October 21 2019
We would like to inform you that the 60th IRCMS Seminar has been scheduled as below. We would be pleased to see many of you participating in the seminar.
Date : November 13, 2019 (Wednesday)
Time : 15:00-16:00
Venue : IRCMS 1F Meeting Lounge
Speaker : Gang Huang, Ph.D.
Divisions of Pathology and Experimental Hematology and Cancer Biology,
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
(Visiting Professor, IRCMS)
Tilte :Two Drops of the Cytokine Storm in HLH
Hemophagocytic lymphohistiocytosis (HLH) is a heterogenous disease with hyperinflammatory responses caused by overactivated macrophages and cytotoxic T cells. Significantly elevated serum IL-18 and IL-10 are hallmarks of secondary HLH patients. This study aims to understand the pathophysiological roles of these two cytokines in vivo in transgenic models. First, we generated transgenic mouse models which overexpress murine IL-18 and IL-10 simultaneously (Mx1CreH11LSL-Il18-2a-Il10/wt) or IL-18 alone (Mx1CreH11LSL-Il18-2a/wt) driven by hematopoietic cell specific Mx1-Cre.
ELISA showed a 26-fold increase for IL-18 and an 85-fold increase for IL-10 in the serum of Mx1CreH11LSL-Il18-2a-Il10/wt model mice compared to controls. These mice presented severe pancytopenia, anemia and splenomegaly. Disease progressed rapidly with a median survival of 58 days. We found a significant number of hemophagocytes in the bone marrow and spleens of these mice. Importantly, no signs of HLH symptoms were detected in the Mx1CreH11LSL-Il18-2a/wt mice. These mice had a 10-fold increase in serum IL-18 but unaltered CBC and spleen size, suggesting a cooperative role for IL-18 and IL-10 in HLH development. Since inflammasome and caspases activation, which are physiologically inhibited by Xiap, are required for the cleavage of pro-IL-18, we further bred Mx1CreH11LSL-Il18-2a-Il10/wt mice with Xiap-/y mice to enhance the level of serum IL-18. Indeed, the Mx1CreH11LSL-Il18-2a-Il10/wtXiap-/y model, with 100-fold increases of both cytokines, presented more severe HLH including shorter survival (median 41 days) and higher frequency of hemophagocytes in tissues. Thus, IL-10 cooperates with IL-18 to drive HLH. These models will be useful for understanding HLH pathophysiology and developing novel therapies.