title: Rapamycin combined with allogenic immature dendritic cells selectively expands CD4+CD25+Foxp3+ regulatory T cells in rats.
abstract: BACKGROUND
  Dendritic cells (DCs) can initiate the expansion of regulatory T cells (Tregs), which play an indispensable role in inducing transplantation tolerance. Some studies have investigated the effect of the immunosuppressant rapamycin (Rapa) on Tregs in vitro. However, the in vivo effect of Rapa combined with immature DCs (iDCs) on Tregs is unknown. This study was undertaken to determine whether allogenic iDCs combined with a short course of Rapa have the ability to selectively expand the CD4+CD25+Foxp3+ Tregs in a rat model.
  
  
  METHODS
  Brown Norway rats were injected intravenously with 2X10(6) Lewis iDCs followed by 1 mg/kg per day Rapa intraperitoneally for 7 consecutive days. On day 8, the levels of CD4+CD25+Foxp3+ Treg cells in peripheral blood and spleen cells were analyzed by flow cytometry. IL-2, IL-4, TGF-beta1, and IFN-gamma levels in serum were assessed by ELISA. The experimental animals were divided into four groups: control, Rapa-treated, iDC-treated, and combination-treated.
  
  
  RESULTS
  CD4+CD25+Foxp3+ Tregs comprised 7%-8% of CD4+ T cells in control rats. Rapa combined with iDCs enhanced this percentage in the peripheral blood and spleen. However, the levels of Tregs did not significantly change after treatment with Rapa or iDCs alone. The levels of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3- T cells in CD4+ T cells did not significantly change in the combined group. The TGF-beta1 level in serum from the combined group increased significantly compared with the other groups.
  
  
  CONCLUSIONS
  A significantly higher percentage of CD4+ CD25+ Foxp3+ Tregs was found in rats treated with allogenic iDCs and a short course of Rapa, along with an increase in the TGF-beta1 level in serum. This improved protocol may be a promising therapeutic strategy to increase Tregs, which are beneficial to the induction of peritransplant tolerance.
authors.affiliation: Liver Transplantation Center, Third Affiliated Hospital, Transplantation Research Institute, Sun Yat-Sen University, Organ Transplantation Research Center of Guangdong Province, Guangzhou 510630, China.
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Chen
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D003713:Dendritic Cells / Q000637:transplantation*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007108:Immune Tolerance / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D015847:Interleukin-4 / Q000097:blood; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000097:blood; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D007371:Interferon-gamma; D020123:Sirolimus