As an outgrowth of the longstanding interest of this laboratory in identifying antigens recognized on melanoma tumors by T cells from patients with this disease, we have discovered that many such antigens are expressed in melanocytes and concerned with pigment production. This observation is also intriguing because skin depigmentation due to melanocyte destruction often accompanies spontaneous or immunotherapy based remission from melanoma. In addition, T cells directed against some of these antigens have been found in the skin of patients with autoimmune skin depigmentation (vitiligo). We have recently developed a preclinical model using transgenic mice expressing a human class I MHC molecule and a peptide Ag derived from murine tyrosinase (Tyr369) that is highly homologous to its human counterpart and presented by HLA-A*0201. We have also developed transgenic mice that express T cell receptors specific for this tyrosinase epitope, and have observed that, despite the occurrence of some level of self-tolerance, the animals develop a progressive vitiligo that shows both regional localization and bilateral symmetry. These characteristics are similar to those observed in patients with generalized vitiligo. This represents a unique model in which to examine several factor that contribute to the development of vitiligo, including the nature of the immunological effector cells, the mechanisms they use to cause melanocyte destruction, and the factors that cause such cells to enter the skin. It is our expectation that this work will illuminate mechanisms that are relevant to an understanding of other skin-based autoimmune and inflammatory conditions. In the context of this R21 application, our goals are to develop a basic understanding of facets of this model that will set the stage for a more comprehensive R01-based investigation.
The specific aims of this application are: To determine whether Tyr369-specific CD8 T cells are both necessary and sufficient for development of ear vitiligo in neonates and disseminated vitiligo in adults; To characterize the cellular infiltration of the skin associated with the development of vitiligo in neonatal and adult TCR transgenic mice; To examine the skin-associated homing mechanisms that may contribute to vitiligo development.
