PATHOGENESIS OF CUTANEOUS T-CELL LYMPHOMA - IMPLICATIONS FOR THE USE OF RECOMBINANT CYTOKINES AND PHOTOPHERESIS

Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin invasive malignancy of CD4(+) cells with the phenotype of mature helper T cells . We previously demonstrated that the leukaemic form of CTCL (Sezary), is characterized by prominent immunological defects including depress ed cell-mediated immunity. We also demonstrated increased production o f T-helper type 2 (Th2) cytokines (IL-4, IL-5) and deficient Th1 cytok ines (IL-2 and IFN-gamma) by their peripheral blood mononuclear cells (PBMC) and detected IL-4 and IL-5 mRNA within lesional skin of patient s with all stages of CTCL. A marked defect in IL-12 production has als o been noted, which may also play a role in depressed cell-mediated im munity. These results suggested that the malignant CD4(+) cells were T h2 cells. Thus, the immune aberrations have been attributed to the cyt okine abnormalities triggered by the malignant T-cell population. Beca use CTCL responds to biological response modification, we focused on s trategies for reversing the cytokine and immune defects by in vitro te sting of novel biological response modifiers. Our results indicate tha t IFN-alpha potently suppresses the abnormal IL-4 and IL-5 production, that IL-12 can correct the deficient lFN-gamma production and cell-me diated cytotoxicity, and that retinoids can enhance IFN-gamma and IL-1 2 production. We also studied the in vitro growth characteristics of t he malignant CD4(+) cells and determined that IL-12 and IFN-or signifi cantly suppress growth of these cells. These studies led to a phase I trial of IL-12 to treat CTCL. Also, we have determined that photophere sis produces a high clinical response rate among Sezary syndrome patie nts. This therapy not only augments functions of monocytes but also in duces the malignant T cells to undergo a high rate of apoptosis. We di scuss how these therapies might be employed in concert to produce the optimum desired anti-tumour effect.