Suppression of the immune response against exogenous desmoglein 3 in desmoglein 3 knockout mice

An implication for gene therapy

Manabu Ohyama, Takayuki Ota, Miyo Aoki, Kazuyuki Tsunoda, Reiko Harada, Shigeo Koyasu, Takeji Nishikawa, Masayuki Amagai

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Gene therapies for recessive genetic diseases may provoke unwanted immune responses against the introduced gene product because patients, especially those with null mutation of a certain protein, have no tolerance for the protein of interest. This study used desmoglein 3 knockout (Dsg3-/-) mice as a disease model for a genetic defect in DSG3, to investigate whether nonviral gene therapy induces an immune response against Dsg3 and whether the reaction against Dsg3 can be prevented. When mouse Dsg3 cDNA was injected in the skin of Dsg3-/- mice, 50% of treated Dsg3-/- mice developed anti-Dsg3 IgG, which can bind native Dsg3 in vivo. To prevent this response, we used an anti-CD40L monoclonal antibody, MR1, which blocks the costimulatory interaction between CD40 and CD40L. To evaluate the effect of MR1, we grafted Dsg3+/+ skin on Dsg3-/- mice, to mimic stable gene transfer of Dsg3. After skin grafting, all the recipient Dsg3-/- mice were treated with either MR1 (n=8) or control hamster IgG (n=8). All of the control IgG-treated mice developed circulating anti-Dsg3 IgG about 2 wk after grafting, and IgG deposition was observed on the surfaces of keratinocytes in the grafted Dsg3+/+ skin. Such anti-Dsg3 IgG production was significantly prevented, however, when the recipient mice were treated with MR1. These findings suggested that gene therapies for recessive diseases may provoke an immune response against the transgene product, and that the CD40-CD40L interaction might be a reasonable target for effective prevention of such undesirable immune responses, leading, in turn, to a successful gene therapy.

Original languageEnglish
Pages (from-to)610-615
Number of pages6
JournalJournal of Investigative Dermatology
Volume120
Issue number4
DOIs
Publication statusPublished - 2003 Apr 1

Fingerprint

Desmoglein 3
Gene therapy
Knockout Mice
Genetic Therapy
Immunoglobulin G
CD40 Ligand
Skin
Inborn Genetic Diseases
Skin Transplantation
Genetic Models
Gene transfer
Transgenes
Keratinocytes
Cricetinae
Genes
Proteins
Complementary DNA
Monoclonal Antibodies
Mutation
Defects

Keywords

  • CD154
  • CD40 ligand
  • Immunosuppression
  • Recessive genodermatosis
  • Skin graft

ASJC Scopus subject areas

  • Dermatology

Cite this

Suppression of the immune response against exogenous desmoglein 3 in desmoglein 3 knockout mice : An implication for gene therapy. / Ohyama, Manabu; Ota, Takayuki; Aoki, Miyo; Tsunoda, Kazuyuki; Harada, Reiko; Koyasu, Shigeo; Nishikawa, Takeji; Amagai, Masayuki.

In: Journal of Investigative Dermatology, Vol. 120, No. 4, 01.04.2003, p. 610-615.

Research output: Contribution to journalArticle

Ohyama, Manabu ; Ota, Takayuki ; Aoki, Miyo ; Tsunoda, Kazuyuki ; Harada, Reiko ; Koyasu, Shigeo ; Nishikawa, Takeji ; Amagai, Masayuki. / Suppression of the immune response against exogenous desmoglein 3 in desmoglein 3 knockout mice : An implication for gene therapy. In: Journal of Investigative Dermatology. 2003 ; Vol. 120, No. 4. pp. 610-615.
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