Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model

Miyo Aoki-Ota, Mari Kinoshita, Takayuki Ota, Kazuyuki Tsunoda, Toshiro Iwasaki, Sigeru Tanaka, Shigeo Koyasu, Takeji Nishikawa, Masayuki Amagai

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Abstract

Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies against desmoglein 3 (Dsg3). We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from Dsg3 -/- mice. The purpose of this study was to determine the role of CD40/CD154 interaction in the pathogenic antibody production and development of the disease in PV model mice. When anti-CD154 monoclonal antibody (mAb) was administered to recipient mice prior to adoptive transfer, anti-CD154 mAb almost completely blocked the anti-Dsg3 IgG production and prevented blister formation. The blockade of CD40/CD154 interaction induced tolerance against Dsg3 as the suppression of antibody production was observed through day 70, and it was maintained even after challenge by immunization with recombinant mouse Dsg3 or by adoptive transfer of immunized Dsg3-/- splenocytes. Furthermore, the tolerance to Dsg3 was transferable because cotransfer of splenocytes from anti-CD154 mAb-treated mice and naïve Dsg3-/- splenocytes significantly suppressed anti-Dsg3 IgG production in recipient mice. In contrast, when anti-CD154 mAb was injected after the mice had developed the PV phenotype, no significant suppression of the production of anti-Dsg3 IgG was observed. These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti-Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases.

Original languageEnglish
Pages (from-to)105-113
Number of pages9
JournalJournal of Investigative Dermatology
Volume126
Issue number1
DOIs
Publication statusPublished - 2006 Jan

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Desmoglein 3
Pemphigus
Immunoglobulin G
Monoclonal Antibodies
Adoptive Transfer
Autoimmune Diseases
Antibody Formation
Antibodies
Immunization
Blister
Autoantibodies

ASJC Scopus subject areas

  • Dermatology

Cite this

Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model. / Aoki-Ota, Miyo; Kinoshita, Mari; Ota, Takayuki; Tsunoda, Kazuyuki; Iwasaki, Toshiro; Tanaka, Sigeru; Koyasu, Shigeo; Nishikawa, Takeji; Amagai, Masayuki.

In: Journal of Investigative Dermatology, Vol. 126, No. 1, 01.2006, p. 105-113.

Research output: Contribution to journalArticle

Aoki-Ota, Miyo ; Kinoshita, Mari ; Ota, Takayuki ; Tsunoda, Kazuyuki ; Iwasaki, Toshiro ; Tanaka, Sigeru ; Koyasu, Shigeo ; Nishikawa, Takeji ; Amagai, Masayuki. / Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model. In: Journal of Investigative Dermatology. 2006 ; Vol. 126, No. 1. pp. 105-113.
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