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标题： Tuftsin prevents the negative immunoregulation of neuropilin- 1highCD4+CD25+Regulatory T cells and improves survival rate in septic mice

讲者：高玉雷

单位：天津医科大学总医院

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播放： 1615

论文摘要： Sepsis is still the leading cause of death among critically ill patients in intensive care units, and the quality of life of the survivors would usually be impaired[1-5]. As a result, there is a significant loss of immunocytes, including B/T lymphocytes, dendritic cells (DCs), gastrointestinal epithelial cells, even thymocytes at the beginning of sepsis as shown both in animal models and septic patients[6-9]. It has been noted that septic patients gradually enter into a state of immunosuppression after primary hyper-inflammatory response, and defined as immunoparalysis[2,4,6-7]. In recent years, investigators have become interested in the study of the mechanisms regarding immunosuppression and development of new measures to regulate immune response during sepsis, including both activation of Tregs and apoptotic depletion of immunocytes[10].
Tregs, as a class of CD4⁺T cell subsets, are a group of specialized immune cells that play an important role in immune homeostasis [11]. During the development of sepsis, Tregs subdue inflammation and tissue damage, while they may also cause immune dysfunction, such as induction of T-lymphocytic apoptosis, inhibition of CD4⁺/CD8⁺T--lymphocytic function, and mediation of shifting from the helper T cell (Th) 1 to Th 2 response, especially immunoparalysis via expression of CTLA-4 and membrane associated transforming growth factor-β (TGF-β^m+), as well as anti-inflammatory cytokines (IL-10 and TGF-β)[12-17].
Recently, Nrp-1 which characterized as a single-pass transmembrane glycoprotein, is an essential component of the immunological response in humans and animals, is identified as a potent surface marker for CD4⁺CD25⁺Tregs[18-21]. In addition, the expression of Nrp-1 on Tregs was correlated with the expression of Foxp-3 and suppressive capacity[22]. Our previous research showed that Nrp-1^hi^ghCD4⁺CD25⁺Tregs might exhibit primary negative immunoregulation in sepsis, Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis[23].
In 1970s, investigators found a natural immune modulating tetrapeptide (threonine-lysine-proline-arginine) derived from the proteolytic degradation 289-292 amino acid residues of IgG in spleen, and it was described as a phagocytosis-stimulating factor in terms of tuftsin which is the typical ligand of Nrp-1[24-25]. The primary effect of tuftsin or tuftsin-like peptides was to enhance phagocyte respiratory burst, migration/chemotaxis ability, antigen presentation, and monocytic origin, including macrophages, neutrophils, microglia and Kupffer cells, thereby increasing antimicrobial and antitumor activities [26-30]. In animal models, tuftsin or tuftsin-like peptides were found to exert therapeutic effect to improve outcome and their innate immunity. Nevertheless, the potential effect of tuftsin on adaptive immunity remains to be elucidated [28-30].
In the present study, the purpose is to investigate the impact of sepsis on the serum concentration of tuftsin and the expression of Nrp-1 on CD4⁺CD25⁺Tregs, as well as the potential therapeutic value and mechanisms of tuftsin in sepsis. We demonstrated that the serum concentration of tuftsin was significantly down-regulated, and the expression of Nrp-1 was significantly up-regulated in a grade- and time- dependent manner, using the classical septic model, i.e., CLP. Administration of tuftsin improved the survival rate of septic mice in a dose- dependent manner, especially treatment with 2 mg/kg tuftsin after CLP. In vitro study, tuftsin prevented the negative immunoregulation of Tregs, the primary subtype is Nrp-1^hi^ghCD4⁺CD25⁺Tregs, including down-regulated the expression of Foxp-3/CTLA-4, inhibited the secretion of TGF-β, and down-regulated the immunosuppressive function of Nrp-1^highCD4⁺CD25⁺Tregs to conventional CD4⁺CD25^-T cells. In vitro and vivo study, tuftsin markedly down-regulated the demethylation of Foxp3-TSDR of Nrp-1^hi^ghCD4⁺CD25⁺Tregs in a dose-dependent manner. Tuftsin could represent a new potential therapeutic agentia to improve the outcome of septic mice, and associated with preventing the negative immunoregulation of regulatory T cells via Nrp-1.