We have continued to focus our studies on 1) the development of a model that may provide insights into mechanisms involved in autoimmune reactions in skin and in the maintainance of tolerance to epidermally-derived proteins, 2) begun working on a mouse model in which a cytokine storm occurs and 3) determining the role of CD8+ T cells in tumor progression when mice are experienceing a graft vs. host-like diseases (GvHD). The major project that we are pursuing involves the characterization of a model of skin autoimmunity and peripheral immunological tolerance induction. We have developed transgenic mice that have a K14-ovalbumin (K-14 OVA) encoding gene. Some of the mice express the OVA on the epithelial cell surfaces (K14-mOVA) while others express soluble OVA (K14-sOVA). We are studying these mice and have also crossed these mice with those that have a TCR transgene that recognizes ovalbumin in association with H-2b (OT-I). These mice have the TCR for ovalbumin and express ovalbumin in the epidermis but have no apparent disease. We are also using the K-14 OVA mice as targets for immunological reactions in the skin. When T cells from OT-I mice are injected into either the single Tg mice or the double Tg mice their role in causing inflammatory skin lesions has been assessed. We have found that the OT-I CD8+ T cells induce a GvHD-like disease in the single Tg (k14-mOVA) mice....this is characterized by swelling of the feet from days 6-14 and development of redness and scaling of the skin within 7 days. The mice lose weight and die between weeks 2 and 3. The mice probably die because of a mucositis (tongue and esophagus)-they are unable to eat properly. In sharp contrast, the double Tg (K14-mOVA X OT-I) mice, despite their expressing OVA in the skin, are unaffected when the OT-I CD8+ T cells are injected into them. One of the aims of our current studies is to better understand why there is tolerance in these double Tg mice. We have identified IL-15 as a critical molecule that is involved in the GvHD reactions. From these studies, using microarray technology, we have identified a transcription factor, IRF8, that is a potentially important molecule in the CD8 OT-I cells that induce disease. We are currently functionally characterizing this transcription factor in CD8+ cells. We have also continued our studies of K14-OVA mice that produce soluble OVA (K14-sOVA). When OT-I cells are injected into these mice, almost all mice die after 5-7 days. and this is due to an acute mucositis and esophagitis. We are currently studying the mechanism by which this destruction takes place. We found that K14-sOVA crossed with OT-I mice die within 15-21 days of birth. The cause of death is probably due autoreactivity of OT-I cells that have not been deleted by the thymus. Recent studies have shown that we can obviate death by injecting the relevant peptide (SIINFEKL) on days 5 and 9 to these double transgenic mice. Thus, while all of these double transgenic mice die within 21 days if PBS is injected on days 5 and 9 of birth, about 80% survive if 100 micrograms of peptide is injected on days 5 and 9. The mechanism by which these peptides protect the double Tg mice continues to be studied- findings to date suggest that there is a depletion of CD8 cells in these mice and these CD8 T cells express many fewer CD8 molecules than do the double Tg mice that die. There is also downregulation of the V alpha chain of the TCR on these CD8+ T cells. Furthermore, CD8 T cells from healthy (treated) mice were anergic and could not be activated by exogenous IL-2. A block in IL-2/IL-7 signaling via the STAT5 pathway provided the basis for low surface expression of the CD8 coreceptor and failure of IL-2 to break CD8 T cell anergy. Thus, the soluble TCR ligand triggered multiple tolerance mechanisms in these sOVA/OT-I mice, making this treatment approach a potential paradigm for modulating human autoimmune diseases. These same SIINFEKL peptides obviate the intense inflammatory reaction (total obliteration of ears) that occurs when trangenic sOVA mice are crossed with OT-I mice. We have also embarked on studies that test the role of OT-I cells in mOVA Tg mice that are carrying OVA-expressing tumors and are then adoptively transferred with OT-I cells. Preliminary studies indicate that the OT-I cells obliterate the tumor and/or growth is markedly attenuated. Finally, we have had some success in developing a mouse model of cytokine storm that closely resembles what happens in human beings. This model involves the injection of the SIINFEKL peptide into OT-I mice that have a TCR that recognizes this peptide in association with class I MHC molecules. We are going to try to understand the mechanisms underlying this reaction and to develop agents that can block the reaction.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Clinical Sciences
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Miyagawa, Fumi; Zhang, Hong; Terunuma, Atshushi et al. (2012) Interferon regulatory factor 8 integrates T-cell receptor and cytokine-signaling pathways and drives effector differentiation of CD8 T cells. Proc Natl Acad Sci U S A 109:12123-8
Paek, So Yeon; Miyagawa, Fumi; Zhang, Hong et al. (2012) Soluble peptide treatment reverses CD8 T-cell-induced disease in a mouse model of spontaneous tissue-selective autoimmunity. J Invest Dermatol 132:677-86
Paek, So Yeon; Steinberg, Seth M; Katz, Stephen I (2011) Remission in dermatitis herpetiformis: a cohort study. Arch Dermatol 147:301-5
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Takeuchi, Satoshi; Yasukawa, Fumiko; Furue, Masutaka et al. (2010) Collared mice: a model to assess the effects of scratching. J Dermatol Sci 57:44-50
Miyagawa, Fumi; Gutermuth, Jan; Zhang, Hong et al. (2010) The use of mouse models to better understand mechanisms of autoimmunity and tolerance. J Autoimmun :
Kim, Brian S; Miyagawa, Fumi; Cho, Young-Hun et al. (2009) Keratinocytes function as accessory cells for presentation of endogenous antigen expressed in the epidermis. J Invest Dermatol 129:2805-17
Gutermuth, Jan; Nograles, Kristine E; Miyagawa, Fumi et al. (2009) Self-peptides prolong survival in murine autoimmunity via reduced IL-2/IL-7-mediated STAT5 signaling, CD8 coreceptor, and V alpha 2 down-regulation. J Immunol 183:3130-8
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