Immunotoxicity
The use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to the lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials.
Using humanized mice, we evaluated and compared the effects of known immunotoxic biologics, Proleukin®/IL-2 and OKT3 to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research subjects and/or patients at risk. (Source: Yong et al. 2020. Front Immunol. 11:553362)
Proleukin®/IL-2 Induced Immunotoxicity
Figure. Humanized mice exhibit inflammatory responses when administered with Proleukin®/IL-2. (A) Adult HiMice were bled at 0 h to obtain peripheral blood mononuclear cells (PBMCs) and plasma for baseline analysis (n = 15). Each mouse was injected with 600,000 IU of Proleukin®/IL-2 daily for 5 days (n = 10). Mice were bled at 1h, 72h and sacrificed at 144 h to collect organs, PBMCs and plasma for analysis. (B) Histological analysis of organs from both saline treated (n = 5) and Proleukin®/IL-2 treated (n = 10) HiMice. Paraffin slides from indicated organs were processed and stained with H&E or anti-human CD45 antibody. Scale bar applies to all panels. (C) Human-specific cytokine and chemokine release of IL-18, IFN-γ, IL-10, IL-12p70, and IL-17A were measured in the plasma of HiMice administered with saline (n = 5) or Proleukin®/IL-2 (n = 10). Two-tailed Mann–Whitney U test; (*p < 0.05, **p < 0.01, ***p < 0.001). Source: Yong et al. 2020. Front Immunol. 11:553362.
OKT3 Induced Immunotoxicity
Pre-treatment with adalimumab resulted in lower levels of IFNg and IL-10 expression at 6 hours post-dosing of OKT3. Proportion of CD4, CD8 and CD4+ CD8+ cells in the blood of PBMC mice were changed from D23 (pre-OKT3 injection) and D30 (post-OKT3 injection).
Figure. PBMC-Humanized mice administered with 1mg of OKT3 exhibit heightened cytokine and chemokine production.
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