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

AbstractBACKGROUND:
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-x03B3;-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-x03B3; 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.
AuthorsMing Dong, Xin Wang, Jie Liu, Yu-Xia Zhao, Xing-Long Chen, Ke-Qiu Li, Guang Li
JournalInternational archives of allergy and immunology (Int Arch Allergy Immunol) Vol. 167 Issue 3 Pg. 177-85 ( 2015) ISSN: 1423-0097 [Electronic] Switzerland
PMID26302996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 S. Karger AG, Basel.
Chemical References
  • Cytokines
  • Immunosuppressive Agents
  • Inflammation Mediators
  • Sirolimus
Topics
  • Allografts
  • Animals
  • Antigen Presentation (immunology)
  • Bronchiolitis Obliterans (drug therapy, immunology, pathology)
  • Cytokines (metabolism)
  • Dendritic Cells (drug effects, immunology, metabolism)
  • Disease Models, Animal
  • Graft Rejection (drug therapy, immunology)
  • Immunomodulation (drug effects)
  • Immunophenotyping
  • Immunosuppressive Agents (pharmacology)
  • Inflammation Mediators (metabolism)
  • Lymphocyte Activation
  • Male
  • Rats
  • Sirolimus (pharmacology)
  • T-Lymphocyte Subsets (immunology, metabolism)
  • T-Lymphocytes, Regulatory (immunology, metabolism)

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