T-Cell Responses to Tyrosinase-Derived Self-Peptides in Patients with Leukoderma Induced by Rhododendrol: Implications for Immunotherapy Targeting Melanoma

Takagi, Ryukichi; Kawano, Masaaki; Nakamura, Koichiro; Tsuchida, Takaaki; Matsushita, Sho

doi:10.1159/000441217

Cited by 5 publications

(9 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of the immune system against melanocytes is proposed to be a cause of RD-induced leukoderma, because the immunosuppressant FK506 can partially restore melanin synthesis in human patients (Suzuki et al, 2014;Takagi et al, 2016), despite the lack of effect of FK506 on our zebrafish model (data not shown). The transplantation of mouse melanoma B16F10 cells that had been pretreated with RD produces hypopigmented hairs in host mice, suggesting the involvement of acquired immune responses against melanocytes (Takagi et al, 2016).…”

Section: Discussionmentioning

confidence: 81%

Zebrafish as a new model for rhododendrol‐induced leukoderma

Hayazaki

Hatano

Shimabayashi

et al. 2021

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

Rhododendrol (RD: 4-(4-Hydroxyphenyl)-2-butanol) is a melanogenesis inhibitor isolated from the stem bark of Acer nikoense MAXIM.Since RD is structurally similar to L-tyrosine, it competitively inhibits tyrosinase, a rate-limiting enzyme for melanin synthesis (Akazawa et al., 2006). RD was approved as an ingredient in cosmetics for skin lightening in Japan in 2008; however, 5 years later, cosmetic products containing RD were recalled because of the development of depigmentation (idiopathic leukoderma or vitiligo) in the skin. The total number of patients with leukoderma caused by RD was 19,605, accounting for 2%-2.5% of users of the RD-included cosmetic products (Nishigori et al., 2015). Although the symptoms of RD-induced leukoderma were improved or eliminated in 72% of patients, the remaining patients were resistant to conventional therapy (Watabe et al., 2018).A study with cultured melanocytes has reported that tyrosinase converts RD to cytotoxic metabolites, such as RD-catechol and RD-cyclic catechol, which cause melanocyte-specific cell death

show abstract

Section: Discussionmentioning

confidence: 81%

Zebrafish as a new model for rhododendrol‐induced leukoderma

Hayazaki

Hatano

Shimabayashi

et al. 2021

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

show abstract

“…In severe cases, auto‐immune reaction might be a key factor. Takagi et al reported that antibodies to tyrosinase were involved in RIL based on a study using peripheral blood of the patients. Thus, there is a possibility that auto‐immune reaction targeting degenerative melanosomes may lead to subsequent changes in certain conditions and/or patients.…”

Section: Discussionmentioning

confidence: 99%

Leukoderma induced by rhododendrol is different from leukoderma of vitiligo in pathogenesis: A novel comparative morphological study

et al. 2018

View full text Add to dashboard Cite

Background Rhododendrol (rhododenol), an inhibitor of tyrosinase activity, is used as a skin‐whitening component. Many cases of leukoderma after the application have been reported, termed rhododenol‐induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. Methods We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, six cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. Results There were common findings in RIL and vitiligo at the light‐microscopic level: (a) vacuolar changes in the dermo‐epidermal junction, (b) melanophages in the papillary dermis, (c) perifollicular lymphocyte infiltration, (d) loss or decrease of basal melanin pigment and (e) decrease of melanocytes in the lesions. The ultrastructural observations showed specific findings of RIL: (a) remaining melanocytes in depigmented lesions, (b) inhomogeneous melanization in melanocytes and (c) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. Conclusion Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.

show abstract

“…Tyrosinase peptide‐specific cytotoxic T cells have been suggested to be involved in a melanocyte‐specific cytotoxic mechanism. 26 When T‐cell lines were established from peripheral blood monocytes derived from eight patients with RDL (seven of whom were HLA‐DR4 + ), a tyrosinase peptide‐specific T‐cell response, restricted to major histocompatibility complex (MHC) classes I and II, was observed. It is assumed that the antigenicity of tyrosinase peptide is altered to a non‐natural form upon binding to RD (a concealed antigen), and MHC‐restricted cytotoxic T cells may specifically attack melanocytes in the presence of RD.…”

Section: Mechanism Of Rdl Developmentmentioning

confidence: 99%

“…It is assumed that the antigenicity of tyrosinase peptide is altered to a non‐natural form upon binding to RD (a concealed antigen), and MHC‐restricted cytotoxic T cells may specifically attack melanocytes in the presence of RD. 26 However, there remain certain unresolved issues, particularly with respect to the limited number of cases, and it is unknown whether the concealed tyrosinase antigen is actually presented on melanocytes. In addition, the relationship between leukoderma symptoms and tyrosinase reactivity remains poorly understood.…”

Section: Mechanism Of Rdl Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Rhododendrol‐induced leukoderma update II: Pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments in comparison with vitiligo

Inoue

Katayama

Suzuki

et al. 2021

The Journal of Dermatology

View full text Add to dashboard Cite

A small proportion of individuals utilizing cosmetics containing rhododendrol developed leukoderma with various pathological conditions, in some cases indistinguishable from vitiligo. In this review, we investigate and evaluate the major considerations for developing rhododendrol‐induced leukoderma based on data from original or review articles published in the literature to provide a wide range of information regarding the pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments. We compile and discuss the latest information, including data related to the cytotoxicity of rhododendrol, cytoprotective functions, and involvement of the immune system, and consider the possibility of novel treatments based on the differences between individual patients and on the mechanism underlying the onset of the condition. Understanding the pathophysiology of rhododendrol‐induced leukoderma helps not only elucidate the mechanisms of non‐segmental vitiligo onset and progression, but also suggests prevention and treatment.

show abstract

T-Cell Responses to Tyrosinase-Derived Self-Peptides in Patients with Leukoderma Induced by Rhododendrol: Implications for Immunotherapy Targeting Melanoma

Cited by 5 publications

References 14 publications

Zebrafish as a new model for rhododendrol‐induced leukoderma

Zebrafish as a new model for rhododendrol‐induced leukoderma

Leukoderma induced by rhododendrol is different from leukoderma of vitiligo in pathogenesis: A novel comparative morphological study

Rhododendrol‐induced leukoderma update II: Pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments in comparison with vitiligo

Contact Info

Product

Resources

About