IMMUNOBIOLOGY OF CUTANEOUS T CELL LYMPHOMA

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Cutaneous T cell lymphoma (CTCL)is a malignancy of epidermotropic helper/inducer T lymphocytes which subsequently become systemically metastatic. In each individual patient, CTCL cells express a distinctive T cell receptor (TCR) for antigen which is simultaneously a marker of clonality, a tumor specific antigen and an historical link with the normal T cells from which they evolved. In this project, the features of CTCL TCRs will be exploited to achieve four interrelated goals. First, to increase sensitivity of diagnostic techniques and to obtain CTCL cells for in-depth studies, a two step approach will be taken. Peripheral blood and lymph node preparations will be substantially enriched for CTCL cells by fluorescence-activated cell sorting with monoclonal antibody (mAb) BE2 which recognizes a CTCL tumor-associated antigen. The presence of clonal populations of malignant cells in the resulting cell suspensions will be established by Southern blot analysis of their rearranged TCR genes. Second, these BE2-positive CTCL cells will be used to produce clonotypic (anti-TCR) mAbs (mAb- l), Important for the even more sensitive identification and analysis of CTCL cells in the relevant patients. Third, another set of mAbs (mAb-2) will be produced against idiotypic determinants of mAb-l. Some mAb-2 will structurally mimic the CTCL TCR antigen- binding sites and will be used in direct examination of frozen sections of skin to recognize putative targets for CTCL cells and to identify normal "defensive" an:l-CTCL lymphocytes reactive with the CTCL TCR. That such natural or induced anti-CTCL immunity is directed at unique determinants of the CTCL TCRs will be examined by modulation of the TCRs on target CTCL cells by antibody against CD3, a membrane molecule which comodulates with the TCR. Fourth, human and murine cells will be studied to determine whether extracorporeal exposure of CTCL cells to ultraviolet A (UVA)-- irradiated 8-methoxypsoralen (8-MOP) increases the immunogenicity of these cells in CTCL patients by altering membrane antigenicity. Since CTCL cells are preferentially injured by 8-MOP/UVA, their capacity to repair damage in total extractable nuclear DNA and in specific genes (TCR, IL2 receptor and IL2) will be assessed, as will the membrane expression of the products of these genes. The effects of 8-MOP/UVA on the capacity of an established anti- cytochrome C murine tumorigenic T cell hybridoma to vaccinate against its own in vivo growth will be assessed through use of an available mAb which binds selectively to the TCR of those hybridoma cells. Together, these studies should markedly enhance understanding of the immunobiology of CTCL.