Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

Abstract

Background: Obliterative bronchiolitis (OB) ranks as the major obstacle for long-term survival of lung transplantation patients. Rapamycin (Rapa) has recently been confirmed as an immunosuppressant for antirejection due to its suppressive role in T cell activation. Here, we explore the effect of Rapa combined with immature dendritic cells (imDCs) on OB in trachea allograft rats. Methods: The effect of bone marrow-derived imDCs or Rapa-imDCs on lymphocyte cells and CD4⁺ T cells were evaluated by methyl thiazolyl tetrazolium and flow cytometry. Tracheal transplantation was performed from Lewis rats to Wistar recipients. Recipient rats received Rapa+imDCs for 10 consecutive days after implantation. Allograft rejection was assessed by micro-CT image, hematoxylin/eosinHE staining and flow cytometry. The underlying mechanism was also investigated. Results: Rapa-imDCs inhibited lymphocyte and CD4⁺ T cell growth. Furthermore, Rapa-imDC treatment induced T cell hyporesponsiveness by attenuating T cell differentiation into IFN-γ-producing T cells (Th1), but increased CD4⁺CD25⁺Foxp3⁺ T cell (Treg) contents. Importantly, Rapa-imDC administration ameliorated airway obliteration symptoms and CD4⁺ and CD8⁺ T cell infiltration. Furthermore, the proinflammatory factor levels of IL-6, TNF-α, IFN-γ and IL-17 were decreased, concomitant with the upregulation of immunosuppressive cytokines IL-10 and TGF-β1. Further analysis confirmed that Rapa-imDC treatment attenuated the amounts of infiltrated IL-17⁺CD4⁺ T cells (Th17 cells) and Th1 cells, but increased Treg contents in the spleens of recipients. Conclusions: This research may corroborate a protective role of Rapa-imDCs in OB by regulating the balance between effector T cells and Tregs, suggesting a potential applicable strategy to treat OB after lung transplantation.

Recipient bone marrow‐derived stromal cells prolong graft survival in a rat hind limb allotransplantation model

“…In our preliminary study in which transplantation was performed between Brown Norway and LEW rats, the infusion of BMSCs promoted graft rejection, and it was also reported by other researchers that BMSCs promoted rejection between ACI and LEW rats (Inoue et al, ),—as such, we used the combination of WIS and LEW rats for the transplantation model. Some authors used this combination to investigate the in vivo transplantation model, and also in our study the untreated control group showed acute graft rejection with this combination (Dong, Wang, Liu, Zhao, Chen, Li, & Li, ). Third, we did not analyze the other immunological effects of recipient BMSCs, such as their homing effects, the induction of T cell regulation, and the modulation of dendritic cell maturation.…”

Years in Review: Recent Progress in Cellular Allergology

“…This either points to special features of the sensitizing allergens, which become imprinted onto the involved dendritic cells, as discussed and entertained by the authors, or rather mirrors already elevated allergen-specific T effector cell levels present in such specifically sensitized individuals. These findings, together with the observation of Dong et al [57] that rapamycin-treated immature dendritic cells lead to the induction of Treg cells, add additional support to the concept that dendritic cells critically shape the T cellular immune response. Antigen-presenting cells receive important cues, such as ‘danger signals', by specifically sensing their environment with their specific set of surface receptors, including histamine receptors [58].…”

Kaempferol attenuates imiquimod-induced psoriatic skin inflammation in a mouse model

“…Previous studies have shown that rapamycin, a typical mTOR inhibitor, inhibits T cell proliferation by preventing them from entering proliferative cell cycle . It has been generally accepted that rapamycin promotes CD4 + Foxp3 + T reg development . Here we demonstrated that kaempferol suppressed the proliferation of T cells and also dampened their mTOR signaling.…”