Deciphering High-Dose IL-2 Toxicity in Reconstituted HIS Mice
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As HDIL2 side effects have been correlated with the Treg number in patients, the authors focused on this subpopulation in IL-2-treated HIS mice, and found that LDIL2 therapy increases Treg percentage, whereas HDIL2 therapy decreases the relative proportion of Treg (Fig. 2A). This decrease was associated with an increase in the number of effector cells (Foxp3-), an increase in IL‑6 and IL‑12 serum levels—known reducers of Treg function (Fig. 2B)—and a lower Treg-suppressive activity. To confirm the involvement of the observed compromised Treg homeostasis in HDIL2 toxicity, HDIL2-treated HIS mice were administered Kaempferol (Kem), an anti-inflammatory agent preserving Treg-suppressive function. Upon Kem treatment, Treg absolute numbers were increased, body weight loss was mitigated (Fig. 2C), and survival was improved (Fig. 2D). Additionally, serum levels of TNF and IFNɣ were decreased in Kem-treated HDIL2-HIS mice. These data suggest that Treg function is important to prevent immune system activation and the associated toxic side effects of IL-2 immunotherapy. This study shows that reconstituted HIS mice represent a useful and workable system to study and decipher human immune cell interactions in IL-2 immunotherapy. Of note, the reconstituted mouse preclinical model used in this study is available at genOway, designer and provider of multiple preclinical models in immuno-oncology.
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