**5. Concluding Remarks**

It is not easy to assign a particular pathogenic role to the secreted HRF molecules separate from the intracellular TCTP molecules. Targeting HRF is a promising approach toward prevention of allergic diseases such as food allergy and asthma [24,30,65]. However, all of the current HRF inhibitors have ye<sup>t</sup> to be fully characterized as therapeutic agents. It is highly desirable to gain both pharmacological and genetic evidence before the field moves to clinical trials of candidate HRF inhibitors. However, genetic studies without a ffecting the function of intracellular TCTP are di fficult if an experiment is conducted with TCTP conditional knockout (CKO) mice, including inducible CKO mice [40,66]. It is likely that the targeted cells may die because of their dependence of survival on TCTP. With such limitations, RNA interference (siRNA or shRNA) may be better suited to in vitro and in vivo experiments [66]. An alternative approach is to use heterozygous TCTP KO mice. Indeed, Pinkaew et al. showed that atherosclerotic lesions in TCTP+/−Ldlr−/−Apobec1−/− mice contain fewer macrophages and more apoptotic cells compared to TCTP+/+Ldlr−/−Apobec1−/− mice [67]. Transgenic overexpression may also be useful for analysis of HRF. Yeh et al. generated an inducible transgenic mouse model with HRF targeted to lung epithelial Clara cells [68]. They showed that HRF exacerbates the allergic asthmatic responses, although it is not clear whether secreted HRF was responsible for the worsened phenotype. Despite these obstacles, HRF inhibitors may be a promising approach toward preventing or treating food allergy and other IgE/HRF-dependent allergic diseases.

**Author Contributions:** Y.K. and K.K. drafted the manuscript. T.K. and Y.K. finished it.

**Funding:** This study was supported in part by grants from the US National Institutes of Health (HL124283, AI124734 and AI146042).

**Conflicts of Interest:** The authors declare no conflict of interest.
