title: Combination therapy with thymosin alpha1 and dexamethasone helps mice survive sepsis.
abstract: Immune dysfunction is a major cause of mortality in septic patients. Current evidence indicates an important role for dendritic cells (DCs) in the pathophysiology of immune dysfunction, and these cells are potential targets of immunomodulation therapies. In the present study, our aim was to enhance the resistance of endotoxemic mice to bacterial translocation and secondary infection and to improve the outcome of these infections using a combination therapy consisting of thymosin alpha1 and dexamethasone in a timely manner according to the changes of DCs' number. The effect of treatment with dexamethasone (DXM) and thymosin alpha1 (Tα1) on DCs was investigated by examining their number, MHCII and CD86 expression and their capacity to induce T cell activation. Endotoxemic mice were randomly divided into five treatment groups. The survival rates, the levels of TNF-α and IL-10, the occurrence of bacterial translocation, and the ability to clear secondary infections were determined. Additionally, the behavior of DCs over time was also evaluated. Tα1 induced significant increases in DC numbers in vivo, whereas DXM reduced cell numbers both in vitro and in vivo. However, neither drug induced significant changes in the capacity of DCs to induce T cell activation or their expression of MHCII or CD86. Among the five treatment groups, the mice treated with a combination of DXM and Tα1 had the highest survival rate; this increased survival was associated with a decrease in bacterial translocation to extra-intestinal organs and an enhanced ability to eradicate secondary infections by reversing the change in DC numbers during endotoxemia. Immunomodulatory therapy that combines Tα1 and DXM in a timely manner and was based on changes in DCs enhanced the resistance of endotoxemic mice to bacterial translocation and secondary infections, improving the outcome of the infection.
authors.affiliation: Research Institute of General Surgery, Jinling Hospital, Nanjng University, No. 305, Eastern Road of Zhongshan, Nanjing, 210002, Jiangsu Province, China.
authors.forename: Xiao-song
authors.initials: XS
authors.lastname: Xiang
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yun-zhao
authors.initials: YZ
authors.lastname: Zhao
authors.forename: Qiu-rong
authors.initials: QR
authors.lastname: Li
authors.forename: Jie-shou
authors.initials: JS
authors.lastname: Li
mesh_terms: D000818:Animals; D051940:B7-2 Antigen / Q000097:blood; D018988:Bacterial Translocation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000097:blood; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; C556062:IL10 protein, mouse; D007155:Immunologic Factors; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013947:Thymosin; D003907:Dexamethasone; D000077596:Thymalfasin