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

Abstract

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.