| Project/Area Number |
10470189
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Keio University |
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Principal Investigator |
NISHIKAWA Takeji Keio Univ. School of Medicine, Dept.of Dermatology, Professor, 医学部, 教授 (50051579)
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| Co-Investigator(Kenkyū-buntansha) |
KOYASU Shigeo Keio Univ. School of Medicine, Dept.of Dermatology, Professor, 医学部, 教授 (90153684)
MASAYUKI Amagai Keio Univ. School of Medicine, Dept.of Dermatology, Assistant Professor, 医学部, 専任講師 (90212563)
SHIMIZU Hiroshi Keio Univ. School of Medicine, Dept.of Dermatology, Associate Professor, 医学部, 助教授 (00146672)
SUZUKI Harimi Keio Univ. School of Medicine, Dept.of Dermatology, Assistant Professor, 医学部, 専任講師 (70235985)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 1999: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 1998: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Keywords | Autoimmune diseases / Pemphigus / Animal model / Desmoglein / Tolerance / Autoantibody / B cell / Knochout mouse |
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| Research Abstract |
The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens. Knockout mice do not acquire tolerance of the defective gene product. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we established a method to generate an active disease model for this autoantibody-mediated disease. Dsg3ィイD1-/-ィエD1 mice, but not Dsg3ィイD1+/-ィエD1 littermates, produced anti-Dsg3 IgG that was able to bind the native Dsg3 when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3ィイD1-/-ィエD1 mice were then adoptively transferred into Rag-2ィイD1-/-ィエD1 immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for over 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3ィイD1-/-ィエD1 mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.
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