Mesenchymal stromal cell infusion modulates systemic immunological responses in stable COPD patients: a phase I pilot study To the Editor: Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality due to limited therapeutic options for the persistent pulmonary and systemic inflammation that characterises this condition [1]. Recently, pre-clinical studies of mesenchymal stromal cells (MSCs) in COPD demonstrate efficacy in alleviating inflammation and reducing emphysema following either systemic or intra-tracheal administration [2, 3]. Human trials have demonstrated that MSCs did not improve spirometry following their administration to COPD patients; however, it was reported that C-reactive protein (CRP), a marker for systemic inflammation, was reduced 1-3 months after infusion. Earlier time-points were not assessed in detail in these trials, which limits further investigation of these changes [4, 5]. Identifying the fate of intravenously infused MSCs and the potential implications of their biodistribution, as well as short-term MSC-induced systemic changes that were not explored in previous trials will better delineate the utility of MSC treatment for COPD. The study was approved by the Royal Perth Hospital ethics committee (approval number EC2012/103) and all patients had provided written informed consent. A single site, phase I study (Australian clinical trials registry number 12614000731695) was conducted to determine MSC biodistribution, inflammatory and clinical endpoints following systemic MSC infusion in a cohort (n=9) of mild to very severe stable COPD patients (n=1 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I, n=2 GOLD II, n=3 GOLD III, n=3 GOLD IV). All recruited patients had not experienced an exacerbation for at least 3 months prior to trial commencement with no change in regular medications. Patients received two infusions of low passage (p4-5) allogeneic bone marrow-derived MSCs of approximately 2×10 6 MSCs per kg, 1 week apart, with the first infusion comprising radiolabelled cells and the second infusion using unlabelled cells. MSCs used for the first infusion were labelled with indium-111, a low energy radioisotope with a half-life of 68 h to enable tracking across several days. Labelled MSCs were able to adequately suppress peripheral blood mononuclear cell (PBMC) proliferation in vitro compared to unlabelled MSC (p>0.05) and retained regular morphological characteristics. Safety and hospitalisations attributed to acute exacerbations of COPD were monitored up to 1 year later. Wilcoxon matched pairs tests were used for comparison of pre-and post-infusion levels of cell subsets and circulating plasma biomarkers. MSC infusion showed no attributable adverse side-effects and was well tolerated. Following infusion, indium-111 was detected in the lung within 30 min by computed tomography (CT) scan and remained detectable after 24 h, after which uptake was detected in the liver, spleen and bone marrow up to 7 days after infusion (figure 1a ...

Chronic obstructive pulmonary disease (COPD) is characterized by progressive pulmonary and systemic inflammation. Acute exacerbations of COPD (AECOPD) are associated with acute inflammation and infections and increase the rates of morbidity and mortality. Currently, neither the aetiology nor pathogenesis of AECOPD are entirely understood. Exosomes have been reported to regulate immunity and inflammation via specific intercellular communications through an array of macromolecules (e.g. microRNA and proteins) contained within these microvesicles. We evaluated the level of circulating exosomes in relation to systemic inflammation in patients with AECOPD (n = 20) or stable COPD (sCOPD; n = 20) in comparison to non-smoking healthy controls (n = 20). Exosomes in plasma were isolated by precipitation-based method, and quantified using a CD9 expression based enzyme-linked immunosorbent assay (ELISA). Plasma biomarkers of systemic inflammation, C-reactive protein (CRP), soluble tumour necrosis factor receptor-1 (sTNFR1) and interleukin (IL)-6 were also quantified using ELISA. Levels of plasma exosome were higher in AECOPD patients (p < 0.001) and sCOPD patients (p < 0.05) compared to controls. Plasma levels of CRP and sTNFR1 were highest in AECOPD, followed by sCOPD patients compared to healthy controls (p < 0.05). Plasma IL-6 was elevated in AECOPD (p < 0.05) and sCOPD patients (p < 0.01) compared to controls. The level of exosome correlated with the levels of CRP, sTNFR1 and IL-6 in plasma. Exosomes may therefore be involved in the inflammatory process of AECOPD. Further studies involving exosomal phenotyping and molecular characterization are required to fully understand their role in the pathophysiology of COPD.

Control of early HIV-1 infection was associated with an increase in HIV-1 p24-specific PROAb responses, which was mediated by HIV-1 p24-specific IgG1 antibodies. These findings provide further evidence that antibodies to HIV core proteins may contribute to control of HIV-1 infection.