The long term objective of this research is to define the stepwise progression of T cell lymphomagenesis in the skin. For this purpose the model of lymphomatoid papulosis (LyP) has been identified. LyP is a recurrent eruption of skin lesions comprised of malignant appearing T cells. After many cycles of eruption and spontaneous regression, 10-20% of LyP patients develop malignant lymphoma, usually mycosis fungoides, Hodgkin's disease or large cell immunoblastic lymphoma. The similar morphologies, immunophenotypes, and in some cases genotypes of these lymphomas, and the cells which comprise LyP lesions indicate that lymphomas arising in LyP patients derive from clonal expansion and malignant progression of the atypical T lymphocytes present in precursor LyP skin lesions.
The first aim of this proposal will be to trace the clonal evolution of the atypical T cells in multiple LyP lesions over time and in LyP associated lymphomas. In LyP patients who develop lymphomas, the T cell antigen receptor (TCR) will be cloned from the lymphoma. Specific primers and polymerase chain reaction (PCR) will be used to identify and quantitate the lymphoma specific TCR from earlier, concurrent and later LyP lesions. In patients who do not develop lymphoma, the clonality of the atypical LyP cells will similarly be assessed by TCR amplification and cloning to determine if clonal progression occurs. The clonal evolution of T cells in LyP lesions will be correlated with clinical evidence of tumor progression.
Aim 2 will establish cell lines from cutaneous lesions at various steps in disease progression, characterizing, comparing and arranging them in a logical order such that the various steps leading to malignancy can be defined.
Aim 3 will address the hypothesis that regression of LyP lesions depends on the host immune response and that lymphoma supervenes when the clonal T cell population eludes or overwhelms the immune system. Tumor infiltrating lymphocytes (TILs) will be identified and compared in regressing LyP lesions and subsequent or coexistent lymphomas with the long term goal of testing cytotoxicity of clonal TILs against autologous tumor cells. This cutaneous model will help to clarify early stages of lymphomagenesis, hopefully leading to novel approaches for prevention, earlier diagnosis, and specific therapy of malignant lymphomas.
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