This laboratory studies the role of the skin as an immunological organ. We study the mechanisms involved in delayed type hypersensitivity (DTH) reactions in the skin and use this knowledge to better understand lymphocyte-mediated skin diseases. In the past year we have continued to focus our studies on 1) the development of a model that may provide insight into mechanisms involved in autoimmune reactions in skin and in the maintainance of tolerance to epidermally-derived proteins 2) the identification of the specific precursors of Langerhans cells and 3) understanding the very early molecular changes seen when allergic contactants are applied to skin,? ? The major project that we are pursuing involves the development 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. 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 TCD8+ T cells induce a GvHD-like disease in the single Tg 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 an esophagitis-they are unable to eat properly. In sharp contrast, the double Tg mice, despite their expressing OVA in the skin, are unaffected when the OT-I CD8+ T cells are injected into them. We are currently focussing our studies on understanding why there is tolerance in these double Tg mice. We have been unable to clearly delineate a CD4+CD25+ T regulatory cell in the double Tg mice but have recently identified a CD3+ double negative cell population in these mice and are focussing on the possibility that they are somehow serving as regulatory cells. We have also started focussing on K14-OVA mice that produce soluble OVA. When OT-I cells are injected into these mice, some (#%) mice die after 5-7 days. this is due to an acute mucositis and esophagitis. We are currently studying the mechanism by which this destruction takes place.? ? In other studies, we are trying to identify the specific precursors of Langerhans cells. To do this we are using X-irradiated bone marrow reconstituted mice and using A X B donors into A recipients. We are using various cell populations that are presorted to determine which ends up being a Langerhans cell. Furthermore, we are able to accelerate the repopulation of Langerhans cells in skin by using topical agents that promote the egress of host Langerhans cells from the skin. We have also used IL-7Recptor KO mice to determine the lymphoid dependence (or independence) of dendritic cells.? ? Finally, we are continuing studies started many years ago in trying to identify the earliest events in the generation of allergic contact sensitivity. We are doing this using gene array technology-taking epidermis shortly after painting with haptens and characterizing the cRNA that is derived from the epidermis.

National Institute of Health (NIH)
Division of Clinical Sciences - NCI (NCI)
Intramural Research (Z01)
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Clinical Sciences
United States
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