Increased interleukin 5 production in eosinophilic Sézary syndrome: regulation by interferon alfa and interleukin 12.

BACKGROUND: Peripheral eosinophilia occurs in a small subpopulation of patients with cutaneous T-cell lymphoma (CTCL) and denotes a poor prognosis. Clinical studies have suggested that the Sézary cell is a T(H)2 type helper T cell that produces cytokines that enhance the differentiation and activation of eosinophils. Interferon alfa (IFN-alpha) and interleukin 12 are effective therapeutic agents for CTCL and other hematologic disorders. OBJECTIVE: Our purpose was to determine the inhibitory activity of IFN-alpha and IL-12 on IL-5 production in vitro by peripheral blood mononuclear cells (PBMCs) obtained from patients with CTCL and eosinophilia. METHODS: Suppression of IL-5 production by IFN-alpha and IL-12 was assessed by comparing IL-5 production by PBMCs from patients with Sézary syndrome and eosinophilia when cultured alone or in the presence of either IFN-alpha or IL-12. RESULTS: A marked increase in IL-5 production by PBMCs from patients with Sézary syndrome and eosinophilia was observed. IL-5 production was markedly reduced when PBMCs were exposed to IFN-alpha or IL-12. CONCLUSION: These results suggest that IFN-alpha and perhaps IL-12 may produce a therapeutic response in patients with CTCL and eosinophilia through direct suppression of IL-5 production by malignant Sézary cells.

The potential therapeutic role of interleukin-12 in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a lymphoproliferative disorder characterized by skin invasion of clonally derived malignant CD4+ lymphocytes that phenotypically resemble mature T-helper (Th) cells. Sezary syndrome (SzS) represents an advanced form of CTCL associated with generalized erythroderma and involvement of the peripheral blood by the malignant cell population. We have previously demonstrated aberrant cytokine production by peripheral blood mononuclear cells (PBMCs) 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, indicating that the clonal T-cell population is likely derived from the T-helper type 2 (Th2) subset of helper T lymphocytes. Furthermore, a variety of immune abnormalities have been observed in association with SzS 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 assessed the production of IL-12 by PBMCs from SzS patients, and whether IL-12 could alter the unfavorable cytokine balance typical of SzS and, thus, possibly lead to correction of immune defects. In this review, we present our data, which indicate that patients with SzS exhibit marked defects in monocyte production of IL-12 p70. Moreover, in vitro culture of PBMC from SzS patients with recombinant IL-12 leads to reconstitution of normal IFN-gamma production and markedly enhances cell-mediated cytotoxicity.

Humoral hypercalcemia of malignancy: a syndrome in search of a hormone.

A women with hypercalcemia and a hypernephroma confined to the left kidney underwent nephrectomy and subsequent resolution of hypercalcemia. Serum parathyroid hormone was undetectable in peripheral blood as well as in the left renal vein at surgery. Parathyroid hormone was also undetectable in the tumor extract using three different antisera to parathyroid hormone. Measurement of plasma prostaglandin E and 13, 14-dihydro-15-keto-prostaglandin E2 revealed levels within the normal range. The serum 1,25-dihydroxyvitamin D concentration was below normal and nephrogenous cyclic adenosine monophosphate was markedly elevated. The humoral agent responsible for hypercalcemia in this patient was not identified. This case emphasizes the need to search for new hypercalcemic factors in patients with hypercalcemia of malignancy.