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S. Rathod et al.
ways of ASNase-induced hypersensitivity are clinically relevant in humans. Furthermore, while our results sug- gest that ASNase hypersensitivities can be masked by pre- treatment with antihistamine and a PAF receptor antago- nist, any pretreatment medication to mitigate ASNase hypersensitivity in patients must ensure that adequate drug levels are achieved to avoid the possibility of mask- ing the hypersensitivity without achieving therapeutic ASNase drug levels.
The onset of ASNase hypersensitivities in our model requires two ASNase doses to sensitize mice before hypersensitivity reactions can be induced (Online Supplementary Figure S9D), likely due to the non-detectable levels of anti-ASNase IgG or IgE antibodies measured through Day 23 of our protocol (Figure 1D). Nevertheless, ASNase hypersensitivities were induced 10 days after the last sensitization dose (Day 24, Figure 4A), which corre- lates with the detection of high anti-ASNase antibody lev- els (Figure 1D).21 A similar correlation exists between anti- ASNase IgG levels and the onset of clinical ASNase hyper- sensitivities.2 Murine hypersensitivity reactions can be monitored via a decrease in core body temperature due to the increased permeability of vascular endothelium that is induced by histamine and other mast cell-produced vasoactive mediators.20,26,37-39 Increased endothelial perme- ability results in vascular fluid leak and hypovolemia, which causes shock that is most easily detected as hypothermia.40,41 Other markers of anaphylaxis include decreased physical activity, increased plasma levels of degranulation products (e.g., mMCP-1), and hemoconcen- tration (increased hematocrit levels) due to vascular leak- age.20,42 Our study detected hypersensitivities via the development of hypothermia and the release of mMCP-1. Previous studies on ASNase hypersensitivity have demon- strated a correlation between the dose of ASNase, the severity of ASNase hypersensitivity, and the levels of mMCP-1 released, supporting that our methods accurate-
ly measure the onset, severity, and extent of hypersensi- tivity.21
Our data support a hypothesis that the mechanism of ASNase-mediated hypersensitivity involves antigen-specif- ic IgG and/or IgE and the immunoglobulin receptors FcγRIII and/or FcεRI. Our results also indicate that both mecha- nisms can simultaneously or independently contribute to the onset and extent of ASNase hypersensitivity. We show that cells expressing FcγRIII and FcεRI can bind ASNase ex vivo and, therefore, it is likely that multiple cells play a role during the onset of hypersensitivity reactions, including mast cells, which are not present in systemic circulation. Our study has several possible clinical implications regard- ing predicting, overcoming, and preventing ASNase hyper- sensitivities. The ex vivo binding of ASNase to basophils cor- relates with the onset of ASNase hypersensitivity reactions, suggesting that ASNase binding to basophils may be a use- ful biomarker of ASNase hypersensitivity regardless of whether anaphylaxis is mediated by the classical and/or alternative pathway. Similarly, the ASNase BAT can detect IgE/FcεRI- or IgG/FcγRIII-dependent basophil activation in our study; however, human markers of IgG/FcγR-mediated basophil activation are not available. In addition, our results suggest that both PAF and histamine are important media- tors of ASNase hypersensitivity and that receptor antago- nists of these molecules may be able to block the clinical manifestation of ASNase hypersensitivity. Future research will attempt to demonstrate the specificity and sensitivity of both basophil binding and basophil activation by ASNase for predicting ASNase hypersensitivity and verify the possibility of the alternative pathway of ASNase hyper- sensitivity in humans.
Funding
This study was supported by the University of Pittsburgh School of Pharmacy and NIH Grants RO1 CA216815 and CA142665.
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