On January 27, 2014,researchers at Haiyan Liu’s group published an article entitled “IL-1b and TLR4 Signaling Are Involved in the AggravatedMurine Acute Graft-versus-Host Disease Caused by Delayed BortezomibAdministration” in Journal of Immunology.
It was shown that the proteasomeinhibitor, bortezomib, administered immediately following allogeneic bonemarrow transplantation resulted in marked inhibition of acute graft-versus-hostdisease (aGVHD), with retention of graft-versus-tumor effects. However,continuous bortezomib administration resulted in significant acceleration ofgraft-versus-host disease–dependent morbidity. We carried out studies todissect the mechanisms of aggravated aGVHD caused by delayed bortezomibadministration. First, we demonstrated that IL-1b was critically involved, andthe subsequent aGVHD could be alleviated by IL-1b blockade. Bortezomibtreatment after dendritic cell (DC) activation resulted in drastically elevatedIL-1b production, whereas bortezomib treatment before DC activation inhibitedIL-1b production, suggesting that the timing of bortezomib administrationsignificantly affected IL-1b production by DCs. We further demonstrated thatdelayed administration of bortezomib accelerated aGVHD through TLR4 signaling.Because the LPS levels were much lower with reduced-intensity conditioningcompared with high-dose irradiation, the accelerated graft-versus-hostdisease–dependent morbidity with delayed bortezomib administration could berescued by reduced-intensity conditioning. Our studies suggested that TLR4pathway activation and delayed bortezomib administration amplified theproduction of IL-1b and other inflammatory cytokines, which resulted inaccelerated aGVHD-dependent morbidity. These results indicated that decreasedtoxicity of continuous bortezomib administration could be achieved byreduced-intensity conditioning or by inhibiting IL-1b.
Dr. Yong Liang and ShoubaoMa are the first authors of the paper. Contributing author are Yanming Zhang, Ying Wang, Qiao Cheng, Yan Wu, Yue Jin,Donghui Zheng and Depei Wu. Prof. Haiyan Liu is thecorresponding author of the paper. This work was supported by grantsfrom the National Natural Science Foundation of China (91029703, 81072436, and81273268), project funding from Suzhou City (SS201032 and SZS201109), a projectfunded by Priority Academic Program Development of Jiangsu Higher EducationInstitutions, a Qing Lan project of Jiangsu Province, the Jiangsu ProvincialInnovative Research Team, and the Program for Changjiang Scholars andInnovative Research Team in University (IRT1075).