Cell therapy in the treatment of bronchiolitis obliterans in a murine model

Espinel, Júlio de Oliveira; Uribe, Carolina; Meyer, Fabíola Schons; Bringheti, Rafael; Kulczynski, Jane; Saueressig, Mauricio Guidi

doi:10.1590/0100-69912015003010

Cited by 2 publications

(1 citation statement)

References 34 publications

(43 reference statements)

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“…Therefore, multiple doses of ASCs were selected to be administered on days 1, 3, 5, 8, 12, 15, 20 and 25 post-transplant. This may help to explain the discrepancy in another report that single dose of ASCs fails to alleviate the OB in a murine model [31]. Administration of MSCs with multiple doses has been proven to be safe.…”

Section: Discussionmentioning

confidence: 92%

Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO

Zheng

Qiu

et al. 2017

Respir Res

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BackgroundLong-term survival of lung transplantation is hindered by the development of obliterative bronchiolitis (OB). Adipose-derived stem cells (ASCs) were documented to have more potent immunosuppressive ability than mesenchymal stem cells (MSCs) from bone marrow and placenta. The goal of our study is to evaluate the effect of repeated administration of ASCs on OB and the involvement of indoleamine 2,3-dioxygenase (IDO) mediating the protective effect of ASCs in a heterotopic tracheal transplantation (HTT) model.MethodsFor studies in vitro, ASCs were treated with interferon-γ (IFN-γ). For in vivo study, tracheas from BALB/c or C57BL/6 donors were transplanted into C57BL/6 recipients to create a HTT model. On days 0, 1, 3, 5, 8, 12, 15, 20 and 25 post-transplant, the allogeneic recipient mice were administered intravenously with phosphate buffered saline, 1 × 106 human ASCs, or 1 × 106 human ASCs plus 1-methyltryptophan (1-MT), an IDO inhibitor. On days 3, 7, 14 and 28, serum, trachea and spleen samples were harvested for analysis.ResultsASCs homed to heterotopic tracheal grafts after infusion. Multiple doses of ASCs significantly increased tracheal IDO levels in allografts. There were significant increases in graft and serum IFN-γ levels in allografts compared with isografts. IFN-γ elevated IDO expression and activity in ASCs in vitro. ASCs alleviated OB in allografts as evidenced by reduced epithelial loss, epithelial apoptosis, and intraluminal obstruction. The effects of ASCs on OB were blocked by 1-MT. 1-MT also blocked the alterations in pro and anti-inflammatory cytokines as well as CD3+ T cell infiltration induced by ASCs. ASCs induced not only splenic levels of CD4+CD25+Foxp3+ regulatory T cells (Treg) but also IL-10 and TGF-β-producing Treg. Furthermore, IDO inhibition abolished the changes of splenic Treg induced by ASCs. In addition, Treg reduction by cyclophosphamide treatment did not alter the effects of ASCs on tracheal IDO expression in allografts confirming Treg induction is downstream of IDO.ConclusionsRepeated doses of ASCs are capable of ameliorating OB. ASCs act at least in part via elevating IDO expression. ASCs promote the generation of Treg and suppress T cell infiltration via an IDO-dependent mechanism.

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Section: Discussionmentioning

confidence: 92%