Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma

Abstract

In experimental house dust mite (HDM)-induced allergic asthma, therapeutic administration of a single dose of adipose tissue-derived mesenchymal stromal cells (MSCs) ameliorates lung inflammation but is unable to reverse remodeling. We hypothesized that multiple doses of MSCs might exert better therapeutic effects by reducing lung inflammation and remodeling but might also result in immunosuppressive effects in experimental asthma. HDM was administered intranasally in C57BL/6 mice. After the last HDM challenge, mice received two or three doses of MSCs (10 5 cells per day) or salineintravenously. An additional cohort of mice received dexamethasone as a positive control for immunosuppression. Two and three doses of MSCs reduced lung inflammation; levels of interleukin (IL)-4, IL-13, and eotaxin; total leukocyte, CD4 + T-cell, and eosinophil counts in bronchoalveolar lavage fluid; and total leukocyte counts in bone marrow, spleen, and mediastinal lymph nodes. Two and three doses of MSCs also reduced collagen fiber content and transforming growth factor-β levels in lung tissue; however, the three-dose regimen was more effective, and it reduced these parameters to control levels, while also decreasing α-actin content in lung tissue. Two and three doses of MSCs improved lung mechanics. Dexamethasone and two and three doses of MSCs similarly increased galectin levels, but only the three-dose regimen increased CD39 levels in the thymus. Dexamethasone and the three-dose, but not the two-dose, regimen also increased the levels of programmed death receptor-1 and IL-10, while reducing CD4 + CD8 low cell percentage in the thymus. In conclusion, multiple doses of MSCs reduced lung inflammation and remodeling while causing immunosuppression in HDM-induced allergic asthma. K E Y W O R D Sadipose stem cells, cellular therapy, immunosuppression, lung, mesenchymal stromal cells

A preview of selected articles

“…In an attempt to improve the efficacy of MSC‐based asthma therapies, researchers from the laboratory of Patricia Rieken Macedo Rocco (Federal University of Rio de Janeiro, Brazil) explored the impact of multiple‐dose MSC administrations on experimental allergic asthma. Reporting in a recent STEM CELLS Translational Medicine article, Castro et al evaluated the therapeutic outcomes of two or three intravenous doses of human adipose tissue‐derived MSCs provided 24 hours after the intranasal delivery of HDM in C57BL/6 mice . Interestingly, multiple doses of MSCs significantly reduced lung inflammation and remodeling while improving lung mechanics; however, this approach also prompted an immunosuppressive effect.…”

“…As MSCs display pro‐regenerative, immunomodulatory, and anti‐inflammatory capabilities, they may serve as a potentially exciting treatment option for patients with severe asthma; however, important questions remain concerning the dosing regimens required to optimize therapeutic effects and the exact mechanisms involved in the anti‐asthmatic response following MSC administration. In our second Featured Article from STEM CELLS Translational Medicine , Castro et al report that while multiple doses of MSCs can reduce lung inflammation and remodeling and improve lung mechanics in a mouse model of allergic asthma, this approach also results in immunosuppressive side‐effects . In a Related Article published in STEM CELLS , Braza et al demonstrated that lung macrophages phagocytose MSCs following administration to a mouse model of asthma, with macrophages then becoming polarized into an immunosuppressive phenotype to induce the anti‐inflammatory effects observed …”

Autologous bone marrow-derived mononuclear cell therapy in three patients with severe asthma

“…Bone marrow was aspirated from the posterior iliac crest of patients (volume = 160.5 ± 51.7 mL; number of collected cells = 8.8×10 7 ± 1.0×10 7 ; cell viability = 94.3 ± 1.2%) and prepared for separation, characterization, and transplantation. Tables 1 and 2 depict, respectively, cell populations in total bone marrow and BMMCs obtained after separation.…”

“…Three individuals with severe asthma were included in the study and periodically followed up for 1 year after BMMC transplantation (2×10 7 (Table 3). Whole-body 99m Tc-BMMC scintigraphy was performed 2h after administration and demonstrated a normal biodistribution of labeled cells, with greater uptake in the liver, lungs (especially the right), heart, blood pool, kidneys, and bladder ( Figure 2).…”

“…Bone marrow-derived mononuclear cells (BMMCs) and mesenchymal stromal cells (MSCs), administered either locally or systemically, have yielded favorable therapeutic outcomes in a wide spectrum of experimental models [3][4][5]. In animal models of allergic asthma, cell-based therapies reduced airway inflammation and remodeling significantly, thus improving lung function [4,[6][7][8][9][10][11]. Furthermore, we previously found that, in a model of ovalbumin-induced allergic asthma, BMMCs induced better therapeutic responses compared to MSCs in some endpoint assessments, including reduction of alveolar collapse area and collagen fiber content in lung tissue [10].…”