC Pharmaceutical Form: Solution for infusion INN or Proposed INN: HUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS Other descriptive name: HUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS Concentration unit: Other Concentration type: equal Concentration number: 4000000‐ Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous use CONDITION: Pulmonary emphysema Therapeutic area: Body processes [G] ‐ Circulatory and Respiratory Physiological Phenomena [G09] PRIMARY OUTCOME: Main Objective: Primary Objective: to detect the difference in the level of expression of PECAM‐1 (CD31) on pulmonary microvascular endothelial cells (pMVECs) present in lung tissue harvested from patients at LVRS2 after 4 weeks of treatment with autologous BM‐MSCs and patients treated with placebo. Primary end point(s): The difference in expression of PECAM‐1 (CD31) on pulmonary microvascular endothelial cells per micrometer alveolar septum present in lung tissue harvested from patients at LVRS 2 after 4 weeks of treatment with autologous MSC or placebo. Secondary Objective: 1.to demonstrate safety of i.v. adm. of MSC to pts with mod. to sev emphysema; 2.the diff in the level of expr of CD31 on pMVECs present in lung tissue harvested from pts at LVRS2 after 12 wks of treatment with placebo and pts treated with MSC.; 3.the diff in the nr of CD3+ and CD4+ T‐cells present in lung tissue harvested from LVRS2 from pts after 4 or 12 wks of treatment with placebo and pts treated with BMSC.; 4.As in 2 & 3, but then the diff between LVRS2 and 1.; 5.the diff in the nr of type II alveolar cells present in lung tissue harvested from LVRS2 from pts after 4 or 12 wks of treatment with placebo and pts treated with BMSC.; 6.The diff. in shear stress response of isolated pMVECs from LVRS1 and 2 of pts treated with either MSC or placebo; 7.The diff. in Cytosplore resp of isolated immune cells from LVRS1 and 2 of pts treated with either BMSCs or placebo.; 8.The corr with lung phys response prm and the outcome of the primary obj of the study for pts treated with BM‐MSCs.; Timepoint(s) of evaluation of this end point: When all randomized patients have completed the study, all lung tissue samples will be investigated in one run for immunohistochemistry. SECONDARY OUTCOME: Secondary end point(s): 1. The differences in expression of Surfactant Protein‐C expression by alveolar type II cells in lung tissue obtained from study patients treated with placebo or MSC. ; 2. The difference in immunostaining of various leukocytes in resected lung tissue, including T lymphocytes, B lymphocytes, macrophages and neutrophils obtained from study patients treated with placebo or MSC. ; 3. The difference in the composition of the immune cells present in surgically resected lung tissue parts and paired peripheral blood mononuclear cell samples analysed by CyTOF obtained from patients treated with MSC or placebo. ; 4. The difference in shear stress responses, expressed as % elongation of 100 cells, of isolated pMVECs ex vivo obtained from study patients treated with placebo or MSC. ; 5. The difference in immune‐modulatory and regenerative capacity, determined by flow cytometry value, of MSC from emphysema patients and healthy controls stored in our biobank. ; 6. The difference in endothelial microparticles concentration and concentration of immunological markers in blood samples from study patients treated with placebo or MSC. ; Safety parameters will be measured during MSC treatment of each randomized study participant. INCLUSION CRITERIA: In order to be eligible to participate in this study, a subject must meet all of the following criteria: ; 7. The correlation between arterial pO2 or gas transfer value TLCO at 12 weeks after discharge of admission for LVRS 2 (measured as standard of care) and the outcome of the primary objective of the study for patients treated with MSC or placebo. ; In addition Safety parameters will be measured during and up to 2 hr after i.v. infusion of autologous bone marrow derived MSC or placebo and will be evaluated according to the WHO toxicity criteria by grade. Timepoint(s) of evaluation of this end point: When all randomized patients have completed the study, all lung tissue samples will be investigated in one run for immunohistochemistry or CytoF experiments, except for the MSC that will be studied for item number 5. This work will be performed will the bone marrow is harvested from all study particpants during the first lung volume reduction surgery session. ‐Age lower than 65; ‐emphysema as reported by a radiologist present in CT images of the lung; ‐gradient of emphysema severity towards the lung apex as assessed by CT‐derived lung densitometry by Pulmo CMS software (Medis, NL) and equally distributed between left and right lung; ‐FEV1 between 25% and 45% pred ; ‐TLCO between 30% and 45% pred.; ‐patients in a stable clinical condition. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range