A Cosmetic Product Containing PEG Derivatives Induces Anti-PEG IgM Mainly through Stimulation of the Spleen Cells in Mice

Abstract

Polyethylene glycol (PEG) is widely utilized in pharmaceuticals and cosmetics as a safe and less- or nonimmunogenic synthesized biocompatible polymer. However, the increasing detection of pre-existing anti-PEG antibodies in untreated individuals has raised concerns that daily exposure to PEG derivatives through cosmetics could induce immune responses against PEG. We have shown that daily topical applications of this type of cosmetic product cause anti-PEG IgM production in normal mice, and the efficacy of PEGylated therapeutics was suppressed by this induced anti-PEG IgM. In this study, the mechanism underlying anti-PEG IgM production caused by topical applications of a cosmetic product containing PEG derivatives, which are yet to be identified, was investigated in mice. Daily applications of such a cosmetic product to the compromised skin of mice elicited anti-PEG IgM production. Splenectomy, performed before the topical applications, markedly suppressed the anti-PEG response. In addition, when splenectomy was carried out after 14 days of daily topical applications, there was a remarkable decline in the anti-PEG IgM response that had already been induced. In this study, however, splenectomy completely diminished neither anti-PEG IgM production nor pre-existing anti-PEG IgM titers. Although immunodeficient C.B-17/Icr-scid/scid (SCID) mice caused no anti-PEG IgM production, the adoptive transfer of splenocytes obtained from normal mice to SCID mice restored the anti-PEG response to daily topical applications of this cosmetic product. Furthermore, anti-PEG IgM production was observed in T cell-deficient BALB/cAJcl-nu/nu (BALB/c-nu) mice. In the lymph node-deficient ALY/NscJcl-aly/aly (aly/aly) mice, daily topical applications of this cosmetic product also caused anti-PEG IgM production, but the titer was lower than that in normal mice. The results of this study show the spleen to be the primary contributor, while lymph nodes play a partial role, in the production of anti-PEG IgM via daily topical applications of this cosmetic product in a T cell-independent manner in mice. This study provides mechanistic insight into how daily topical exposure to PEG could lead to the formation of pre-existing anti-PEG IgM, which in turn would alter the pharmacokinetics and therapeutic efficacy of PEGylated therapeutics.