Abstract
Alloantibody-mediated rejection (AMR) and failure of desensitization in highly sensitized patients remain significant problems in transplantation. Interleukin 6, a pleomorphic cytokine with important roles in immune regulation and inflammation, is a potential target for new therapeutic strategies in combating AMR. Suppression of donor specific antibody (DSA) by IL6 system blockage was studied using an anti-IL6 receptor (anti-IL6R) and an anti-IL6 antibody in a mouse model of allosensitization by skin allograft. Both anti-IL6R and anti-IL6 treatments significantly suppressed serum amyloid A (SAA), an acute phase reactant induced by IL-6 (p<0.01 vs. control) following skin transplantation. De novo DSA, including both IgM and IgG were significantly reduced by anti-IL6R (p<0.01 vs. control group) and by a 3-dose regimen of anti-IL6 (p<0.05). Interestingly, an intensified dosing regimen of anti-IL6 (15-dose group) consisting of 15 daily IP injections had no effect (p>0.05) in DSA responses despite robust SAA inhibition. Serum IL-6 concentrations in the 15-dose group significantly increased by 2.6-fold at day 1(p<0.01 vs. control), 24-fold at day 7(p<0.01), and 188-fold (p<0.01) at day 14, indicating profound disturbance in IL-6 homeostasis. In contrast, 3-dose anti-IL6 treatment and anti-IL6R treatment, which exhibited evidence of DSA suppression exhibited a modest accumulation of IL-6 and soluble IL-6R in the blood. In recall alloantibody responses to a 2nd skin allograft, anti-IL6R treatment was able to significantly attenuate DSA IgG responses (p<0.05 vs. control). Anti-IL6 treatment, which exhibited a weighty increase in blood IL6, however, failed to suppress DSA. Targeting of IL-6 pathway with pharmaceutic antibodies is an applicable approach to allogeneic desensitization in transplantation. To achieve a safe and effective antibody suppression, we are obligated further investigation to determine the root cause of IL-6 accumulation in the blood and the mechanism(s) by which anti-IL6 antibodies induce disturbance in homeostasis of IL6 and soluble IL6R.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
