Protective Effects Of ANti-IL-6R Monoclonal ANtibody In Septic Rat Model Are Linked To The Inhibition Of Th17 Cells

Sepsis is a serious infection caused by a systemic inflammatory responsesyndrome (SIRS).A variety of proinflammatory and anti-inflammatory factorsinfluence the process of interaction with each other. In this process, a variety ofinflammatory factors involved, leading to uncontrolled systemic inflammatoryresponse. IL-6 is a pleiotropic cytokine which is released in the early stage of sepsisand plays a dual role of pro-inflammatory and anti-inflammatory. Previous studiesfound that anti-IL-6 monoclonal antibody has a protective effect in septic rats becauseof significantly increasing the survival rate of septic rats. With the discovery ofTh17 cells, the function of IL-6 has a new meaning. Previous studies found that IL-6plays a key role of inducing differentiation from naive immune cells to the Th17 cellin vivo and vitro. Th17 cells secrete IL-17 as the main feature, it is involved in thedevelopment of various inflammatory diseases and autoimmune disease. Previousstudies have confirmed that Anti-IL-6R monoclonal antibodies is able to significantlyreduce the inflammatory response in mice with collagen-induced autoimmune arthritis.Further studies showed that the protective effect of the inflammatory response isassociated with the inhibition of Th17 cells.Pro-inflammatory response of Th17 cells play an important role in2 thepathogenesis of sepsis. Whether Anti-IL-6R monoclonal antibody have a protectiverole in septic rats by inhibit ion of the Th17 cells, there have been no studies about it.Objective: To investigate the effects of anti-rat IL-6R monoclonal antibody in theseptic model of CLP (cecal ligation and puncture) rats, and to explore its potentialmechanisms.Methods: 1.Establishment of the classical model of septic rat:cecal ligation andpuncture(CLP).Identification of CLP model by comparison of survival rate, weight,immune organs (thymus and spleen) and various inflammatory factors (TNF-α,IL-6,IFN-γ,IL-17)in serum.2.Replication the model,and then different doses ofanti-interleukin-6 receptor monoclonal antibody (anti IL-6R mb) were used to intervene the septic rats, compared to the rabbit IgG group and the sham group of thesurvival rate.3. The serum cytokines (TNF-α, IL-6, IL-17A, 1L-21) is detected in eachgroup by ELISA, exploring whether the proective role of anti-IL-6R monoclonalantibody on septic rats is associated with the Th17 cells.Results:1. After the sepsis happened,we founded that:CLP group,compared to thesham group,has the lower survival rate,lower weight,bigger spleen and increasedlevels of cytokines . These results suggest that the overall survival of rats after CLP isconsistent with previous studies, the model successfully established, we can use thismodel for further study.2.Compared with control group, anti-rat IL-6R monoclonalantibody treatment resulted in significantly improved survival rate, which was dosedependent, and the highest dose led to the best survival.3. Compared with the shamoperation group, serum levels of cytokines in the CLP were significantly increased.There were no differences in the serum concentration of IL-6 and TNF-αbetween ratstreated with rabbit IgG and those treated with anti-rat IL-6R monoclonal antibody. Incontrast, the concentration of IL-17A and IL-21 in IL-6R monoclonal antibody treatedrats, compared with IgG group, was significantly reduced(P<0.05).Conclusion: Anti-rat IL-6R monoclonal antibody has protective effects in septic ratmodel, which might be associated with the inhibition of Th17 cells.