Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats

• Published in: Gene Vol. 576; no. 1; pp. 412 - 420
• Main Authors: Ebrahimi, Ammar, Kardar, Gholam Ali, Toolabi, LadanTeimoori, Ghanbari, Hossein, Sadroddiny, Esmaeil
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.01.2016
• Subjects: Animals; Cell Differentiation; Engineered lung; Gene Expression Regulation, Enzymologic; Graft Rejection - genetics; Immunosuppression; Indoleamine 2,3-dioxygenase; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Lentivirus; Lung Transplantation; Male; Rats; Rats, Wistar; Stem Cells - cytology; Tissue Engineering; IFNγ; PBS; TNFα; IHC; RANTES; H&E; MOI; Lung transplantation; HPRT; ELT IDO; ELT; Engineered lung; ECM; SAGM; Immunosuppression; IDO; TGF-β1; Indoleamine 2,3-dioxygenase; MSC; AEC; COPD
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2015.10.054

Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNγ and TNFα were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects. •Acute rejection score of IDO+ allografts was significantly lower than controls.•ECM proteins along with SAGM media could guide rat MSCs into type I and II AECs.•Inducible expression of IDO significantly downregulated IFNɣ and TNF-α expression.•Local IDO expression could upregulate FOXP3, a Tregulatory cell marker.•RANTES were downregulated in IDO expressing allografts.