IL-12 reverses cytokine and immune abnormalities in Sezary syndrome.

Abstract

Cutaneous T cell lymphoma is a lymphoproliferative disorder typically characterized by skin invasion of clonally derived malignant CD4+ lymphocytes that phenotypically resemble mature Th cells. Sezary syndrome (SzS) represents an advanced form of cutaneous T cell lymphoma associated with generalized erythroderma and involvement of the peripheral blood by the malignant cell population. We have previously demonstrated aberrant cytokine production by PBMC in SzS characterized by increased IL-4 and deficient IL-2 and IFN-gamma production, as well as increased expression of mRNA for IL-4 and IL-5 within active skin lesions, suggesting that the clonal T cell population is derived from the Th 2 subset of helper T lymphocytes. These findings have been associated with a constellation of immune abnormalities that have been attributed to the cytokine abnormalities. Because IL-12 is a potent inducer of IFN-gamma production, and causes the activation of cytotoxic lymphocytes, we examined the production of IL-12 by PBMC from SzS patients and whether IL-12 could alter the unfavorable cytokine balance typical of SzS and thus lead to correction of immune defects. Despite normal numbers of peripheral blood monocytes and normal TNF-alpha production, mean Staphyloccus aureus and LPS-induced IL-12 p40 and p70 production by SzS PBMC was significantly decreased compared with PBMC from normal controls. Mean IFN-gamma production by patient PBMC in response to PHA alone was depressed, but increased to levels comparable with normal after addition of 1 ng/ml IL-12. Pretreatment of PBMC for 24 h with IL-12, IFN-alpha, or both together resulted in a decrease in PHA-stimulated IL-4 production from a base line of 1818 pg/ml to 1520, 1350, and 1058 pg/ml, respectively. Lastly, culture of patient PBMC with IL-12 for 24 h also resulted in significant increases in NK activity against K562 cells. These results indicate that PBMC from patients with SzS manifest a defect in IL-12 production and that the cytokine abnormalities associated with SzS can be favorably altered by IL-12.