IL-12 REVERSES CYTOKINE AND IMMUNE ABNORMALITIES IN SEZARY-SYNDROME

Cutaneous T cell lymphoma is a lymphoproliferative disorder typically characterized by skin invasion of clonally derived malignant CD4(+) ly mphocytes that phenotypically resemble mature Th cells. Sezary syndrom e (SzS) represents an advanced form of cutaneous T cell lymphoma assoc iated with generalized erythroderma and involvement of the peripheral blood by the malignant cell population. We have previously demonstrate d aberrant cytokine production by PBMC in SzS characterized by increas ed IL-4 and deficient IL-2 and IFN-gamma production, as well as increa sed expression of mRNA for IL-4 and IL-5 within active skin lesions, s uggesting that the clonal T cell population is derived from the Th 2 s ubset of helper T lymphocytes. These findings have been associated wit h 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 whet her 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 St aphyloccus aureus and LPS-induced IL-12 p40 and p70 production by SzS PBMC was significantly decreased compared with PBMC from normal contro ls. Mean IFN-gamma production by patient PBMC in response to PHA alone was depressed, but increased to levels comparable with normal after a ddition of 1 ng/ml IL-12. Pretreatment of PBMC for 24 h with IL-12, IF N-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-l 2 for 24 h also resulted in significant increases in NK activity against K562 c ells. These results indicate that PBMC from patients with SzS manifest a defect in IL-12 production and that the cytokine abnormalities asso ciated with SzS can be favorably altered by IL-12.