Aberrant cytokine production by sezary syndrome patients: Cytokine secretion pattern resembles murine TH2 cells

Sezary syndrome (SzS), the leukemic stage of cutaneous T-cell lymphoma (CTCL), is typically a CD4⁺ T-cell lymphoproliferative disease characterized by numerous immunologic abnormalities, including decreased T-cell responses to antigens and mitogens, decreased natural killer and lymphocyte-activated killer cell activities, eosinophilia, and increased levels of immunoglobulins, particularly IgE and IgA. Because this constellation of abnormalities is reminiscent of the pleiotropic in vitro activities of IL-4 and IL-5, we examined the possibility that malignant T cells in SzS may be producing increased amounts of IL-4 with a concomitant decrease in IL-2 and IFN-γ production. Such a cytokine secretion pattern would be similar to that produced by murine Th2 cells. Serum IL-4 enzyme-linked immunosorbent assay measurements revealed that 33% of SzS patients (n = 21) had levels of IL-4 significantly higher (mean, 7.2 pg/ml; range, 0-48, p <0.05) than normal controls (mean, 1.59; range, 0-3.1). Although the majority of tested patients had elevated serum IgE, no direct correlation between serum IL-4 levels and serum IgE levels was observed. Peripheral blood mononuclear cells (PBMC) isolated from SzS patients and stimulated with phytohemagglutinin (PHA) produced significantly higher levels of interleukin (IL)-4 and significantly lower levels of IL-2 and interferon (IFN)-γ than did PBMC from normal controls (p <0.02, p <0.05, and p <0.02, respectively). PBMC from SzS patients in remission produced IL-4 and IL-2 levels similar to that of the normal controls. To determine if IFN-γ could inhibit the increased IL-4 production by PHA-stimulated PBMC from SzS patients, IFN-γ was added to culture at 0, 24, or 48 h prior to the addition of PHA. Significant decreases in IL-4 production were seen only in cultures incubated with IFN-γ for 24 and 48 h prior to the addition of PHA. IL-2 levels were not affected by IFN-γ incubation. The increased IL-4 and decreased IL-2 and IFN-γ production by PBMC from SzS patients suggests that Sezary cells have a cytokine profile similar to murine Th2 cells. Moreover, this cytokine secretion pattern may play an integral role in the immunopathogenesis of advanced CTCL. The results also suggest that IFN-γ may be a useful component in the spectrum of therapeutic approaches to SzS.