Autoimmune vitiligo as a roadmap to melanoma therapy

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DESCRIPTION (provided by applicant): In autoimmune vitiligo, melanocytes are destroyed by cytotoxic T cells that recognize melanocyte differentiation antigens including MART-1 and gp100. This leads to progressive depigmentation of the skin and hair. However debilitating and cosmetically disfiguring this disease may be, the effective immune response underlying the depigmentation process is very desirable for melanoma patients. In malignant melanoma, T cells infiltrating the tumors frequently recognize the same differentiation antigens involved in vitiligo, yet the anti-tumor immune response that is mounted seldom leads to actual tumor regression and if it does, such tumor regression can be accompanied by progressive depigmentation of the skin (leukoderma) as well. This difference among T cell reactivity in vitiligo and melanoma is potentially a consequence of clonal deletion of T cells responding to self-antigens in the case of melanoma, whereas high affinity T cells are aberrantly introduced into the circulation in autoimmune vitiligo. The main hypothesis to be tested is that T cells derived from skin of actively depigmenting patients are more reactive towards melanocytic cells than T cells derived from melanoma tumors, and that such enhanced efficacy can be ascribed at least in part to the expression of higher affinity T cell receptors. To test this hypothesis, T cells will be isolated from either source, propagated and cloned, the target antigens identified (focussing on gp100 and MART-1) and subjected to functional assays. The T cell receptor genes from HLA-A*0201 restricted clones reactive with gp100 or MART-1 will be cloned into retroviral vectors and expressed against the same background (in Jurkat cells) for further characterization of the relative contribution of the TCR to differential reactivity. Finally, differential T cell avidity will be put to the test in an In Vivo model. High affinity T cell receptor genes will be expressed in patient PBL and introduced into immunodeficient mice challenged with melanoma tumor cells from the same patient. Tumor shrinkage will be measured and part of the tissue will be analyzed by immunohistology. The current project will provide insight into the burning question of factors defining an efficient immune response to melanocytic cells in vitiligo that is not encountered in melanoma. Importantly, the cloning of high affinity T cell receptors in retroviral vectors may be suitable for introduction into patient PBL for treatment of malignant melanoma.