Induction of T‐cell‐mediated skin disease specific for antigen transgenically expressed in keratinocytes

Transgenic mice were generated to establish an animal model for T‐cell‐mediated autoimmune skin disease. A membrane‐bound form of OVA (mOVA) was specifically expressed under the control of thekeratin 5 (K5) promoter in the epidermal and hair follicular keratinocytes of mice. Syngeneic, wild‐type mic...

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Bibliographic Details
Published in:European journal of immunology 2003-07, Vol.33 (7), p.1879-1888
Main Authors: Azukizawa, Hiroaki, Kosaka, Hiroshi, Sano, Shigetoshi, Heath, William R., Takahashi, Isao, Gao, Xing‐Hua, Sumikawa, Yasuyuki, Okabe, Masaru, Yoshikawa, Kunihiko, Itami, Satoshi
Format: Article
Language:English
Subjects:
Animals
Cross‐priming
CTL
Keratinocyte
Keratinocytes - immunology
Lymph Nodes - immunology
Mice
Mice, Transgenic
OVA
Ovalbumin - genetics
Ovalbumin - immunology
Skin Diseases - immunology
Skin Transplantation - immunology
T-Lymphocytes - immunology
Transgenic
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Summary:Transgenic mice were generated to establish an animal model for T‐cell‐mediated autoimmune skin disease. A membrane‐bound form of OVA (mOVA) was specifically expressed under the control of thekeratin 5 (K5) promoter in the epidermal and hair follicular keratinocytes of mice. Syngeneic, wild‐type mice rejected the skin grafts of K5‐mOVA mice with the generation of OVA‐specific CTL. To study the CTL response against K5‐mOVA skin, we used OT‐I transgenic mice, which produce Kb‐restricted, OVA‐specific CD8+ T cells. Accelerated rejection of K5‐mOVA skin was demonstrated when transplanted onto OT‐I mice. Furthermore, OT‐I cells, when adoptively transferred into K5‐mOVA mice, underwent activation and vigorous proliferation in the skin‐draining lymph nodes. A bone‐marrow‐reconstitution assay demonstrated that Kb presentation by bone‐marrow‐derived cells, but not epithelial cells, was required for this response, indicating that cross‐priming was the basis for immunity in this model. Finally, transferred OT‐I cells, activated by cross‐priming, targeted the skin of K5‐mOVA mice, resulting in development of skin lesions that were reminiscent of toxic epidermal necrolysis. We conclude that our system provides a useful model for autoimmune skin diseases and will aid understanding of the pathomechanism of drug eruption, viral exanthema, and graft‐versus‐host disease.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200323630