Here, to the best of our knowledge, we first established that IVIg exerts suppressive effects on both PIPN and DIPN. Briefly, we have shown that IVIg suppresses PIPN and DIPN via macrophage modulation using rats or mice. Meregalli et al. reported that IVIg exerts a similar effect on bortezomib-induced peripheral neurotoxicity 11. These results indicate that IVIg could have a suppressive effect on peripheral neurotoxicity caused by anticancer drugs (regardless of drug types, such as platinum compounds, antitubulins, thalidomide, and bortezomib) 1,2. However, the mechanism of CIPN induction varies with the anticancer drug. Thus, IVIg does not directly interfere with anticancer drugs and may act on a factor, which is common in the CIPN pathway.
If IVIg can be proven to suppress CIPN, it can be used in combination with anticancer drugs that are effective in patients with CIPN. As IVIg does not cause serious adverse effects and is a multifunctional drug, combination therapy is a rational strategy. Moreover, IVIg is a polyclonal preparation comprising antibodies pooled and concentrated from the plasma of thousands of healthy individuals. Thus, they are highly effective as an immune replacement therapy in immunocompromised patients with cancer receiving chemotherapy. Therefore, IVIg administration could prove beneficial owing its dual roles of suppressing CIPN and alleviating immune deficiency caused by chemotherapy.
Notably, our results showed that in the absence of macrophages, IVIg loses its CIPN-suppressive effect. Macrophages are the key coordinators of the immune system. Furthermore, IVIg can normalize immune system-related abnormalities. Thus, we speculate that the immunomodulatory effects of IVIg are mediated by macrophages. Although the development of PIPN after macrophage depletion remains unclear, it is possible that in our study, clodronate failed to completely deplete the macrophages in the peripheral neurons; therefore, further exploratory investigations are required. Moreover, the subset of macrophages essential for IVIg action may differ from those required for the onset of PIPN. Nevertheless, based on our results, we can conclude that macrophages are essential for IVIg action.
Our study outcomes emphasize a strong relationship between IVIg action and macrophages. Interestingly, we also confirmed the same phenomenon in a model of recurrent miscarriage, a condition completely different from CIPN. In a model of recurrent miscarriage 16 depleting macrophages eliminated the effect of IVIg (Supplementary Fig. 1). Thus, the action of IVIg may not change with the model. Moreover, in our previous study in a mouse model of chronic inflammatory demyelinating polyneuropathy, we found that IVIg can modulate macrophage levels 17. IVIg reportedly exhibits immunostimulatory effects in infectious diseases and an immunosuppressive effect in autoimmune diseases. These seemingly contradictory effects can be explained by understanding how IVIg modulates macrophages, which are the key coordinators of the immune system. Thus, IVIg may act by normalizing the immune system via macrophage modulation. Thus, our study provides new insights to elucidate the mechanisms underlying the dual roles of IVIg.
Here, we demonstrated two distinct and important possibilities of therapeutic application of IVIg suppression in CIPN. First, we found that IVIg acts on macrophages to normalize immunity. Thus, our study further validates that macrophages could be a new target for the development of novel multifunctional drugs. Second, our results showed that a combination therapy may be developed using IVIg to treat cancer and reduce adverse effects. To date, all studies in this field have focused on the direct effects of drugs on cancer. The range of cancer therapy will expand in the future if IVIg is found useful in combination therapy with drugs that are effective in combating cancer. We expect to examine this possibility in the future to expedite therapeutic strategies for cancer patients.
Finally, our data will help to elucidate the action mechanism of IVIg, and its future therapeutic applications. Moreover, to our knowledge, the current therapeutic guidelines for CIPN do not include IVIg therapy. In the present study, we conducted experiments only on rodents, but further studies in other animals are needed to verify the effectiveness of IVIg therapy in alleviating CIPN, and our study emphasizes this urgent need.